Haematology Flashcards
What would be blood results of anaemia of chronic disease?
low/normal ferritin and wide distribution of red blood cell volume
What are side effects of ferrous sulphate?
Black stools, constipation, diarrhoea, nausea
What are triggers for sickle cell crisis?
Infection, dehydration, hypoxia, acidosis, exposure to cold
Why does sickle cell not present till 6 months?
High levels of HbF mask the effect of this until they start to fall at 6 months
What are some complications of myeloma?
Hypercalcaemia, spinal cord compression, hyperviscosity, acute renal failure.
Why are people with myeloma susceptible to other infections?
Possible bone marrow infiltration; immunoparesis secondary to overexpression of one immunoglobulin and underexpression of any other immunoglobulins.
What is the treatment for CLL and how is it given?
Imatinib - tyrosine kinase inhibitor, oral
CML vs CLL
CLL - usually an incidental finding with no symptoms
CML - will have symptoms, usually massive splenomegaly (described as sense of fullness sometimes)
AML vs CML
AML - low neutrophils and platelets
CML - anaemia, raised neutrophils and platelets
ALL blood findings
- Raised lymphocytes
- Low neutrophils
- Low platelets
What is raised with beta thalassaemia major?
HbA2
PT vs APTT
PT - extrinsic - Factors 3 and 7 (play tennis outside)
APTT - intrinsic - Factors 9,11,13 (play table tennis inside)
New B symptoms in someone with CLL?
Richters transformation -> CLL transforms into aggressive large cell lymphoma
Patients over the age of 60 who present with iron deficiency anaemia
Investigate for colorectal cancer -> colonoscopy
Causes of the renal impairment in myeloma?
AL type amyloidosis, Bence Jones nephropathy, nephrocalcinosis, nephrolithiasis
Isolated rise in GGT in the context of a macrocytic anaemia
Alcohol excess
‘starry sky’ appearance on lymph node biopsy
Burkitt lymphoma - associated with EBV/HIV
Complications of blood transfusions
Non-haemolytic febrile reaction: Fever and chills -> slow/stop transfusion + paracetamol
Minor allergic reaction: urticaria and pruritic -> stop transfusion and give antihistamine
Acute haemolytic reaction: fever, abdominal pain, hypotension -> stop transfusion, recheck patient identity, send blood for repeat testing
Transfusion-associated circulatory overload: hypertension, pulmonary oedema -> slow/stop transfusion + loop diuretic and oxygen
Transfusion-related acute lung injury: hypoxia, hypotension, fever -> stop transfusion, oxygen
What is the most common clotting abnormality?
Von-Wilebrand disease
What is the treatment for beta thalassaemia major?
Lifelong blood transfusions
low platelets, increased clotting time and raised fibrin degradation products (FDPs)
DIC
When does heparin-induced thrombocytopenia present?
5-14 days post op with low platelets, nothing else
Which drugs can cause haemolytic in patients with G6PD?
- Ciprofloxacin
- Sulphasalazine
- Sulfonylureas
- Sulphonamides
Hereditary spherocytosis vs G6PD?
HS - extra vascular haemolysis -> causes splenomegaly
G6PD - intravascular haemolysis -> normal spleen
Inheritance of G6PD vs HS?
G6PD - X linked recessive -> transmitted from mother
HS - Autosomal dominant
What can precipitate renal failure in patients with myeloma?
NSAIDs
unexplained nosebleeds and menorrhagia + an immune condition
Think ITP
IgA deficiency increases the risk of what?
Anaphylactic reactions to blood transfusions
Which leukaemia is associated with polycythaemia?
AML
Blood test findings for leukaemia?
AML: increased myeloblasts + anaemia and thrombocytopenia
ALL: increased lymphoblasts + anaemia and thrombocytopenia
CML: increased granulocytes + anaemia
CLL: increased lymphocytes (usually B cells) + anaemia
What are negative prognostic factors for lymphoma?
- The presence of B symptoms
- Male gender
- Being aged >45 years old at diagnosis
- High WCC, low Hb, high ESR or low blood albumin
- Lymphocyte depleted subtype
What infection can trigger an aplastic crisis in patients with hereditary spherocytosis?
Parvovirus
Which subtype of Hodgkins has the best prognosis?
Lymphocyte predominant
Malaria prophylaxis can trigger what?
Haemolytic anaemia in those with G6PD deficiency
hyper-segmented neutrophil polymorphs
Megaloblastic anaemia
Abdominal pain, constipation, neuropsychiatric features, basophilic stippling
Lead poisoning
What are irradiated blood products used for?
Reduce the risk of graft vs host disease by destroying T cells
What are the adverse effects of tamoxifen?
Increased risk of VTE and endometrial cancer
Most common organism which causes neutropenic sepsis?
Staph epidermis
Which drugs can cause aplastic anaemia?
- Phenytoin
- Chloramphenicol
- Cytotoxics
- Sulphonamides
IgM paraprotein
Waldenstrom’s macroglobulinaemia
pain, oedema, dermatitis, ulceration, abnormal skin pigmentation, hyperpigmentation, gangrene, lipodermatosclerosis
post-thrombotic syndrome
When should G6PD enzyme assays be done?
At presentation and 3 months after to avoid false negatives
Mycoplasma infection can cause what?
Cold Autoimmune haemolytic anaemia
What ITU treatment could be considered for someone with sickle cell crisis
Exchange transfusion -> reduce number of sickle cells and increase normal RBC to improve oxygenation
What is a common complication of Burkitts lymphoma?
Tumour lysis syndrome
What electrolyte imbalances are seen in tumour lysis?
hyperkalaemia
hyperphosphataemia
hypocalcaemia
hyperuricaemia
acute renal failure
‘tear drop’ poikilocytes
Myelofibrosis
intense itching which usually occurs after exposure to hot water or hot and humid weather
Polycythaemia vera
What can be given prior to chemo to prevent tumour lysis syndrome?
Allopurinol or rasburicase
Beta thalasaaemia major vs trait?
Major would have profound anaemia usually Hb <60
Sickle cell + abdominal pain + anaemia
Sequestration crisis
Transfusion thresholds?
Normal patients <70
Patients with ACS <80
What is the treatment for ITP?
Oral steroids / IVIG if signs of major bleeding
Rouleaux formation
Multiple myeloma
Target cells and Howell-Jolly bodies
Coeliac disease -> hyposplenism
decrease in haptoglobin levels
Haemolysis
large multinucleate cells with eosinophilic nucleoli
Reed-Sternberg
What are complications of CLL?
- Anaemia
- Recurrent infections due to hypogammaglobulinaemia
- Warm AIHA
- Transformation into non-Hodgkins
High HBA2?
Beta thalassaemia
What is the treatment for post thrombotic syndrome?
Compression stockings
Complications of polycythaemia?
- Thrombotic events (patients given aspirin as prophylaxis)
- Myelofibrosis
- Acute leukaemia
normocytic anaemia with low serum iron, low TIBC but raised ferritin
Think anaemia of chronic disease
Aplastic crisis vs sequestration crisis in sickle cell?
Aplastic - reduced reticulocytes
Sequestration - increased reticulocytes
Thalassaemias will cause what?
Haemolysis -> raised bilirubin
Management of anti-phospholipid in pregnancy?
Aspirin + LMWH
What is the reversal agent for dabigatran?
Idarucizumab
Myeloma Investigations
Bloods - anaemia
Blood film - rouleaux formation
Urine protein electrophoresis - Bence Jones (IgA/IgG)
Bone marrow - Raised plasma cells
CXR/MRI - osteolytic lesions
What mutation would be seen in polycythaemia?
JAK-2
How does heparin work?
Activate antithrombin III - measure APTT
Elderly patient with fatigue, splenomegaly, weight loss/night sweats?
Think myelofibrosis
‘myeloid blast’ cells are suggestive of what?
AML
What are signs of low Hb on examination?
Pallor, tachycardia, tachypnoea, flow murmur
What are causes of late transfusion complications?
Iron overload, graft versus host disease, post transfusion purpura, infection
What is a massive blood transfusion?
Transfusion of 10 units/a patients entire blood volume within 24 hours
How to test for pernicious anaemia?
Intrinsic factor - most useful
gastric parietal cell antibodies
Pernicious anaemia predisposes to what?
Gastric cancer
How is haemophilia inherited?
X linked recessive
What is the most common inherited thrombophilia?
Factor V Leiden deficiency
small, single, peripherally-located, rounded inclusion in 50-60% of the erythrocytes.
Howell-Jolly body -> Hyposplenism
Metallic aortic valves can cause what?
Non-immune haemolytic anaemia
What can be given to reduce the frequency of sickle cell crises?
Hydroxycarbamide (hydroxyurea)
How to manage high INR in patients needing emergency surgery?
Give IV Vit K and recheck INR in 6-12 hours
If surgery cannot be postponed give 4 factor prothrombin + IV Vit K to reverse warfarin
What is a safe INR for surgery?
<1.5
What organisms are people with sickle cell susceptible to?
Strep pneumoniae
TACO vs TRALI
TACO - SOB and hypertension
TRALI - hypotension
What is the management of ITP?
Emergency: Platelet transfusion/IV Methylpred/IVIG
Platelet > 30 - Observe
Platelet <30 - Oral pred
What are features of blood film post splenectomy?
Howell- Jolly bodies
Pappenheimer bodies
Target cells
Irregular contracted erythrocytes
finger abduction weakness
Lesion at T1
TPP Symptoms?
- Fever
- Neuro symptoms
- Renal failure
- Anaemia
- Low platelets
ITP VS TTP VS DIC
DIC will have raised PT/INR/APTT + low platelets whereas for ITP and TTP this will be normal
How can tumour lysis syndrome be diagnosed?
- Increased serum creatinine
- Cardiac arrhythmia
- Seizure
Aplastic crisis vs sequestration
Aplastic - sudden fall in Hb after parvovirus infection
Sequestration - sickling within organs such as spleen/lungs causing pooling of blood
Polycythaemia + sudden drop in Hb?
AML
Isolated rise in Hb?
Polycythaemia
Bite and blister cells
G6PD deficiency
What is the main management of sickle cell crises?
- IV analgesia, fluids + oxygen
- Consider Abx if infection and blood transfusion if Hb is low
ITP vs VWD?
ITP - destruction of platelets so platelet count is low with normal PT and APTT
VWD - platelets are fine but they take longer to stop bleeding so platelet count is normal, PT and APTT are prolonged
Hand foot mouth syndrome - sudden swelling, pain and erythema?
Think Sickle cell disease
How is tranexamic acid given followng major haemorrhage?
IV bolus followed by slow infusion
anisocytosis, macrocytosis and hyposegmentation of the neutrophils.
Myelodyplastic syndrome -> can progress to AML
Over how long are RBC transfused?
90-120 minutes in non urgent cases
Microcytic anaemia with high ferritin + transferrin saturation?
Think sideroblastic anaemia - basophilic stippling
Warm vs Cold AIHA?
Warm - IgG - associated with CLL
Cold - IgM (M for Mountains - cold) - associated with lyMphoma / Mycoplasma / EBV
What is the pathological process behind myeloma?
Clonal proliferation of plasma cells with paraprotein production
What is the treatment for myeloma?
- Chemo
- Bisphosphonates often given for bone protection
What translocation causes Philadelphia?
t(9:22) - gene BCR/ABL
What blood test will be raised with Hodgkins?
LDH
Why does sickle cell often present in >1ys?
Fetal Hb protects against sickling therefore by 1 transformation to adult haemoglobin is completed
What is the action of LMWH?
Anti-thrombin and anti-Xa
What are the best blood tests to examine synthetic liver function?
INR and albumin
What does cryoprecipitate contain?
Factor 8, VWF, fibrinogen and factor 13
What does plasma contain?
All clotting factors
What is the pathophysiology of DIC?
- Diffuse thrombin activation by a trigger which activates coag cascade
- This leads to platelet consumption and clotting factor consumption
What are triggers for DIC?
- Sepsis
- Trauma
- Malignancy
- Vasculitis
- Toxins
- Pancreatitis
Beta thalassaemia major vs trait?
Major - homozygous mutation, Trait - heterozygous mutation
What may be seen on blood film in beta thalassaemia?
- Basophilic stippling
- Microcytosis
- Hypochromic red cells
What should be given to patients with beta thalassaemia major with blood transfusion?
Desferrioxamine
What blood abnormality does warfarin cause?
Prolonged PT, normal APTT
Which organisms cause post splenectomy sepsis?
- Strep pneumoniae
- H influenzae
- Meningococci
All patients with IHD should take what?
Aspirin
Warfarin can rarely cause what?
Skin necrosis
Ileocecal resection can result in what?
Vit B12 deficiency
How can painful vaso-occulsive crises be diagnosed?
Clinically
DIC is associated with what?
Schistocytes
Men of any age with a Hb below 110g/L should what?
Refer for upper and lower GI endoscopy as 2 week wait
What is the reversal agent for heparin overdose?
Protamine sulphate
What is the management of heparin induced thrombocytopenia?
If anticoag needed, switch to direct thrombin inhibitors e.g. argatroban
Prosthetic heart valves can cause what?
Haemolytic anaemia
pain when exposed to cold, jaundice, anaemia?
Sickle cell
platelet count < 30 x 109 and clinically significant bleeding
Platelet transfusion needed
Raised haemoglobin, plethoric appearance, pruritus, splenomegaly, hypertension
Polycythaemia
Haemoarthroses (bleeding in joints) are a sign of what?
Haemophilia
Transfusions can cause what?
Hyperkalaemia and hypocalcaemia
Investigations for polycythaemia?
- FBC/Blood film
- JAK2 mutation
How often should sickle cell patients receive the PCV vaccine?
Every 5 years
Reversal for rivaroxaban and apixaban
andexanet alfa
Macrolides can cause what?
Drug induced neutropenia
Sideroblastic anaemia vs iron deficiency?
Sideroblastic - high ferritin and serum iron levels
What is the definitive investigation for sickle cell?
Haemoglobin electrophoresis
Dry tap bone marrow aspirate?
Think primary myelofibrosis
How is sideroblastic anaemia inherited?
X linked
What does rituximab target?
CD20
ADAMTS-13 deficiency is associated with what?
TTP
Blood film showing Schistocytes?
AIHA
Target cells with asymptomatic anaemia?
Beta thalassaemia trait
Non Hodgkins vs CLL
CLL - significant lymphocytosis
Anaemia with raised bilirubin + LDH?
Haemolytic anaemia
What is permissive hypotension?
A strategy in bleeding of trauma patients where you use less fluids and maintain lower BP to prevent clots
What are electrolyte imbalances following large blood transfusion?
- Hyperkalaemia
- Hypocalcaemia
- Iron overload
Blood film changes
Target cells - Iron deficiency anaemia, sickle cell, hyposplenism, liver disease
Spherocytes - spherocytosis, AIHA
Basophilic stippling - lead poisoning, thalassaemia, sideroblastic anaemia
Heinz bodies - G6PD
Schistocytes - G6PD, DIC
Pencil poilkilocytes - Iron deficiency
Management of AIHA
- Supportive care
- Steroids to suppress immune system
- Splenectomy in severe cases
What happens to EPO in polycythaemia?
Reduces
Schistocytes will be seen in what?
Haemolysis
Raised red cell distribution width?
Think mixed deficiency e.g iron and folate
Recurrent DVTs in someone already on a DOAC?
Increase dose, check adherence or switch to another anticoagulant e.g. warfarin
Increased concentration of haemltocrit is what?
Polycythaemia
Major haemorrhage protocol involves providing what?
Packed red cells, platelets and FFP
Blood oozing from a cannula site is a classic sign of what?
DIC
<40 year old with raised platelets but no raised Hb?
Essential thrombocytopenia
Types of autoimmune haemolytic anaemia (AIHA)?
‘warm’ and ‘cold’ types according to what temp the antibodies best cause haemolysis
Causes of autoimmune haemolytic anaemia (AIHA)?
idiopathic most common
secondary to lymphoproliferative disorder, infection or drugs
Ix for autoimmune haemolytic anaemia (AIHA)?
+ve direct antiglobulin test (Coombs’ test)
- anaemia
- reticulocytosis
- low haptoglobin
- raised LDH and indirect bilirubin
- blood film: spherocytes and reticulocytes
What does blood film for autoimmune haemolytic anaemia show?
spherocytes and reticulocytes
What test is specific for autoimmune haemolytic anaemia?
positive direct antiglobulin test (Coombs’ test)
Warm AIHA?
most common type
the antibody (IgG) causes haemolysis best at body temp and haemolysis tends to occur in extravascular sites, for example the spleen
Causes of warm AIHA?
- idiopathic
- autoimmune disease eg. SLE
- neoplasia: lymphoma, CLL
- drugs eg. methyldopa
Mx of warm AIHA?
- Tx underlying disorder
- steroids +/- rituximab 1st line
Cold AIDA?
usually IgM and causes haemolysis best at 4 deg C
haemolysis is mediated by complement and is more commonly intravascular
Features of cold AIHA?
Raynaud’s and acrocyanosis
Mx of cold AIHA?
respond less well to steroids
Causes of cold AIHA?
- neoplasia: lymphoma
- infections: mycoplasma, EBV
SLE can rarely be associated with what?
mixed-type autoimmune haemolytic anaemia
most commonly warm AIHA
Types of haemolytic anaemias (causes)?
- Autoimmune= cold and warm AIHA
By cause…
- Hereditary= membrane, metabolism (G6PD def), haemoglobinopathies (sickle cell, thalassaemia)
- Acquired= immune and non-immune
By site….
- Intravascular haemolysis
- Extravascular haemolysis
Hereditary haemolytic anaemias can be subdivided into what?
membrane, metabolism or haemoglobin defects
Hereditary causes of haemolytic anaemia?
- membrane= hereditary spherocytosis/elliptocytosis
- metabolism= G6PD def
- haeemoglobinopathies= sickle cell, thalassaemia
Acquired haemolytic anaemias can be subdivided into what?
immune and non-immune causes
Acquired immune causes of haemolytic anaemia, are they Coombs-positive or negative?
positive
Acquired non-immune causes of haemolytic anaemia, are they Coombs-positive or negative?
negative
Acquired immune causes of haemolytic anaemia (Coombs-positive)?
- autoimmune= cold/warm antibody type
- alloimmune= transfusion reaction, haemolytic disease newborn
- drug= methyldopa, penicillin
Acquired non-immune causes of haemolytic anaemia (Coombs-negative)?
- microangiopathic haemolytic anaemia (MAHA)= TTP/HUS, DIC, malignancy, pre-eclampsia
- prosthetic heart valves
- paraoxysmal nocturnal haemoglobinuria
- infections= malaria
- drug= dapsone
- Zieve syndrome
Zieve syndrome?
rare clinical syndrome of Coombs-negative haemolysis, cholestatic jaundice, and transient hyperlipidaemia associated with heavy alcohol use, typically following a binge
typically resolves with abstinence from alcohol
What happens in intravascular haemolysis?
free Hb is released which then binds to haptoglobin
as haptoglobin becomes saturated Hb binds to albumin forming methaemalbumin (detected by Schumm’s test)
free Hb is excreted in urine as haemoglobinuria, haemosiderinuria
Intravascular haemolysis causes?
- mismatched blood transfusion
- G6PD def (is elements of extravascular but classed still as intra)
- red cell fragmentation: heart valves, TTP, DIC, HUS
- paroxysmal nocturnal haemoglobinuria
- cold autoimmune haemolytic anaemia
Extravascular haemolysis causes?
- haemoglobinopathies: sickle cell, thalassaemia
- hereditary spherocytosis
- haemolytic disease of newborn
- warm autoimmune haemolytic anaemia
What is haemolytic anaemia?
condition where RBCs are destroyed faster than bone marrow can produce them; called haemolysis and can lead to shortage of RBCs
causes symptoms like fatigue, weakness, SOB
can be inherited or acquired
Intrinsic vs extrinic haemolytic anaemia?
Intrinsic= caused by defects within RBCs usually due to genetic mutations affecting the cell’s membrane, enzymes, or hemoglobin. These structural or functional abnormalities make RBCs more prone to breaking down prematurely.
Extrinsic= RBC destruction is due to external factors acting on otherwise normal cells, such as autoimmune attacks, mechanical damage, infections, or toxic exposure.
Intravascular vs extravascular haemolysis?
Intravascular= destruction of RBCs occurs within blood vessels; more abrupt and can lead to severe symptoms due to rapid release of Hb into blood eg. jaundice, severe- kidney damage
Extravascular= RBCs destroyed outside blood vessels primarily in spleen or liver; slower and occurs when macrophages in spleen identify RBCs as abnormal and break them down. Less likely to cause haemoglobinuria or kidney damage; splenomegaly, jaundice and anemia over time
Lab findings in intravascular haemolysis (haemolytic anaemia) vs extravascular?
Intravascular= high LDH, low haptoglobin, haemoglobinuria, haemoglobinaemia
Extra= elevated indirect bilirubin and LDH, low or normal haptoglobin, increased reticulocyte count as bone marrow tries to compensate
Iron def occurs as a result of what?
long-term negative iron balance
Iron def spectrum?
ranges from iron depletion to iron def anaemia
Iron def anaemia?
diminished RBC production due to low iron stores in the body
Anaemia definition?
Hb level two standard deviations below the normal for age and sex
Anaemia in men aged over 15yrs?
Hb below 130g/L
Anaemia in non-pregnant women aged over 15yrs?
Hb below 120g/L
Anaemia in children aged 12-14yrs?
Hb below 120g/L
Anaemia in pregnant women?
Hb below 110g/L throughout pregnancy.
Hb level of 110g/L or more appears adequate in 1st trimester
Level 105g/L appears adequate in 2nd and 3rd trimesters
Anaemia in postpartum women?
below 100g/L
Causes of iron def anaemia?
often mutlifactorial
- dietary def
- malabsorption
- increased loss
- or increased requirements
Symptoms of iron def anaemia?
fatigue, dyspnoea, headache
cognitive dysfunction, restless leg syndrome
dizziness/lightheaded
weakness
dysgeusia
irritability
pica eg. ice
pruritus
sore tongue
palpitations
tinnitus
impairment of body temp regulation (preg women)
Signs of iron def anaemia?
pallor, atrophic glossitis
dry and rough skin dry and damaged skin
less common= tachycardia, nail changes (koilonychia), angular cheilosis
diffuse and moderate alopecia
worsening of pre-existing tachy, murmurs, cardiac enlargement and HF is anaemia severe (Hb <70)
may be no signs even if severe
What biochemical test most reliably correlates with relative total body iron stores?
serum ferritin
Diagnosis of iron def anaemia?
serum ferritin level less than 30 micrograms/L confirms diagnosis
Why are ferritin levels difficult to interpret when diagnosing iron def anaemia?
if infection or inflam present, levels can be high even in presence of iron def
ferritin levels may be less reliable in pregnancy
What is important to determine and treat in pt presenting with iron def aneamia?
underlying cause
When to urgently refer pt with iron def anaemia?
suspected ca pathway for colorectal ca if they have a faecal immunochemical testing (FIT) result of at least 10 micrograms of Hb per g of faeces
When to refer to gastroenterology for pt with iron def anaemia?
All men and postmenopausal women with iron deficiency anaemia unless they have overt non-gastrointestinal bleeding.
Men with a Hb level <120 g/L and postmenopausal women with an Hb level <100 g/L should be investigated more urgently, as lower levels of Hb suggest more serious disease.
All people aged 50 yrs+ with marked anaemia, or a significant Fx of colorectal carcinoma, even if coeliac disease is found.
Premenopausal women if they are aged <50yrs and have colonic symptoms, a strong Fx of GI ca, persistent iron def anaemia despite treatment, or if they do not menstruate.
When to refer women to gynaecology if present with iron def anaemia?
- menorrhagia unresponsive to medical Mx
- postmenopausal= 55yrs+ urgent suspected ca pathway; <55yrs consider urgent suspected ca pathway
Pt <50yrs with rectal bleeding (and iron def anaemia)?
consider urgent referral
What should be considered in iron def anaemia in premenopausal women with Hx of menorrhagia or pregnant women (if no suspicion of coeliac disease)?
Diagnostic trial of iron Tx for 2-4w
Do not do this for men and postmenopausal women
What to exclude in pt with iron def anaemia who is a man or postmenopausal?
GI sources of bleeding
Mx of iron def anaemia?
- all pts= 1 tablet OD of oral ferrous sulfate, ferrous fumarate or ferrous gluconate- continue for 3m after iron def corrected to allow stores to be replenished
- if not tolerated then 1 tablet on alternate days or alternative oral preparation
- parenteral iron if contraindicated or ineffective
- DO NOT WAIT for Ix before prescribing
- Monitor to ensure response
- Refer when appropriate
How to check response to Mx in iron def anaemia?
- Hb levels (FBC) checked 2-4w to assess response
Pt with iron def anaemia who has had oral ferrous sulfate (oral iron Mx); when should they undergo specialist assessment?
if lack of response (increase of less than 20g/L in Hb level) after 2-4w
What may suggest underlying GI bleeding resulting in iron def anaemia?
recent illness
GI disorders
colorectal carcinoma
What pts with iron def anaemia may have few symptoms?
pt with chronic, slow blood loss may be able to tolerate v low levels of Hb (eg. less than 70g/L)
Slow onset iron def anaemia?
may have no or very few symptoms eg. fatigue, mild SOB after exertion
Very common and common symptoms of iron def anaemia?
V common= dyspnoea, fatigue, headache
Common= cognitive dysfunction, restless leg syndrome
Rare symptoms of iron def anaemia?
- dysphagia (in association with oesophageal web which occurs in Patterson-Brown-Kelly or Plummer-Vinson syndromes).
- Haemodynamic instability
- syncope
Symptoms of iron def without anaemia?
fatigue, lack of concentration, irritability
Serious symptoms of iron def anaemia eg. if Hb is <70g/L?
worsening pre-existing anginal pain, ankle oedema, dyspnoea at rest
indicates additional heart or lung pathology
Nail changes in iron def anaemia?
longitudinal ridging
koilonychia (spoon-shaped nails)
Angular cheilosis?
ulceration of corners of mouth
in iron def anaemia
Angular cheilosis and koilonychia?
iron def anaemia
Ix for iron def anaemia?
- FBC
if show low Hb and low MCV.. - check ferritin level (less reliable in preg) (<30 micrograms/L)
- total iron binding capacity (high- reflects low iron stores) and a low transferrin
- blood film
- can do vit B12 and folate too (esp if older age as more risk of pernicious anaemia)
MCV in iron def anaemia?
likely if MCV is <95 femotolitres
Red blood cell changes associated with iron def anaemia?
- microcytosis (low MCV)
- reduced mean cell Hb (hypochromia)
- increased % of hypochromic red cells
- anisocytosis (variation in size of RBCs)
- poikilocytosis (presence of irregulary shaped RBCs)
Anisocytosis?
variation in size of RBCs
Poikilocytosis?
presence of irregularly shaped RBCs
Pregnant women and suspect iron def anaemia?
- FBC is routine in preg
- may do blood film
Blood film in iron def anaemia in pregnant women?
microcytic hypochromic red cells and characteristic ‘pencil cells’
hypochromia may also occur in haemoglobinopathies (eg. thalassaemia)
Physiological reduction in Hb conc in pregnancy?
does not represent anaemia
increase in red cell mass and plasma volume, plasma vol increases more than red cell mass, leading to haemodilution and fall in haematocrit from 40% to 33%
Normal pregnancy is associated with what?
- physiological reduction in Hb conc (doesn’t mean anaemia)
- slight increase in MCV (approx 4 femtolitres)
When might MCV not fall below the normal range in iron def anaemia?
in milder cases of iron def anaemia
What level of serum ferritin level confirms diagnosis of iron def anaemia?
<30 micrograms/L
When are ferritin levels increased independently of iron status?
in acute and chronic inflam conditions, malignant diease, liver disease
infection
Serum ferritin conc of what level indicates iron depletion in all stages of pregnancy? When should Tx be considered?
<15 micrograms/L
Tx should be considered when levels fall below 30 micrograms/L, as this indicates early iron depletion which will continue to fall unless treated
What should be considered as 1st line diagnostic test for normocytic or microcytic anaemia in pregnant women with no haemoglobinopathy?
oral iron trial
if known haemoglobinopathy check serum ferrritin before starting
(if unknown need NHS sickle cells and thalassaemia screening programme)
Diagnosed with iron def anaemia, what Ix should you then do to determine the cause?
- coeliac serology (anti-TTG)
- test urine for blood
- FIT
- stool exam if travel Hx to detect parasites
When is Ix to determine underlying cause for iron def anaemia not necessary?
- young pt with Hx suggesting cause eg. regular blood donor
- menstruating young women no Hx of GI symptoms or FHx colorectal ca
- pregnant unless severe anaemia, no response to iron or exam & Hx suggest alternative cause eg. IBD
- terminally ill pts or unable to undergo Ix eg. Mx would not be influenced by results
- pts who refuse
Differential diagnosis of microcytic anaemia?
TAILS
- Thalassaemia
- Anaemia of chronic disease (80% normocytic and normochromic but can be microcytic, hypochromic anaemia )
- Iron def
- Lead poisoning eg. exposure to lead paint
- Sideroblastic anaemia (very rare)
How to describe type of anaemia in iron def anaemia?
microcytic, hypochromic anaemia
Differential diagnosis of normocytic anaemia?
AAA HH
A.naemia of chronic disease
A.cute blood loss
A.plastic anaemia
H.aemolytic anaemia
H.ypothyroidism
(also CKD)
Microcytic anaemai?
MCV <80
problem producing RBCs or Hb
MCV stands for?
mean capsular volume
Normocytic anaemia?
MCV 80-95 (normal)
increase destruction of RBCs
Macrocytic anaemia?
MCV >95
Macrocytic anaemia?
Megaloblastic= B12 & folate def
Non-Megaloblastic= liver disease, alcohol, drugs, reticulocytosis, hypothyroidism
Megaloblastic macrocytic anaemia?
impaired DNA synthesis; megaloblasts present
Non-megaloblastic macrocytic anaemia?
erythrocytes normal
Why do tests in Thalassaemia and sideroblastic anaemia show an increase in serum iron and ferritin, with a low total iron-binding capacity?
both associated with an accumulation of iron
When to refer women to obstetrics with iron def anaemia?
significant symptoms and/or severe anaemia (haemoglobin less than 70 g/L), if pregnancy is at advanced gestation (over 34 weeks), or if there is failure to respond to a trial of oral iron.
Pt with iron def anaemia, initially responded to iron Tx but develops anaemia again without an obvious cause?
refer
Should iron replacement therapy be given whilst awaiting Ix for iron def anaemia?
yes unless colonoscopy imminent
Dietary iron advice if iron def anaemia if thought to be cause?
dark green vegetables, iron-fortified bread, meat, apricots, prunes and raisins
consider referral to dietitian
Aim of Tx in iron def anaemia?
restore Hb levels and red cell indices to normal, and to replenish iron stores
Dose of elemental iron (as ferrous sulfate) oral for iron def anaemia?
65mg elemental iron (ferrous sulfate 200mg) OD on empty stomach
do not recommend perparations that contained iron combined with folic acid, vit B12 or other nutrients
Advice to give pt who is taking iron supplements?
- may get adverse effects but usually settle with time, important to be compliant
- if get GI adverse effects, can be minimised by taking with or after food or reducing dose to alternate days
- explain monitoring requirements
- safe storage eg. if have young children as overdose can be fatal
Monitoring for pt being Tx for iron def anaemia?
- Hb within 1st 4w; Hb should rise by 20 over 3-4w
- then check FBC at 2-4m to check Hb returned to normal
- once Hb conc and red cell indices normal= continue iron for 3m then stop
- monitor FBC periodically= 3,6,12 and 24m
- if drop then prescribe iron supplements; consider prophylactic dose in pt who risk of iron def anaemia
When may an ongoing prophylactic dose of iron (200mg ferrous sulfate daily) be beneficial in pt with iron def anaemia?
- recurring anaemia eg. elderly and further Ix not appropriate or indicated
- diet unlikely to meet daily iron eg. plant based diets
- malabsorption eg. coeliac
- menorrhagia
- had gastrectomy
- pregnant
- undergoing hameodialysis
How to manage pt if inadequate response to initial iron Tx in iron def anaemia?
- assess compliance
- adress adverse effects
- specialist advise
- refer if lack of response after 2-4w : If the person has already had normal upper and lower gastrointestinal Ix for iron deficiency anaemia and the anaemia persists or recurs, consider testing for Helicobacter pylori, and eradicate if present
Adverse effects and how to manage in pt taking oral iron supplement for iron def anaemia?
- constipation= laxative
- black stools= reassure
- recommend to take iron with or after meals
- reduce dose frequency to alternative days
- consider alternative oral preparations
Why does iron def lead to reduction in RBCs/Hb (anaemia)?
iron needed to make Hb in RBCs
Iron def anaemia has highest incidence in who?
preschool aged children
Main causes of iron def anaemia?
XS blood loss, inadequate dietary intake, poor intestinal absorption, increased iron requirements
Most common cause of anaemia?
iron def
Eg. of XS blood loss causing iron def anaemia?
menorrhagua
GI bleeding (suspected colon ca)
What conditions can lead to poor iron absorption?
conditions affecting small bowel eg. coeiliac disease
Why may children or pregnant women get iron def anaemia?
increased iron requirements
children= increased demands due to growth
pregnant= supply for baby; also increase in plasma vol causes dilution of iron (proportion of fluid in comparison to RBCs increases)
Koilonychia?
spoon shaped nails
iron def anaemia
What does FBC demonstrate in iron def anaemia?
hypochromic microcytic anaemia
What does hypochromic anaemia mean?
when RBCs appear plaer than normal due to reduced levels of Hb
often associated with microcytic RBCS
High total iron-binding capacity (TIBC) reflects…
low iron stores
Blood film for iron def anaemia?
anisopoikilocytosis (RBCs of diff sizes and shapes), target cells and ‘pencil’ polikilocytes
Males and post-menopausal women who present with unexplained iron def anaemia should be considered for what?
endoscopy to rule out ca
Post-men women Hb ≤10 and men ≤11 refer to gastro for this within 2w
Common side effects of iron supplements?
nausea, abdo pain, constipation, diarrhoea
Iron def anaemia: serum iron, TIBC, transferrin saturation and ferritin?
Serum iron= low <8
TIBC= High
Transferrin sat= low
Ferritin= low
Anaemia of chronic disease: serum iron, TIBC, transferrin saturation and ferritin?
Serum iron= low <15
TIBC= low
Transferrin sat= low
Ferritin= High
Why is there low serum iron in iron def anaemia?
Serum iron reflects the amount of circulating iron in the blood. In iron deficiency anemia, there’s a lack of iron
Why in iron def anaemia is the TIBC high?
TIBC is a measure of the blood’s capacity to bind iron, largely determined by transferrin, the main protein that transports iron in the bloodstream. In iron deficiency, the liver increases transferrin production to maximize iron transport and absorption from dietary sources. This results in a high TIBC, indicating an increased iron-binding capacity in the blood.
In iron def anaemia, why is the transferrin saturation low?
Transferrin saturation is calculated by dividing serum iron by TIBC. In iron deficiency anemia, both low serum iron and high TIBC contribute to a low transferrin saturation. This low saturation means that only a small percentage of transferrin is bound to iron, indicating a lack of available iron for the body’s needs.
In iron def anaemia, why is the ferritin low?
Ferritin is the main storage protein for iron, and low ferritin levels indicate depleted iron stores in the body. It is one of the earliest indicators of iron deficiency, as the body first draws on stored iron before serum iron levels begin to drop.
Megaloblastic causes of macrocytic anaemia?
vit B12 def
folate def
eg. secondary to methotrexate
Normoblastic (non-megaloblastic) causes of macrocytic anaemia?
alcohol
liver disease
hypothyroidism
preg
reticulocytosis
myelodysplasia
drugs: cytotoxins
History of a normal Hb level associated with microcytosis?
In patients not at risk of thalassaemia, this should raise the possibility of polycythaemia rubra vera which may cause an iron-deficiency secondary to bleeding.
New onset microcytic anaemia in elderly pts?
urgently Ix to exclude malignany
In beta-thalassaemia minor, the microcytosis is often…
disproportionate to the anaemia
Under homeostatic conditions (normal balanced), the process of coagulation and fibrinolysis are coupled (work alongside eachother). Explain this?
1) Coagulation Activation= the coagulation cascade is triggered, producing thrombin that then converts fibrinogen into fibrin, forming a stable fibrin clot- the final product of hemostasis
2) Fibrinolysis= the break down fibrinogen and fibrin. When the fibrinolytic system is activated, plasmin is generated (in presence of thrombin) which is responsible for the lysis of fibrin clots. The breakdown of fibrinogen and fibrin results in polypeptides (fibrin degradation products).
3) Role of plasmin= in a state of homeostasis, the presence of plasmin is critical- it is the central proteolytic enzyme of coagulation and necessary for fibrinolysis.
Explain the coagulation cascade?
1) Intrinsic pathway
- trigger= Activated by damage within the blood vessel or when blood comes into contact with negatively charged surfaces, such as collagen exposed by vessel injury.
- Process:
1. Begins with Factor XII (Hageman factor), which becomes activated upon contact with the damaged vessel.
2. Activated Factor XII (XIIa) activates Factor XI.
3. Activated Factor XI (XIa) then activates Factor IX.
4. Factor IXa, with the help of Factor VIII and calcium ions, activates Factor X.
- Result: The intrinsic pathway leads to the activation of Factor X, which then moves into the common pathway.
2) Extrinsic pathway
-trigger: Activated by external trauma that causes blood to escape from the blood vessels, exposing tissue factor (TF), a protein not normally in contact with blood.
- process:
1. Tissue damage exposes tissue factor, which binds with Factor VII in the blood.
2. The TF-Factor VII complex activates Factor X.
- Result: This pathway provides a rapid response to trauma, directly activating Factor X and feeding into the common pathway.
3) Common Pathway
- trigger: Both the intrinsic and extrinsic pathways activate Factor X, which is central to the common pathway.
- process:
1. Activated Factor X (Xa), along with Factor V and calcium ions, converts prothrombin (Factor II) to thrombin (Factor IIa).
2. Thrombin then converts fibrinogen (a soluble protein) into fibrin (an insoluble protein), forming a mesh-like structure that stabilizes the clot.
3. Thrombin also activates Factor XIII, which cross-links fibrin strands, strengthening the clot.
- Result: The formation of a stable fibrin clot, which effectively stops bleeding at the injury site.
What is the coagulation cascade?
complex series of steps involving clotting factors that work together to form a blood clot, which prevents bleeding after injury.
Cascade can be divided into 3 main pathways: intrinsic, extrinsic and common/ These activate in response to diff types of damage but all coverge to produce a stable fibrin clot.
Role of thrombin in coagulation cascade?
Converts fibrinogen to fibrin
How does clot stabilsation occur in the coagulation cascade?
Factor XIII cross-links fibrin strands, creating a strong, stable clot.
Summarise the body’s response to vessel injury? (Hemostasis)
1) Vasoconstriction= reduces blood flow to injury site
2) Platelet plug formation= provides initial seal and a surface for clot formation
3) Coagulation cascade= produces thrombin and fibrin to form a stable clot
4) Clot retraction and fibrinolysis= breakdown fibrin mesh into fibrin degradation products using plasmin, gradually removing the clot and restoring normal blood flow
Describe the platelet plug formation that occurs after vessel injury (in primary hemostasis)?
1) When vessel is injured, the endothelium (inner layer of vessel wall) exposes the underlying collagen and von Willebrand factor (vWF)
2) Platelet circulating in the blood bind to vWF and adhere to the exposed collagen anchoring them to the injury site
3) Upon adhesion, platelets become activated, change shape to increase surface area and release chemical signals (ADP, thromboxane A2 and serotonin) that recruit more platelets to the injury
4) These chemicals also make the platelets ‘sticky’ promoting further aggregation
5) Platelet aggregation= activated platelets bind together, forming a temporary platelet plug that covers the wound
6) Platelet plug provides initial seal to stop small injuries from bleeding and creates surface for coagulation cascade to occur
(coagulation cascade activated also by damage that forms a stable fibrin clot that securely seals the injury)
Hemostasis?
body’s process of stopping bleeding at site of blood vessel injury
Stages of hemostasis?
1) Vasoconstriction
2) Primary hemostasis (platelet plug formation)
3) Secondary hemostasis (coagulation cascade and clot formation)
then once vessel healed
4) Fibrinolysis to dissolve the clot
What happens in disseminated intravascular coagulation (DIC)?
processes of coagulation and fibrinolysis are dysregulated= widespread clotting with resultant bleeding
DIC pathophysiology in different conditions?
Regardless of what causes/triggers DIC, once initiated the pathophysiology is similar in all conditions
Critical mediator of DIC?
the release of a transmembrane glycoprotein (tissue factor=TF)
What is tissue factor (TF)?
present on surface of many cell types (incl endothelial cells, macrophages and monocytes) and is not normally in contact with general circulation (blood); but it is exposed to circulation after vascular damage
What plays a major role in the development of DIC in septic conditions?
TF is released in response to exposure to cytokines (particularly interleukin 1), tumour necrosis factor and endotoxin.
Why may DIC readily develop in patients with extensive trauma?
As TF is abundant in tissues of the lungs, brain and placenta.
Pathophysiology of DIC?
1) DIC trigged by massive release of TF into blood eg. due to sepsis, severe trauma, malignancy
2) When TF released in large amounts, it binds with factor VII and activates extrinsic pathway, then activates factor X and then thrombin generated.
3) The thrombin generated: activates additional clotting factors (XI and VIII) in intrinsic pathway, this amplifies the clotting process leading to activation of intrinsic pathway. Thrombin also activates platelets - provide surface for further clotting factor activation supporting both I and E pathways.
4) Upon activation of DIC, tissue factor binds with coagulation factors that then trigger the extrinsic pathway (via Factor VII) which subsequently triggers the intrinsic pathway (XII to XI to IX) of coagulation.
5) This cross activation becomes pathological as both E and I pathways are continuously activated without regulation.
6) Results in widespread clot formation in small vessels throughout body, consuming platelets and clotting factors. Eventually body depletes clotting components and leafs to risk of severe bleeding (clotting factors become exhausted).
DIC: why does the extrinsic pathway trigger the instrincic?
extrinsic pathway triggers the intrinsic pathway due to an overwhelming and inappropriate activation of the coagulation system. This widespread activation leads to clotting throughout the body rather than being localized at an injury site.
(As the extrinsic pathway triggers massive thrombin generation, it overflows into the intrinsic pathway, causing continuous activation of clotting factors.)
Why in DIC do you get systemic imbalance where both haemorrhage and thrombosis occur simultaneously?
The body attempts to break down clots through fibrinolysis, which releases fibrin degradation products (FDPs), further impairing clotting. Combination of clotting and bleeding.
Causes of DIC…
- sepsis
- trauma
- malignancy
- obstetric complications eg. HELLP syndrome, amniotic fluid embolism
What is the reason for example sepsis or trauma may cause DIC?
Due to trauma or sepsis (or other causes) a massive release of tissue factor is released into bloodstream (normally should not be in contact with blood) and activates coagulation cascade (extrinsic pathway).
TF may be released in response to exposure to cytokines (particularly interleukin 1), tumour necrosis factor, and endotoxin.
Typical blood picture of DIC?
↓ platelets
↓ fibrinogen
↑ PT & APTT
↑ fibrinogen degradation products
schistocytes due to microangiopathic haemolytic anaemia
What does DIC stand for?
disseminated intravascular coagulation
Prothrombin time, APTT, bleeding time and platelet count in warfarin administration?
PT= prolonged
APTT= normal
Bleeding time= normal
Platelet count= normal
Prothrombin time, APTT, bleeding time and platelet count in aspirin administration?
PT= normal
APTT= normal
Bleeding time= prolonged
Platelet count= normal
Prothrombin time, APTT, bleeding time and platelet count in heparin administration?
PT= often normal (may be prolonged)
APTT= prolonged
Bleeding time= normal
Platelet count= normal
Prothrombin time, APTT, bleeding time and platelet count in DIC?
PT= prolonged
APTT= prolonged
Bleeding time= prolonged
Platelet count= low
What is PT (prothrombin time)?
assesses the extrinsic and common pathways of the coagulation cascade, specifically measuring how long it takes blood to clot.
Factors Involved: PT primarily reflects the activity of Factors I (fibrinogen), II (prothrombin), V, VII, and X.
Use: Often used to monitor warfarin therapy and diagnose liver disease, vitamin K deficiency, or bleeding disorders that affect the extrinsic pathway.
Normal Range: Typically 11-13.5 seconds, although ranges may vary between laboratories.
A prolonged PT suggests what?
deficiencies in factors of the extrinsic pathway or issues in the common pathway
What is APTT (activated partial thromboplastin time or PTT)?
evaluates the intrinsic and common pathways of the coagulation cascade, measuring the time it takes for blood to clot when stimulated by a specific activator.
Factors Involved: APTT reflects the function of Factors VIII, IX, XI, and XII in the intrinsic pathway, as well as Factors I, II, V, and X in the common pathway.
Use: Commonly used to monitor heparin therapy and diagnose bleeding disorders related to the intrinsic pathway, such as hemophilia.
Normal Range: Usually between 25-35 seconds, but this varies by laboratory.
Prolonged APTT can indicate what?
deficiencies in intrinsic pathway factors or the presence of an inhibitor (like lupus anticoagulant).
What is bleeding time?
assesses platelet function and the ability of blood vessels and platelets to form a primary hemostatic plug.
Factors Involved: Reflects platelet function and interactions with the blood vessel wall, rather than specific clotting factors.
Use: Used less frequently today, but it may help diagnose platelet function disorders, such as von Willebrand disease or thrombocytopathy (platelet dysfunction).
Normal Range: Typically 2-7 minutes.
Prolonged bleeding time suggests what?
defect in platelet function or blood vessel integrity, not coagulation factors.
What is platelet count?
measure of the number of platelets in the blood, expressed in thousands per microliter (μL).
Factors Involved: Directly reflects platelet quantity rather than their functionality.
Use: Helps diagnose conditions with abnormal platelet levels, such as thrombocytopenia (low platelets) or thrombocytosis (high platelets).
Normal Range: Usually 150,000 to 450,000 per μL.
Low platelet count (thrombocytopenia) may be seen in what? High?
Low platelet count (thrombocytopenia) may be seen in bone marrow disorders, immune thrombocytopenia, or disseminated intravascular coagulation (DIC).
High platelet count (thrombocytosis) may occur with chronic inflammation, certain cancers, or post-splenectomy.
Difference between PT and APTT?
PT:
- pathways tested= extrinsic and common
- factors measured=Factors I (fibrinogen), II (prothrombin), V, VII, and X
- trigger of test= Measures clotting after adding tissue factor
- uses= Monitors warfarin therapy; screens for liver disease or extrinsic pathway deficiencies
- normal range= 11-13.5 seconds (often reported as INR)
- interpretation of prolongation= Prolonged in vitamin K deficiency, liver disease, or Factor VII deficiency
APPT:
- pathways tested= intrinsic and common
- factors measured= Factors VIII, IX, XI, XII and Factors I, II, V, and X
- trigger of test= measures clotting after adding activator and calcium
- uses= monitors heparin therapy; identifies intrinsic pathway deficiencies such as hemophilia
- normal range= typically 25-35 seconds
- interpretation of prolongation= prolonged in hemophilia, Factor VIII, IX, XI, or XII deficiencies, or heparin therapy
What is PT and APTT used to monitor?
PT is used to monitor warfarin
APTT is used to monitor heparin
What pathway does warfarin affect? (anticoag)
extrinsic
What pathway does heparin affect (anticoag)?
intrinsic
Prolonged PT vs prolonged APTT?
PT= Prolonged in vitamin K deficiency, liver disease, or Factor VII deficiency
APTT= Prolonged in hemophilia, Factor VIII, IX, XI, or XII deficiencies, or heparin therapy
Haemochromatosis?
autosomal recessive disorder of iron absorption and metabolism resulting in iron accumulation
Inheritance of haemochromatosis?
autosomal recessive
What causes haemochromatosis?
inheritance of mutations in HFE gene on both copies of chromosome 6
Symptoms in early disease in haemochromatosis?
often asymptomatic in early disease and initial symptoms non-specific eg. lethargy and arthralgia
Epidemiology of haemichromatosis?
1 in 10 people of European descent carry a mutation in the genes affecting iron metabolism, mainly HFE
prevalence in people of European descent = 1 in 200, making it more common than cystic fibrosis
Features of haemochromatosis?
- early= fatigue, erectile dysfunction, arthalgia (often of hands)
- ‘bronze’ skin pigmentation
- diabetes mellitus
- liver: hepatomegaly, cirrhosis, hepatocellular deposition, stigmata of chronic liver disease
- cardiac failure
- hypogonadism
- arthritis (esp of hands)
Features of the liver in pts with haemochromatosis?
stigmata of chronic liver disease, hepatomegaly, cirrhosis, hepatocellular deposition
Why do pts with haemochromatosis get heart failure?
secondary to dilated cardiomyopathy
Why do pts with haemochromatosis get hypogonadism?
secondary to cirrhosis and pituitary dysfunction- hypogonadotrophic hypogonadism
Reversible Cx of haemochromatosis (reversible with Tx)?
- cardiomyopathy
- skin pigmentation
Irreversible Cx of haemochromatosis (can’t be Tx)?
- liver cirrhosis (LFTs and hepatomegaly may be reversible but cirrhosis is not)
- DM
- dypogonadotrophic hypogonadism
- arthropathy
Fatigue, erectile dysfunction, bronze skin pigmentation, DM, arthritis of hands and hepatomegaly?
haemochromatosis
Autosomal recessive disorder of iron absorption and metabolism resulting in iron accumulation?
haemochromatosis
Ix for haemochromatosis?
Screen for iron overload:
- iron profile= transferrin sat, ferritin (not usually abnormal in early stages)
- genetic testing for HFE mutation in family members
Other tests:
- LFTs
- molecular genetic testing for C282Y and H63D mutations
- MRI: quantify liver and/or cardiac iron
- liver biopsy if suspected hepatic cirrhosis
Typical iron study profile in pt with haemochromatosis?
- transferrin saturation >55% in men or >50% in women
- raised ferritin (eg. >500ug/l) and iron
- low TIBC
Mx for haemochromatosis?
- venesection 1st line
- 2nd line: desferrioxamine
Monitoring the adequancy of venesection used in the Mx of haemochromatosis?
transferrin saturation should be kept below 50% and serum ferritin conc below 50ug/l
Alpha thalassaemia?
genetic blood disorder
deficiency of alpha chains in Hb
Alpha thalassaemia: how many alpha globin chains are there in normal healthy pt?
2
Alpha thalassaemia: normal healthy pt with no thalassaemia?
2 separate alpha-globulin genes are located on each chromosome 16 (so 4 in total)
In alpha thalassaemia, what does clinical severity depend on?
number of alpha globulin genes affected
Diagnosis of alpha thalassaemia?
FBC: low Hb, small RBC (microcytosis) and sometimes hypochromia
Hb electrophoresis: abnormal Hb
genetic testing
Tx of alpha thalassaemia?
depends on severity
- silent carrier and trait (1/2)= generally no Tx needed
- 3 genes deleted= may need regular blood transfusions, folic acid supplement, severe then splenectomy or bone marrow transplant
- Hydrops Fetalis (4 deleted): typically poor prognosis, some cases can consider in-utero blood transfusion
Alpha thalassaemia: if 1 or 2 alpha globin alleles are affected?
blood picture= hypochromic and microcytic but Hb would typically be normal
1 gene= generally asymptomatic, typically normal bloods with no anaemia
2 genes= mild anaemia, often asymptomatic but with microcytosis
Alpha thalassaemia: 3 globin alleles (genes) affected?
hypochromic microcytic anaemia with splenomegaly
known as Hb H disease
Alpha thalassaemia: all 4 alpha globin genes affected (homozygote)?
death in utero (hydrops fetalis, Bart’s hydrops)
Thalassaemia?
inherited blood disorder caused by mutations in the genes responsible for producing hemoglobin.
Decreased production or complete absence of either the alpha or beta globin chains that make up Hb, leading to ineffective oxygen transport and varying degrees of anemia.
The disorder is classified mainly into alpha thalassemia and beta thalassemia.
Genes affected in alpha and beta thalassaemia?
Alpha= HBA1 and HBA2 on chromosome 16 (healthy person has 4 genes, 2 copies of each on each chromosome)
Beta= HBB on chromosome 11 (healthy person has 2 genes, one on each chromosome)
Beta thalassaemia?
genetic blood disorder that reduces production of beta-globin chains essential for making nomral Hb
arises form mutations in HBB gene on chromosome 11, affects ability to produce enough functional Hb leading to anaemia and other Cx
Types of Beta Thalassemia?
severity depends on whether one or both beta-globin genes affected and nature of mutation
1) BT Minor (Trait)= one gene affected
2) BT Intermedia= both genes affected but still produce some beta globin (heterozygous for a mild and severe mutation)
3) BT Major (Cooley’s anaemia)= both beta-globin genes affected severely leading to almost no beta globin production (homo/heterozygous for severe mutations)
Beta Thalassaemia Minor (Trait)?
mild hypochromic microcytic anaemia (microcytosis is characteristically disproportionate to the anaemia)
HbA2 raised (>3.5%)
Beta-thalassaemia is what type of inheritance?
autosomal recessive
Beta thalassaemia trait is characterised by what?
mild hypochromic microcytic anaemia (blood findings), asymptomatic and doesn’t need Tx
CP of beta-thalassaemia trait?
usually asymptomatic
Beta thalassaemia intermedia?
moderate anaemia that can worsen over time, requires occasional blood transfusions, esp during times of stress, illness or preg
Varying degree of microcytosis, hypochromia and potential splenomegaly
Beta thalassaemia Major: features?
- presents in first yr of life with failure to thrive and hepatosplenomegaly
- microcytic anaemia
- HbA2 & HbF raised
- HbA absent
Mx of beta-thalassaemia major?
repeated transfusions (every 2-4w to manage anaemia) + iron chelation therapy eg. desferrioxamine
- BM or stem cell transplant potential only occur esp in children
- folic acid supplement
Why is iron chelation therapy important to give alongside repeated transfusions in beta-thalassaemia major?
repeated transfusion leads to iron overload and so organ failure
Symptoms of beta thalassaemia major?
severe anaemia starting a few m after birth as fetal Hb (HbF) production declines
fatigue, pallor, jaundice, growth delays, facial bone deformities from expanded BM activity
Blood findings in beta-thalassaemia major?
severe microcytic and hypochromic with marked abnormal RBCS
Diagnosis of beta thalassaemia?
- FBC: low Hb levels, small (microcytic) red blood cells, and reduced red blood cell counts.
-Hemoglobin Electrophoresis: Identifies abnormal levels of different types of hemoglobin (increased HbA2 and HbF in beta thalassemia minor and major)
- genetic testing
Haemophilia?
X-linked recessive disorder of coagulation. Blood doesn’t clot properly due to def or dysfunction of specific clotting factors
up to 30% pts have no FHx
Haemophilia A vs B(Chritmas disease)?
A= due to deficiency of factor VIII
B= lack of factor IX; less common
Features of haemophilia?
Hemarthrosis
haematomas
prolonged bleeding after surgery or trauma
Haemophilia: hemarthrosis?
bleeding into a joint cavity
Haemophilia: hematomas?
collection of blood which pools outside of blood vessels eg. in organ, tissue or body space
Ix for haemophilia?
clotting screen= prolonged APTT but bleeding time, thrombin time and prothrombin time normal
Up to 10-15% of pts with haemophilia A develop antibodies to what?
factor VIII Tx so harder to treat
Tx for haemophilia?
Factor replacement therapy= XIII concentrate for A and factor IX concentrate for B (prophylactic or during bleeds)
A= desmopressin for mild to stimulate release of stored factor VIII in blood
Antfibrinolytic meds eg tranexamic acid to reduce bleeding eg. during minor surgery or dental procedures
Common symptoms in haemophilia?
Prolonged bleeding after cuts, surgeries, or dental procedures
Spontaneous bleeding into joints, causing pain, swelling, and limited movement
Bruising easily and excessive bleeding from minor injuries
Blood in urine or stool
Spontaneous bleeding into joints so pain and limited movement, brusising easily, XS bleeding/prolonged bleeding after minor cut or dental procedure
haemophilia
Causes of hyposplenism?
- splenectomy
- sickle-cell
- coeliac disease, dermatitis herpetiformis
- Graves’ disease
- SLE
- amyloid
Hyposplenism?
spleen has reduced function so impairs ability to filter blood and mount adequate immune response
increased risk of infections, blood cell quality and lifespan affected
Howell-Jolly bodies and
siderocytes
hyposplenism
Features of hyposplenism
Howell-Jolly bodies and
siderocytes
Loss of splenic tissue eg. following splenectomy results in what?
inability to readily remove immature or abnormal RBCs from circulation
RCC does not alter significantly but cytoplasmic inclusions may be seen eg. Howell-Jolly bodies
What happens in the first few days following a splenectomy?
target cells, siderocytes and reticulocytes will appear in the circulation
What happens immediately following a splenectomy?
a granulocytosis (mainly composed of neutrophils) is seen and then this is replaced by a lymphocytosis and monocytosis over the following weeks
What happens to platelet count following splenectomy?
increased and may be persistent so oral antiplatelets may be needed in some pts
Hyposplenism can result from what?
splenic atrophy due to certain medical conditions or interventions like splenic artery embolisation and splenectomy
Hyposplenism diagnosis?
challenging, peripheral markers eg. Howell-Jolly bodies (occur when there is no spleen or no functioning spleen) not fully reliable
- most sensitive diagnositc test= radionucleotide-labelled red cell scan
Risks associated with hyposplenism?
- increased risk of post-splenectomy sepsis, esp from encapsulated organsims (due to spleens role in detecting and responding to these pathogens)
- vaccination and Abc prophy cruical for prevention
Recommendations to try and prevent post-splenectomy sepsis (esp if hyposplenism as at increased risk)?
- vaccination prophylaxis
- antibiotic prophylaxis
- travel protection
Vaccination prophylaxis to try and prevent post-splenectomy sepsis?
Pneumococcal, Haemophilus type b, and Meningococcal type C vaccines should be administered two weeks before or after splenectomy.
Schedule:
- Men C and Hib at two weeks post-splenectomy.
- MenACWY vaccine one month later.
- Children under 2 may need a booster at 2 years.
- Pneumococcal vaccines
Annual influenza vaccination for all patients
Role of spleen?
- filter blood= remove old or damaged RBC and destroy microorganisms
- produce lymphocytes
- control WBC, RBC and platelet levels
- stores iron and blood
What 2 vaccines 2w post-splenectomy? Then 1m later?
Men C and Hib 2ws post
1m later= MenACWY
pneumococcal every 5yrs
and annual flu
children <2yrs may need booster at 2yrs
IF ELECTIVE then do 2w PRIOR TO OP
Abx prophylaxis to try and prevent post-splenectomy sepsis?
- Penicillin V
- for at least 2yrs and at least until pt is 16yrs, but majority are on for life
guidance unclear
Travel protection to try and prevent post-splenectomy sepsis?
asplenic pts should use pharmacological and mechanical protection when travelling to malaria-endemic areas
Following splenectomy, pts are at particular risk of what infections?
pneumococcus, Haemophilus, meningococcus and Capnocytophaga canimorsus (usually from dog bites)
Vaccination when pt has splenectomy?
if elective, should be done 2 weeks prior to operation
Hib, meningitis A & C
annual influenza vaccination
pneumococcal vaccine every 5 years
Indications for splenectomy?
Trauma: 1/4 are iatrogenic
Spontaneous rupture: EBV
Hypersplenism: hereditary spherocytosis or elliptocytosis etc
Malignancy: lymphoma or leukaemia
Splenic cysts, hydatid cysts, splenic abscesses
Elective splenectomy?
Very different to emergency.
Spleen often large.
Most cases= laparoscopically- spleen will often be macerated inside a specimen bag to facilitate extraction.
Cx of splenectomy?
Haemorrhage (may be early and either from short gastrics or splenic hilar vessels
Pancreatic fistula (from iatrogenic damage to pancreatic tail)
Thrombocytosis: prophylactic aspirin
Encapsulated bacteria infection e.g. Strep. pneumoniae, Haemophilus influenzae and Neisseria meningitidis
Examples of encapsulated bacteria (increased risk of following splenectomy?
Strep. pneumoniae, Haemophilus influenzae and Neisseria meningitidis
Post-splenectomy changes?
Platelets will rise first (therefore in ITP should be given after splenic artery clamped)
Blood film will change over following weeks, Howell-Jolly bodies will appear
Other blood film changes include target cells and Pappenheimer bodies
Increased risk of post-splenectomy sepsis= prophylactic antibiotics and pneumococcal vaccine should be given.
Post-splenectomy sepsis?
Typically occurs with encapsulated organisms
Opsonisation occurs but then not recognised
How to manage a women with sickle-cell disease or thalassaemia who wishes to become pregnant?
- refer all to haem for assessment and monitoring
- Ensure all women with disease= 5mg folic acid daily throughout preg
- if carries (trait)= advise women who carry the sickle cell (S) gene that they may have problems in situations where there are changes in levels of available oxygen.
Advise women who are beta-thalassaemia carriers that the size of their red blood cells and levels of haemoglobin can cause confusion with iron deficiency anaemia, so testing for iron deficiency is important before taking iron supplements.
Advise that if their partner is also a carrier of an unusual haemoglobin gene, their baby may inherit a haemoglobin condition, therefore testing is advised.
haematopoiesis
the process of producing new blood cells and plasma
Myelofibrosis?
a myeloproliferative disorder thought to be caused by hyperplasia of abnormal megakaryocytes
the resultant release of platelet derived growth factor is thought to stimulate fibroblasts
haematopoiesis develops in the liver and spleen
Features of myelofibrosis?
e.g. elderly person with symptoms of anaemia e.g. fatigue (the most common PC)
massive splenomegaly
hypermetabolic symptoms: weight loss, night sweats etc
elderly person with symptoms of anaemia e.g. fatigue, massive splenomegaly, hypermetabolic symptoms: weight loss, night sweats etc and tear drop poikilocytes on blood film
Myelofibrosis
Ix for myelofibrosis?
- anaemia
- high WBC and platelets early in disease
- ‘tear drop’ poikilocytes on blood film
- unobtainable bone marrow biopsy= ‘dry tap’ therefore trephine biopsy needed
- high urate and LDH (reflect increased cell turnover)
What mutations cause myelofibrosis?
in genes that regulate blood cell production:
JAK2
CALR
MPL
JAK2, CALR, MPL mutations?
myelofibrosis
What is myelofibrosis?
rare type of bone marrow cancer and one of the myeloproliferative neoplasms (MPNs), which causes extensive scarring (fibrosis) in the bone marrow, leading to impaired blood cell production. Over time, this scarring disrupts the normal production of red blood cells, white blood cells, and platelets, leading to a range of symptoms and complications.
Tx for myelofibrosis?
managing symptoms, reducing spleen size, slowing disease progression
JAK inhibitors eg. ruxolitinib
blood transfusions for severe anaemia
hydroxyurea chemo: reduce blood count and spleen size
splenectomy if massive
BM or stem cell transplant: potential cure for young pt
supportive
Thrombocytosis?
abnormally high platelet count, >400 * 10^9/l.
Causes of thrombocytosis?
- malignancy
- reactive= in response to stress eg. severe infection, surgery, iron def
- essential thrombocytosis or as part of another myeloproliferative disorder eg. CML or polycythaemia rubra vera
- hyposplenism
Reactive thrombocytosis?
reactive: platelets are an acute phase reactant - platelet count can increase in response to stress such as a severe infection, surgery. Iron deficiency anaemia can also cause a reactive thrombocytosis
Essential thrombocytosis?
Megakaryocyte proliferation results in an overproduction of platelets.
One of the myeloproliferative disorders which overlaps with CML, polycythaemia rubra vera and myelofibrosis.
Essential thrombocytosis features?
platelet count > 600 * 10^9/l
both thrombosis (venous or arterial) and haemorrhage can be seen
a characteristic symptom is a burning sensation in the hands
a JAK2 mutation is found in around 50% of patients
Mx of essential thrombocytosis?
- hydroxyurea (hydroxycarbamide) to reduce platelet count
- interferon-a is used in younger pts
- low-dose aspirin may be used to reduce thrombotic risk
How to manage pt with thrombocytopenia?
- ?underlying cause- ca?
if no suspected ca…
- count <20 * 10^9/L or active bleeding= immediate referral (risk of spontaneous haemorrhage v high below 20)
- <50= urgent referral
- 50-100= urgent referral if also- pancytopenia (Hb <100, neutrophils <1); splenomegaly or lymphadenopathy; preg; upcoming surgical or interventional procedure
- 50-100 who don’t meet other criteria= repeat FBC in 1-2w
- <100 and persistent and unexplained (2+ occasions 4-6w apart)
If don’t need referral:
- TUC
- review meds , stop any that may be causing & repeat FBC in 4-6w (count starts to cover within several days to 2w)
- 100-150 with no underlying cause identified= repeat FBC 4-6w (refer if lowering trend or unwell)
-
Why is close clinical observation required in women who are thrombocytopenic and pregnant?
platelets may decrease before other clinical features of preeclampsia become apparent
Pt with ca and thrombocytopenia?
may be due to their chemo so liaise with specialist
What is aplastic anaemia characterised by?
pancytopenia and hypoplastic bone marrow
Pancytopenia?
reduction in all 3 of…
1) RBCs= anaemia
2) WBCs= leukopenia
3) Platelets= thrombocytopenia
What is hypoplastic bone marrow?
BM with reduced number of hematopoietic (blood forming) cells
can lead to pancytopenia
What is aplastic anaemia?
when bone marrow stops producing enough new blood cells, can be idiopathic or triggered by factors like radiation, toxic chemical, viral infections or autoimmune diseases
Causes of hypoplastic bone marrow?
aplastic anaemia, chemo, radio, meds & toxins (immunosupressive, some Abx, anticonvulsants); EBV; SLE; B12 def
Peak incidence of acquired aplastic anaemia?
30yrs
Features of aplastic anaemia?
- normochromic, normocytic anaemia
- leukopenia, with lymphocytes relatively spared
- thrombocytopenia
- may be presenting feature of ALL or AML
- minority later develop paroxysmal nocturnal haemoblobinuria or myelodysplasia
Causes of aplastic anaemia?
idiopathic
congenital: Fanconi anaemia, dyskeratosis congenita
drugs: cytotoxics, chloramphenicol, sulphonamides, phenytoin, gold
toxins: benzene
infections: parvovirus, hepatitis
radiation
Symptoms of aplastic anaemia?
- anaemia= fatigue, weakness, pallor, SOB, dizziness
- leukopenia= increased risk of infections, fever, frequent illness
- thrombocytopenia= easy brusising, nosebleeds, gum bleeding, petechiae, heavy menstrual bleeding
Diagnosis of aplastic anaemia?
- FBC= low RBCs, WBCs and platelets
- Low reticulocyte count
- Bone marrow biopsy definitive= hypocellular marrow with increased fat spaces
Tx for aplastic anaemia?
- RBC and platelet transfusions
- bone marrow transplant with HLA match if young
- Antithymocyte Globulin (ATG) and Cyclosporine= supress immune system if it is attaching bone marrow and so reduces need for transfusions and may allow blood counts to recover
- Infection prophylaxis: Abx/antivirals
Drug causes of pancytopaenia?
cytotoxics
antibiotics: trimethoprim, chloramphenicol
anti-rheumatoid: gold, penicillamine
carbimazole (also causes agranulocytosis)
anti-epileptics: carbamazepine
sulphonylureas: tolbutamide
Polycythaemia?
Abnormally high RBCs (erythrocytes) in blood. Makes blood thicker than normal, so increased risk of Cx like clots, strokes, MI
Types of polycythaemia?
relative, primary and secondary
Causes of relative polycythaemia?
- dehydration
- stress- Gaisbock syndrome
Causes of primary polycythaemia?
polycythaemia rubra vera
Causes of secondary polycythaemia?
- COPD
- altitude
- obstructive sleep apnoea
- XS erythropoietin: cerebellar hemangioma, hypernephroma, hepatoma, uterine fibroids (may cause menorrhagia which leads to blood loss- polycythaemia rarely clinical problem)
How to differentiate between true polycythaemia (primary or secondary) and relative polycythaemia?
In true P the total red cell mass in males >35ml/kg and in women >32ml/kg
What is secondary polycythaemia?
caused by factors external to the bone marrow, often conditions that lead to low oxygen levels in blood, promoting body to produce more RBCs
Another name for polycythaemia vera?
polycythaemia rubra vera
Polycythaemia vera?
myeloproliferative disorder (rare blood ca when BM makes too many blood cells) caused by clonal proliferation of a marrow stem cell leading to increase in red cell volume often accompanied by overproduction of neutrophils and platelets.
What is a myeloproliferative disorder?
rare blood ca when bone marrow makes too many blood cells
What mutation is present in 95% of pts with polycythaemia vera?
JAK2
Incidence of polycythaemia vera peaks when?
6th decade
Features of polycythaemia vera?
- pruritus, typically after a hot bath
- splenomegaly
- hypertension
- hyperviscosity:
arterial thrombosis, venous thrombosis - haemorrhage (secondary to abnormal platelet function)
- low ESR
Ix of polycythaemia vera?
- FBC/film
- JAK2 mutation
- serum ferritin
- renal and LFTs
What does the FBC/film show in polycythaemia vera?
raised haematocrit, neutrophils, basophils, platelets raised in 1/2 pts
may also see low ESR, raised leukocyte alkaline phosphate
Polycythaemia vera: if the JAK2 mutation is negative and there is no secondary causes, what tests should you do?
- red cell mass
- arterial O2 sat
- abdo USS
- serum erythropoietin level
- bone marrow aspirate and trephine
- cytogenetic analysis
- erythroid burst-forming unit (BFU-E) culture
Diagnostic criteria for polycythaemia vera?
JAK2 positive (needs both criteria):
- A1= High haematocrit (>0.52 in men, >0.48 in women) OR raised red cell mass (>25% above predicted)
- A2= mutation in JAK2
JAK2 negative (requires A1 + A2 + A3 + either another A or 2 B criteria):
- A1= Raised red cell mass (>25% above predicted) OR haematocrit >0.60 in men, >0.56 in women
- A2= no mutation in JAK2
- A3= no cause of secondary erythrocytosis
- A4= palpable splenomegaly
- A5= Presence of an acquired genetic abnormality (excluding BCR-ABL) in the haematopoietic cells
- B1= Thrombocytosis (platelet count >450 * 109/l)
- B2= Neutrophil leucocytosis (neutrophil count > 10 * 109/l in non-smokers; > 12.5*109/l in smokers)
- B3= radiological evidence of splenomegaly
- B4= endogenous erythroid colonies or low serum erythropoietin
Erythrocytosis?
abnormally high haematocrit and Hb conc
Absolute erythrocytosis?
occurs when there is an increase in total number of RBCs in circulation (increased red cell mass)
How is erythrocytosis classified?
- primary erythrocytosis
- secondary erythrocytosis
- idiopathic erythrocytosis
Primary erythrocytosis?
caused by polycythaemia vera, when the increased red-cell mass is caused by neoplastic proliferation of hematopoietic cells in the bone marrow. Thrombocytosis and leucocytosis may also occur with polycythaemia vera.
Secondary erythrocytosis?
when the increased red-cell mass is caused by an increased production of erythropoietin. Most commonly erythropoietin is increased due to a physiological response to chronic tissue hypoxia caused by chronic lung disease. Inappropriate production of erythropoietin by the kidney can also occur with certain kidney disorders, renal tumours, and hepatomas.
Idiopathic erythrocytosis?
when the increased red-cell mass has no identifiable cause
Apparent erythrocytosis?
defined as increased haematocrit and haemoglobin concentration with a normal red-cell mass. It is caused by a low plasma volume which most commonly occurs in people taking thiazide diuretics, and those who are heavy smokers or heavy alcohol users.
Erythrocytosis causes what?
increased blood viscosity, leading to elevated risk of thrombosis and cardiovascular events. Other complications vary, depending on the type and underlying cause of polycythaemia
Cx of polycythaemia vera?
risk of haemorrhage may be increased, particularly in people with severe thrombocytosis. In a minority of people, the disease progresses to the myelofibrotic stage, where the bone marrow is replaced by dense fibrous bands of reticulin, and cytopenias are common. Rarely, progression to acute myeloid leukaemia occurs.
Cx of secondary erythrocytosis?
prognosis is dependent on underlying condition
How to confirm a diagnosis of erythrocytosis?
blood sample (taken without a tourniquet, if possible): for Hb, MCV, haematocrit, WBCs, platelets, LFTs, U&Es, e-GFR.
An absolute erythrocytosis is defined as a haematocrit of more than 0.56 in women and more than 0.60 in men. Investigations may also be considered if there is an observed trend of increasing haematocrit.
additional tests to confirm polycythaemia vera
JAK2 V617F mutation testing, and measurement of erythropoietin levels (usually reduced in polycythaemia vera, often raised in secondary erythrocytosis)
Features which can differentiate the diagnosis of erythrocytosis?
Specific clinical features of polycythaemia vera, such as generalized pruritus after bathing, splenomegaly, thrombocytosis, and neutrophil leucocytosis.
Presence of potential underlying causes of secondary erythrocytosis, such as chronic lung disease, cyanotic heart disease, or chronic renal disorders.
Presence of factors that raise suspicion for apparent erythrocytosis.
erythropoietin levels usually reduced in polycythaemia vera, often raised in…
secondary erythrocytosis
What if pt has suspected apparent erythrocytosis?
the underlying cause should be managed, where possible, and the haematocrit remeasured after two months to confirm a reduction.
What if pt has suspected secondary erythrocytosis?
referral to an appropriate specialist is usually required to manage the underlying cause. The haematocrit should be remeasured two months after the implementation of any measures to manage the underlying condition (such as oxygen therapy for hypoxic lung disease).
What if pt has suspected polycythaemia vera?
referral to a haematologist is recommended for consideration of treatment with aspirin; venesection; and in people at high risk of thrombosis, pharmacological cytoreduction.
What should be managed for all pts with erythrocytosis of any cause?
Cardiovascular risk factors (including hyperlipidaemia, smoking, hypertension, and diabetes)
Polycythaemia vera vs erythrocytosis?
Polycythaemia vera is a chronic blood disorder with more significant risks and broader blood cell involvement, while erythrocytosis is usually a response to other conditions or environmental factors.
Cause:
- PV= JAK2 mutation (bone marrow disorder)
- E= external factors (low O2, tumours)
Cell types affected:
- PV= red cells, often white cells and platelets
- E= only red cells
Risk of Cx:
- PV= higher risk of blood clots
- E= less risk
Tx focus:
- PV= controlling blood count and clotting risk
- E= TUC
Erythrocytosis?
Broad term for increased red blood cell count, often secondary
Hyperviscosity, pruritus and splenomegaly?
polycythaemia vera
What causes polycythaemia vera?
clonal proliferation of a marrow stem cell leading to increase in red cell volume, over production of neutrophils and platelets
Myeloproliferative disorder caused by clonal proliferation of a marrow stem cell leading to increase in red cell volume, over production of neutrophils and platelets?
polycythaemia vera
Differential diagnosis of polycythaemia vera?
- essential thrombocythaemia
- CML
- congenital polycythaemia
Mx of polycythaemia vera?
- aspirin 75mg daily= reduces risk of thrombotic events
- venesection= 1st line, to maintain haematocrit of <0.45
- chemotherapy= hydroxyurea (slightly increased risk of secondary leukaemia); phosphorus-32 therapy
Monitor closely under the direction and supervision of haematology.
Prognosis of polycythaemia vera?
thrombotic events are a significant cause of morbidity and mortality
5-15% of patients progress to myelofibrosis
5-15% of patients progress to acute leukaemia (risk increased with chemotherapy treatment)
Erythrocytosis: symptoms caused by hyperviscosity?
- chest and abdo pain
- myalgia and weakness
-fatigue - headache: fullness of head and neck, dizzy and/or perspiration
- tinnitus
- blurred vision, temp loss of vision in one or both eyes
- paresthesia
- slow mentation, sense of depersonalisation
What symptoms may indicate polycythaemia vera as the cause of erythrocytosis?
- bruising
- pruritis, esp on contact with warm water
- abdo discomfort (splenomegaly)
- insomnia
- vasomotor symptoms: hot flushes, hyperhidrosis or night sweats
- tenderness or painful burning and/or redness of fingers, palms, heels or toes
What factors may indicate polycythaemia vera?
> 40
Hx of haemorrhage, thrombosis, Budd-Chiari
FHx of PV
Polycythaemia Ix results?
leukocytosis
thrombocytosis
high Hb
high haematocrit
MCV usually low
LFTs usually normal (but if elevated ?Budd-Chiari
Features suggestive of myelofibrosis?
- anaemia
- Sustained loss of requirement for either venesection (in the absence of cytoreductive therapy) or cytoreductive treatment for erythrocytosis.
- A leukoerythroblastic peripheral blood picture.
Increasing splenomegaly, defined as either an increase in palpable splenomegaly of greater than, or equal to, 5 cm (distance of the tip of the spleen from the left costal margin), or the appearance of a newly palpable splenomegaly. - Development of at least one of three constitutional symptoms: greater than 10% weight loss in 6 months, night sweats, or unexplained fever (>37.5°C).
Sickle cell disease?
encompasses a group of inherited conditions of sickle Hb
Sickle Hb?
abnormal beta-globin chain which causes it to polymerise when deoxygenated distorting the erythrocyte into a sickle shape
Why is sickle Hb bad?
deformed erythrocytes form clusters, which block blood vessels, damage large and small blood vessels; are sequestered in liver and spleen; and cause intense pain (sickle cell crisis), anaemia, infections, chest problems
How severe is sickle cell disease?
can be life-threatening, particularly for young children
Inheritance of sickle cell disease?
inherited gene for sickle Hb (Hb S) from one parent and a gene for abnormal Hb variant from the other
if 2nd abnormal gene is also for Hb S then pt= homozygous sickle cell disease (Hb SS) and this is called sickle cell anaemia
Sickle cell anaemia?
most common and severe type of sickle cell disease
when pt is homozygous sickle cell disease (HbSS)
Sickle cell trait?
when pt inherits a gene for normal Hb (HbA) from one parent and gene for sickle cell Hb (HbS) so their genotype is HbAS
Sickle cell trait symptoms?
rarely have symptoms
have 50% chance of passing sickle cell gene to their child
If both parents have sickle cell trait (carriers of sickle cell gene- HbAS) what is the chance their child will be born will sickle cell disease?
1 in 4
Is sickle cell disease common?
yes, affects 1 in every 2000 births
When should sickle cell disease be suspected?
- very young infants with signs and symptoms of haemolysis or splenic sequestration
- chilren >4m with S&S of sickle cell disease eg. dactylitis
- people from high-risk ethnic groups with features of an acute crisis, or chronic Cx of sickle cell disease
High-risk ethnic groups for sickle cell disease?
African or African-Caribbean
Sickle cell crisis?
sudden onset pain, infection, anaemia or other symptoms (eg. stroke or priapism), often Hx of previous crisis
in pt with sickle cell disease
Follow up for pt with sickle cell disease?
all will be followed up regularly in secondary care by MDT and have individual care plan
Primary care= adherence to immunisations, malaria prophylaxis and Abx prophylaxis; how to identify sickle cell crisis; support pts with chronic Cx eg. chronic pain
How are most cases of sickle cell disease diagnosed?
as part of National Newborn Screening Programme
When does sickle cell disease present?
until around 6m old
some very young infants may present with signs and symptoms of:
- haemolysis (jaundice, pallor or tachycardia)
- splenic sequestration crisis (pallor, tachycardia or shock)
Signs of symptoms of sickle cell disease in children aged 4 months and older?
- swelling of joints, esp dactylitis
- leukocytosis in absence of infection
- invasive infection
- protuberant abdo (due to splenomegaly), often with umbilical hernia
- cardiac systolic flow murmur secondary to anaemia
- maxillary hypertrophy with overbite, due to extramedullary haematopoiesis may occur
Dactylitis in sickle cell disease?
painful swelling of hands or feet as result of vaso-occlusion
common presenting symptom in infants aged 9-18m
many children don’t have this and may only present later with vaso-occlusion affecting long bones (30% children in 1st yr and resolves in few days)
Diagnosis of sickle cell disease?
National Newborn Screening Programme
- FBC, reticulocyte count, blood film, other labs tests to identify haemoglobinopathies
Why may pt with acute sickle cell crisis have skeletal pain- painful swollen joints?
acute bone infarction during an acute pain crisis
Precipitating factors of acute sickle cell crisis?
cold, dehydration, exertion, windy weather
When does acute priapism eg. in acute sickle cell crisis become a surgical emergency?
if present for >3hrs
How may acute splenic sequestration in sickle cell crisis present?
pallor, shock, tachycardia, lethargy
more common in young children
look out for acute increase in splenic size
How may transient red cell aplasia present in sickle cell crisis?
pallor, tachpnoea, tachycardia without splenomegaly
most commonly due to parovirus infection
also: fever, headache, myalgia, arthralgia, resp & GI symptoms
The Sickle Cell and Thalassaemia (SCT) Screening Programme screens for what?
- genetic carrier for sickle cell, thalsassaemia, other Hb disorders
- Sickle cell disease
- T
- Hb disorders
Sickle cell disease screening is offered to who?
all newborn babies as part of Newborn Blood Spot Screening Programme, usually when 5 days old
all infants <1yrs who have newly arrived in UK
pregnant women in high prevalence areas before 10w pregnant (Family Origin Questionnaire)
bio fathers if mother is carrier
Mx for sickle cell crisis?
- mild-moderate pain Mx at home= paracetamol, ibuprofen (dihydrocodeine <13yrs or codeine phosphate >13yrs); urgent assessment if pain not controlled. Advice fluid intake, avoiding triggers, coping strategies eg. distraction with TV
- Urgent advice if= fever, resp symptoms, sign of infection, priapism, unusual pallor, weakness, tingling, loss of speech, neuro Cx
Why is increasing fluid intake important in sickle cell crisis?
dehydration may prolong painful episode
Recommended vaccines for children with sickle cells disease?
- Childhood immunisation programme
- Pneumococcal polysaccharide vaccine (PPV23) at 2yrs
- Influenza annually from 6m
- Men ACWY (depends age they present):
<1yr= 2 doses 4w apart until 1st yr then booster 8w after vaccines at 1yrs old
1-2yrs= 1 dose 8w after scheduled 1yr vaccines
2-10yrs= 1 dose
10+= 1 dose
Vaccines for older children and adults with sickle cell disease regardless of previous vaccination?
- PPV23 every 5yrs
- 1 dose MenB and MenACWY, then another MenB 4w later
- anual influenza
Others= Hep B if not recieved
What Abx Tx should be prescribed to protect againist infection in sickle cell disease?
All children from 3m to 5yrs old. Lifelong if high risk of pneumococcal or for adults who prefer to continue.
Phenoxymethylpenicillin (<1yrs= 62.5mg 2xd; 1-5yrs= 125mg 2xd; >5yrs= 250mg 2xd)
Allergic= oral erythromycin (125, 250 or 500mg 2xd)
Does sickle cell disease protect against malaria?
NO
likely to be severe due to splenic hypofunction
Only cure for sickle cell disease?
stem cell transplant
consider if severe
What may pt with sickle cell disease be given if have recurrent hospital admission for acute chest syndrome or acute painful crisis?
hydroxycarbamide
Do sickle cell trait pts have symptoms?
no rare to
but risk of vaso-occlusive episode if oxygen deprived eg. careful at high altitudes (long haul flights, climbing)
inform anaesthetist
triggers= high atmos pressure eg. scuba diving & exercise; stay hydrated
Chance of passing sickle cell trait to child?
1 in 2
if other parent also carrier, 1 in 4 chance child will have the disease
Why is sickle cell anaemia more common in people of African descent?
as heterozygous condition offers some protection against malaria
Sickle cell trait pts only symptomatic if…
severely hypoxic eg. high altitudes, scuba diving, intense exercise (rare)
Why do symptoms in sickle cell disease (homozygotes) tend to develop 4-6 moths of age?
when abnormal HbSS molecules take over from fetal Hb
HbAA?
normal Hb
HbAS?
sickle cell trait
HbSS?
sickle cell disease
HbSC?
mild sickle cell disease
inherited one HbS and one abnormal Hb (HbC)
How does infarction occur in sickle cell disease?
polar amino acid glutamate is substituted by non-polar valine in each of the two beta chains (codon 6). This decreases the water solubility of deoxy-Hb
in the deoxygenated state the HbS molecules polymerise and cause RBCs to sickle:
- HbAS patients sickle at p02 2.5 - 4 kPa
- HbSS patients at p02 5 - 6 kPa
sickle cells are fragile and haemolyse; they block small blood vessels and cause infarction
Definitive diagnosis of sickle cell disease?
haemoglobin electrophoresis
Mx for sickle cell crisis? (severe)
- analgesia eg. opiates
- fluids (rehydrate)
- oxygen
- consider Abx if evidence of infection
- blood transfusion
- exchange transfusion eg. if neuro Cx
Long term Mx of sickle cell disease?
- hydroxyurea
- pneumococcal polysaccharide vaccine every 5 years
Why is hydroxyurea good in the longer-term Mx of sickle cell disease?
increases HbF levels and is used in prophylactic Mx of sickle cell anaemia to prevent painful episodes
Sickle cell anaemia is characterised by periods of…
good health with intervening crises
Types of crisis in sickle cell anaemia?
- thrombotic, ‘vaso-occlusive’, ‘painful crisis’
- acute chest syndrome
- anaemic: aplastic; sequestration
- infection
Sickle cell anaemia: thrombotic crisis?
aka painful crises or vaso-occlusive crises
precipitated by infection, dehydration, deoxygenation (e.g. high altitude)
painful vaso-occlusive crises should be diagnosed clinically - there isn’t one test that can confirm them although tests may be done to exclude other Cx
infarcts occur in various organs including the bones (e.g. avascular necrosis of hip, hand-foot syndrome in children, lungs, spleen and brain
Sickle cell anaemia: acute chest syndrome?
vaso-occlusion within the pulmonary microvasculature → infarction in the lung parenchyma
dyspnoea, chest pain, pulmonary infiltrates on chest x-ray, low pO2
Sickle cell anaemia: most common cause of death after childhood?
acute chest syndrome
Sickle cell anaemia: Mx of acute chest syndrome?
pain relief
respiratory support e.g. oxygen therapy
antibiotics: infection may precipitate acute chest syndrome and the clinical findings (respiratory symptoms with pulmonary infiltrates) can be difficult to distinguish from pneumonia
transfusion: improves oxygenation
Sickle cell anaemia: aplastic crisis?
caused by infection with parvovirus
sudden fall in haemoglobin
bone marrow suppression causes a reduced reticulocyte count
Sickle cell anaemia: sequestration crisis?
sickling within organs such as the spleen or lungs causes pooling of blood with
worsening of the anaemia
associated with an increased reticulocyte count
Blood product transfusion Cx may be broadly classified into what?
- immunological: acute haemolytic, non-haemolytic febrile, allergic/anaphylaxis
- infective
- transfusion-related acute lung injury (TRALI)
- transfusion-associated circulatory overload (TACO)
- other: hyperkalaemia, iron overload, clotting
Blood product transfusion Cx: non-haemolytic febrile reaction?
though to be caused by antibodies reacting with white cell fragments in blood and cytokines that have leaked from the blood cell during storage
Blood product transfusion Cx: non-haemolytic febrile reaction features?
fever, chills
red cell transfusion (1-2%); platelet transfusion (10-30%)
Blood product transfusion Cx: non-haemolytic febrile reaction Mx?
Slow or stop transfusion.
Paracetamol
Monitor
Blood product transfusion Cx: minor allergic reaction?
thought to be caused by foreign plasma proteins
Blood product transfusion Cx: minor allergic reaction features?
pruritus
urticaria
Blood product transfusion Cx: minor allergic reaction Mx?
temporarily stop the transfusion
antihistamine
monitor
Blood product transfusion Cx: anaphylaxis?
caused by hypersensitivity reactions to components within the transfusion
can be caused by pts with IgA def who have anti-IgA antibodies
Blood product transfusion Cx: anaphylaxis features?
hypotension
dyspnoea
wheezing
stridor
angioedema
within mins of starting transfusion
Blood product transfusion Cx: anaphylaxis Mx?
stop transfusion
IM adrenaline
ABC support: oxygen, fluids
consider: antihistamine, corticosteroids, bronchodilators
Blood product transfusion Cx: acute haemolytic reaction?
ABO incompatible blood eg. secondary to human error
Blood product transfusion Cx: acute haemolytic reaction features?
fever
abdo pain
chest pain
hypotension
agitation
mins after transfusion started
Blood product transfusion Cx: acute haemolytic reaction Mx?
stop transfusion
confirm diagnosis= check identity of pt/name on blood product; send blood for direct Coombs test, repeat typing and cross-matching
supportive= generous fluid resus with saline and inform lab
Blood product transfusion Cx: transfusion-associated circulatory overload (TACO)?
due to fluid overload resulting in pulmonary oedema
excessive rate of transfusion, pre-existing heart failure
Blood product transfusion Cx: transfusion-associated circulatory overload (TACO) features?
pulmonary oedema
HTN (key difference from pts with TRALI)
Blood product transfusion Cx: transfusion-associated circulatory overload (TACO) Mx?
slow or stop transfusion
consider IV loop diuretic eg. furosemide and oxygen
Blood product transfusion Cx: transfusion-related acute lung injury (TRALI)?
rare but potentially fatal Cx of blood transfusion
non-cardiogenic pulmonary oedema thought to be due to secondary to increased vascular permeability caused by host neutrophils that become activated by substances in donated blood
Blood product transfusion Cx: transfusion-related acute lung injury (TRALI) features?
Development of hypoxaemia/acute resp distress syndrome within 6hrs of transfusion:
hypoxia
pulmonary infiltrates on CXR
fever
hypotension
Blood product transfusion Cx: transfusion-related acute lung injury (TRALI) Mx?
stop transfusion
oxygen and supportive care
Acute haemolytic transfusion reaction results from what? (blood product transfusion Cx)
mismatch of blood group (ABO) which causes massive intracellular haemolysis
usually the result of RBC destruction by IgM-type antibodies
Acute haemolytic transfusion reaction complications? (blood product transfusion Cx)
disseminated intravascular coagulation, renal failure
Non-haemolytic febrile reaction: Febrile reactions
due to…? (blood product transfusion Cx)
white blood cell HLA antibodies
often the result of sensitization by previous pregnancies or transfusions
paracetamol may be given
Blood product transfusion complications: risk of infectious Cx varies with what?
type of blood products due to their storage conditions, components involved and duration of storage
Blood product transfusion complications: RBC transfusion risk of infection?
Pathogens: RBCs are primarily at risk for transmitting viral agents such as HIV, HBV, and HCV. Bacterial contamination is less common but possible, particularly from skin flora during collection.
Clinical impact: Viral infections can lead to chronic disease states such as chronic hepatitis or AIDS. Bacterial infections may manifest as sepsis if not promptly treated.
Blood product transfusion complications: platelet transfusion risk of infection?
Pathogens: Platelets are stored at room temperature, which increases the risk of bacterial proliferation. Common contaminants include Staphylococcus epidermidis and Bacillus cereus.
Clinical impact: Bacterial contamination of platelets is more likely to lead to rapid onset of sepsis and septic shock, given the optimal growth conditions during storage.
Blood product transfusion complications: infection due to prions?
Transmission of vCJD:
although the absolute risk is very small, vCJD may be transmitted via blood transfusion
a number of steps have been taken to minimise this risk, including:
- from late 1999 onward, all donations have undergone removal of white cells (leucodepletion) in order to reduce any vCJD infectivity present
-from 1999, plasma derivatives have been fractionated from imported plasma rather than being sourced from UK donors. Fresh Frozen Plasma (FFP) used for children and certain groups of adults needing frequent transfusions is also imported
- from 2004 onward, recipients of blood components have been excluded from donating blood
Pernicious anaemia?
autoimmune disorder affecting gastric mucosa that results in B12 def
pernicious means ‘causing harm in gradual or subtle way’- the S&S often subtle and diagnose often delayed
Most common cause of vit B12 def?
pernicious anaemia
Causes of B12 def?
- pernicious anaemia
- vegan or poor diet
- post gastrectomy
- disorders/surgery of terminal ileum (site of absorption)= Crohns- either disease activity or following ileocaecal resection
- malnutrition (eg. alcoholism)
- metformin (rare)
- atrophic gastritis (eg. secondary to H.pylori)
- Zollinger-Ellison syndrome
- Inherited intrinsic factor receptor def
- ileal resection
Pathophysiology of how pernicious anaemia causes B12 def?
antibodies to intrinsic factor +/- gastric parietal cells
intrinsic factor antibodies → bind to intrinsic factor blocking the vitamin B12 binding site
gastric parietal cell antibodies → reduced acid production and atrophic gastritis. Reduced intrinsic factor production → reduced vitamin B12 absorption
What is vit B12 important for?
production of blood cells and the myelination of nerves → megaloblastic anaemia and neuropathy
RFs for pernicious anaemia?
- female
- middle to old age
- other autoimmune disorders: thyroid disease, DMT1, Addisons, rheumatoid, vitiligo
- blood group A
Features of pernicious anaemia?
- anaemia features
- neuro features: peripheral neuropathy, subacute combined degeneration of spinal cord, memory loss
- mild jaundice: combined with pallor results in a ‘lemon tinge’
- atrophic glottitis -> sore tongue
Anaemia features?
pallor
lethargy
dyspnoea
Neuro features of pernicious anaemia?
- peripheral neuropathy= pins and needles, numbness, symmetrical typically, legs>arms
- subacute combined degeneration of spinal cord= progressive weakness, ataxia, paresthesias that may progress to spasticity and paraplegia
- neuropsychiatric= memory loss, poor conc, confusion, depression, irritabilty
peripheral neuropathy, pallor, ‘lemon tinge’, memory loss and confusion?
pernicious anaemia
Ix for pernicious anaemia?
- FBC= macrocytic anaemia (absent in 30%); hypersegmented polymorphs on blood film; may see low WCC and platelets
- Vit B12 and folate
- anti intrinsic factor antibodies and anti gastric parietal cell antibodies
Normal vit B12 level?
> =200 nh/L
Mx of pernicious anaemia?
IM vit B12 replacement (1mg hydroxocobalamin)
- no neuro features= 3 injections for week for 2w then 3 monthly treatment
- neuro features= more frequent
- folic acid supplementation may be required also
Cx of pernicious anaemia other than haematological and neuro?
increased risk of gastric ca
Uses of Vitamin B12?
RBC development and maintenance of nervous system
Where is vit B12 absorbed?
binds to intrinsic factor (secreted from parietal cells in stomach) and is actively absorbed in the terminal ileum
Where is intrinsic factor secreted?
parietal cells in stomach
Importance of intrinsic factor?
vit B12 binds to it so can be absorbed in terminal ileum
What drug may cause vit B12 def but it is very rare?
metformin
Features of B12 def?
macrocytic anaemia
sore tongue and mouth
neurological symptoms
the dorsal column is usually affected first (joint position, vibration) prior to distal paraesthesia
neuropsychiatric symptoms: e.g. mood disturbances
In vit B12 def, for neuro symptoms, what is usally affected first?
dorsal column is usually affected first (joint position, vibration) prior to distal paraesthesia
Mx of vit B12 def?
if no neurological involvement 1 mg of IM hydroxocobalamin 3 times each week for 2 weeks, then once every 3 months for life (or alternative 500-1000micrograms oral dose daily)
neuro invl= urgent specialist advice from haem; 1mg IM alternative days until no more improvement then 1mg IM every 2m
if a patient is also deficient in folic acid then it is important to treat the B12 deficiency first to avoid precipitating subacute combined degeneration of the cord
- If dietary cause consider oral vit B12= cyanocobalamin tablets 50-150micrograms daily or twice yrly 1mg hy.. injection
What if pt is deficient in folate and B12?
treat the B12 deficiency first to avoid precipitating subacute combined degeneration of the cord
Most common causes of megaloblastic anaemia?
folate or B12 def
How is megaloblastic anaemia characterised?
development of larger than normal red blood cells (macrocytosis), with immature nuclei due to defective DNA synthesis.
This results in red cells with a mean cell volume (MCV) above the normal range (greater than 100 femtolitres).
Causes of folate def?
- dietary intake
- malabsorption
- drugs
- XS urinary excretion
- liver disease
- XS requirements= preg, malignany, blood disorders
What drugs can cause Vit B12 def?
colchicine, metformin, nitrous oxide, protein pump inhibitors, H2-receptor antagonists.
What drugs can cause folate def?
alcohol, anticonvulsants, nitrofurantoin, sulfasalazine, methotrexate, trimethoprim.
What Ix should be done if folate levels are low and history suggests malabsorption?
anti-endomysial or anti-TTG to exclude coeliac
Ix for vit B12 or folate def?
- history & exam
- FBC
- blood film
- serum conc of folate
- total B12 (serum cobalamin) or active B12 (serum holotranscobalamin)
- anti-intrinsic factor antibody test if autoimmune gastritis is suspected, or there are strong clinical features of B12 deficiency.
- folate low= anti-TTG to exclude coeliac
Tx of folate def?
oral folic acid 5mg daily for 4m
dietary advice
Good sources of folate?
broccoli, sprouts, asparagus, peas, chickpeas, brown rice
Onset of megaloblastic anaemia (eg. B12 or folate def)?
incidious, gradullay progressive
Clinical features of vit B12 def can occur without…
anaemia and without low serum levels of vit B12
Symptoms of vit B12 and folate def?
Cognitive changes.
Dyspnoea.
Headache.
Indigestion.
Loss of appetite.
Palpitations.
Tachypnoea.
Visual disturbance.
Weakness, lethargy.
with pernicious anaemia may have symptoms of associated disorders eg. myxoedema, vitiligo, stomach ca, Addisions
Vit B12 vs folate S&S?
severe neuropathy does not occur with folate def
Signs of vit B12 and folate def?
Anorexia.
Angina (in older people).
Angular cheilosis.
Brown pigmentation affecting nail beds and skin creases (but not mucous membranes).
Congestive heart failure (in older people).
Episodic diarrhoea.
Glossitis — red smooth and shiny tongue, perhaps with ulcers.
Heart murmurs.
Liver enlargement.
Mild jaundice — a lemon-yellow tint.
Mild pyrexia.
Oropharyngeal ulceration.
Pallor of mucous membranes or nail beds.
Tachycardia.
Weight loss.
Neuro Cx associated with vit B12 def?
Loss of cutaneous sensation.
Loss of mental and physical drive.
Muscle weakness.
Optic neuropathy.
Psychiatric disturbances – these range from mild neurosis to severe dementia.
Symmetrical neuropathy affecting the legs more than the arms — this usually presents with ataxia or paraesthesia.
Urinary or faecal incontinence.
What may be on blood film in vit B12 or folate def?
Oval macrocytes, hypersegmented neutrophils and circulating megaloblasts in the blood film, as well as megaloblastic change in the bone marrow
Thresholds for confirmed B12 def, possible and unlikely?
Confirmed deficiency — total B12 (serum cobalamin) concentration less than 180 nanograms/L (133 picomol/L) or active B12 concentration (serum holotranscobalamin) less than 25 picomol/L.
Possible deficiency — total B12 concentration 180-350 nanograms/L (133-258 picomol/L) or active B12 concentration 25-70 picomol/L.
Unlikely to be deficiency — total B12 concentration more than 350 nanograms/L (258 picomol/L) or active B12 concentration more than 70 picomol/L.
Consider a further test to measure serum methylmalonic acid (MMA) concentrations in people who have symptoms or signs of vitamin B12 deficiency and an indeterminate total or active B12 test result.
Be aware that people of Black ethnicity may have a higher reference range for serum vitamin B12 concentrations than people of White or Asian ethnicity.
Folate levels indicating def?
less than 7 nanomol/L (3 micrograms/L)
there is an indeterminate zone with folate levels of 7–10 nanomol/L (3–4.5 micrograms/L), so low folate should be interpreted as suggestive of deficiency and not diagnostic.
If there is a strong clinical suspicion of folate deficiency but normal serum levels, red cell folate can be measured once cobalamin deficiency has been ruled out.
A red cell folate level below 340 nanomol/L (150 micrograms/L) is consistent with clinical folate deficiency in the absence of vitamin B12 deficiency.
Differential diagnosis for vit B12 and folate def?
non-megaloblastic causes of macrocytosis= alcohol, drugs (hydroxycarbamide, methotrexate and azathioprine); chronic liver disease; pregnancy and neonatal period; severe hypothyroidism; smoking; haem abnormalities:
Myelodysplasia.
Aplastic anaemia.
Pure red cell aplasia.
Plasma protein changes (for example myeloma).
Reticulocytosis.
Oral vs IM vit B12?
oral if def diet related; not diet related then IM
also IM if:
The person has another condition that may deteriorate rapidly and have a major effect on their quality of life (for example, a neurological or haematological condition such as ataxia or anaemia).
There are concerns about adherence to oral treatment, for example, if the person is older, is or has recently been in hospital and has either multimorbidity or frailty, has delirium or cognitive impairment
Monitoring after Tx for vit B12 or folate def started?
FBC and reticulocyte count:
- within 7-10d starting Tx= rise in Hb and reticulocyte count above normal is good; no improvement then check folate
- after 8w= blood counts and MCV normalised; measure folate and iron to ensure these have not been masked def
- on completion of folate Tx to confirm response
When to consider stopping vit B12 Tx?
if symptoms resolved and cause has been addressed eg. increased dietary intake
Why is measuring cobalamin levels when monitoring effects of vit B12 def Tx not helpful?
as levels increase with Tx regardless of how effective it is, retesting not required
may be measured 1-2m after starting Tx if no response
Is ongoing monitoring in Vit B12 def necessary once on Tx?
no unless no improvement or anaemia recurs
How long may neuro recovery take in B12 def once starting Tx?
within 1 week and complete resolution takes between 6w and 3m
Possible causes of bruising in neonates?
- coag disorders= haemorrhagic disease of newborn, haemophilia
- thrombocytopaenia= maternal alloimmune thrombocytopaenia
- birth trauma= cephalohaematoma
- congenital infections eg. rubell
Possible causes of bruising in infants?
- accidental injury
- non-accidental injury
- coag disorders= haemophilia
- thrombocytopaenia= ITP, thrombocytopaenia with Absent Radius (TAR)
- congenital infection
Possible causes of bruising in older children?
- accidental injury
- non-accidental injury
- coag disorders= haemophilia, von Willebrands, liver disease
- Thrombocytopaenia= ITP, ALL, meningococcal septicaemia, TAR, congenital infection
Common sites of bruising due to normal play?
bony prominences eg. shins, elbows, forehead
Bruises which may cause concern?
- XS multiple bruises of diff ages
- patterns that may indicate slapping, being gripped tight (fingertip marks), use of inflicting instruments eg. belt
- sites: face, ears, neck, buttocks, truck, proximal parts of limbs
Colour changes in bruises?
- initially red
- then purple, blue or black (over 1-3d)
- fades to yellow or green
- light bruises typically fade within 2w, more severe longer
What does ITP stand for?
immune (or idiopathic) thrombocytopenic purpura
ITP?
immune mediated reduction in platelet count
example of a type II hypersensitivity reaction
ITP pathophysiology?
antibodies are directed against glycoprotein IIb/IIIa or Ib-V-IX complex
ITP in children vs adults?
more acute in children and may follow an infection or vaccination
Features of ITP?
- bruising
- petechial or purpuric rash
- bleeding less common, epistaxis or gingival bleeding
Child with purupic/petechial rash following infection or vaccination?
?ITP
Ix for ITP?
- FBC= isolated thrombocytopenia
- blood film
- bone marrow exam if atypical features eg. lymph node enlargement/splenomegaly, high/low WBC, failure to resolve/respond to Tx
Mx of ITP?
- usually no Tx needed (resolves in 80% children within 6m with or without Tx)
- avoid activities that may result in trauma eg. team sports
- Tx indicated if platelets low (<10) or signif bleeding, otpions= oral/IV corticosteroid; IV IG; platelet transfusion in emergency eg. active bleeding but only temp measure as soon destroyed by circulating antibodies
Lymphadenopathy?
enlarged lymph nodes typically indicating immune response to infection or malignancy
Pathophysiology of lymphadenopathy?
The lymphatic system, comprising lymph vessels, nodes, and other tissues, plays a critical role in body’s immunity.
Lymph nodes are small, bean-shaped structures that produce and store cells that fight infection and disease.
They filter the lymph fluid as it flows through them, trapping bacteria, viruses, and other foreign substances to be destroyed by white blood cells.
Lymphadenopathy usually occurs when these nodes produce more cells or become filled with debris from a destroyed cell.
Differential diagnosis for lymphadenopathy?
- Infective
- Neoplastic= leukaemia, lymphoma
- autoimmune: SLE, RA
- graft vs host disease
- sarcoidosis
- drugs
Infective causes of lymphadenopathy?
infective mononucleosis; HIV (incl seroconversion illness); eczema with secondary infection; rubella; toxoplasmosis; CMV; TB; roseola infantum
Drugs that may cause lymphadenopathy?
phenytoin
lesser extent= allopurinol, isoniazid
Massive haemorrhage?
loss of one blood volume in 24hr period or loss of 50% circulating blood vol in 3hrs or blood loss of 150ml/min
Normal blood volume in adult and child that equates to their body weight?
adult= 7% of total body weight
child= 8-9% total body weight
Average blood volume in adults?
around 9 pints
4.3 litres
70ml/kg in males and 65ml/kg females
70-75ml/kg in children (1yrs+)
Cx of massive haemorrhage?
- hypothermia
- hypocalcaemia
- hyperkalaemia
- delayed type transfusion reactions
- transfusion related lung injury
- coagulopathy
Cx of massive haemorrhage: hypothermia?
Blood is refrigerated
Hypothermic blood impairs homeostasis
Shifts Bohr curve to the left
Cx of massive haemorrhage: hypocalcaemia?
Both FFP and platelets contain citrate anticoagulant, this may chelate calcium
Cx of massive haemorrhage: hyperkalaemia?
Plasma of red cells stored for 4-5 weeks contains 5-10 mmol K+
Cx of massive haemorrhage: delayed type transfusion reactions?
Due to minor incompatibility issues especially if urgent or non cross matched blood used
Cx of massive haemorrhage: transfusion related lung injury?
Acute onset non cardiogenic pulmonary oedema
Leading cause of transfusion related deaths
Greatest risk posed with plasma components
Occurs as a result of leucocyte antibodies in transfused plasma
Aggregation and degranulation of leucocytes in lung tissue accounts for lung injury
Cx of massive haemorrhage: coagulopathy?
Anticipate once circulating blood volume transfused
1 blood volume usually drops platelet count to 100 or less
1 blood volume will both dilute and not replace clotting factors
Fibrinogen concentration halves per 0.75 blood volume transfused
Common causes of hepatomegaly?
- cirrhosis: early disease, later liver decreases in size. Non-tender firm liver.
- malignancy: metastatic spread or primary hepatoma. Hard, irregular liver edge.
- right HF: firm, smooth, tender liver edge, may be pulsatile
Causes of hepatomegaly?
- cirrhosis
- malignany
- RHF
- viral hepatitis
- glandular fever
- malaria
- abscess: pyogenic, amoebic
- hydatid disease
- haem malignancies
- haemochromatosis
- PBC
- sarcoidosis, amyloidosis
Causes of hepatosplenomegaly?
- chronic liver disease* with portal hypertension
- infections: glandular fever, malaria, hepatitis
- lymphoproliferative disorders
- myeloproliferative disorders e.g. CML
- amyloidosis
*the latter stages of cirrhosis are associated with a small liver
Most common nutritional disorder of childhood?
iron def anaemia
affects 10% children in UK
Prevalence of iron def anaemia in children is higher in what populations?
Asian, Afro-Caribbean, Chinese
Causes of iron def anaemia in children?
socioeconomic - iron supplemented milk formulas may be more expensive
unmodified cow’s milk - a poor source of iron due to it being in a form that is not absorbed well, therefore should be introduced after 1 year of age (whilst breast milk is relatively low in iron it is present in a form that is easily absorbed)
ethnic origin - e.g. Asian mothers may introduce solids later
Prevention of iron def anaemia in children?
supplementary iron in milk
dietary education
free formulas for at risk infants
Causes of abnormal coagulation?
heparin, warfarin, DIC, liver disease
Heparin causing abnormal coagulation: factors affected?
prevents activation factors 2,9,10,11
Warfarin causing abnormal coagulation: factors affected?
affects synthesis of factors 2,7,9,10
DIC causing abnormal coagulation: factors affected?
1,2,5,8,11
Liver disease causing abnormal coagulation: factors affected?
1,2,5,7,9,10,11
APTT increased, PT normal, bleeding time normal
haemophilia
APTT increased, PT normal, bleeding time increased
von Wilebrand’s disease
APTT increased, PT increased, bleeding time normal?
Vit K def
Acute intermittent porphyria (AIP)?
rare autosomal dominant condition caused by a defect in porphobilinogen deaminase, an enzyme involved in the biosynthesis of haem. The results in the toxic accumulation of delta aminolaevulinic acid and porphobilinogen
AIP commonly presents with what?
abdo and neuropsychiatric symptoms in 20-40yr olds
more common in females
Presentation of AIP?
abdominal: abdominal pain, vomiting
neurological: motor neuropathy
psychiatric: e.g. depression
hypertension and tachycardia common
Diagnosis of AIP?
classically urine turns deep red on standing
raised urinary porphobilinogen (elevated between attacks and to a greater extent during acute attacks)
assay of red cells for porphobilinogen deaminase
raised serum levels of delta aminolaevulinic acid and porphobilinogen
Mx of AIP?
avoiding triggers
acute attacks= IV haematin/haem arginate
IV glucose should be used if haematin/haem arginate is not immediately available
Antiphospholipid syndrome?
cquired disorder characterised by a predisposition to both venous and arterial thromboses, recurrent fetal loss and thrombocytopenia.
It may occur as a primary disorder or secondary to other conditions, most commonly systemic lupus erythematosus (SLE)
Cx of antiphospholipid syndrome in pregnancy?
recurrent miscarriage
IUGR
pre-eclampsia
placental abruption
pre-term delivery
venous thromboembolism
Mx of antiphospholipid syndrome in pregnancy?
low dose aspirin when preg confirmed on urine testing
LMWH once fetal heart seen on USS; discontinue at 34w
increases the live birth rate 7 fold
Blood films- pathological red cell forms?
target cells
tear drop poikilocytes
spherocytes
basophilic stippling
Howell-Jolly bodies
Heinz bodies
Schistocytes (helmet cells)
pencil poikilocytes
burr cells (echinocytes)
ancanthocytes
Blood film abnormality not affecting red cells?
hypersegmented neutrophils: megaloblastic anaemia
Blood films- pathological red cell forms: target cells?
sickle-cell
thalassaemia
iron def anaemia
hyposplenism
liver disease
Blood films- pathological red cell forms: tear drop poikilocytes?
myelofibrosis
Poikocytes?
abnormal shaped RBCs
Blood films- pathological red cell forms: spherocytes?
hereditary spherocytosis
autoimmune haemolytic anaemia
Spherocytes?
spherical RBCs without area of central pallor, smaller in size than avergae
Blood films- pathological red cell forms: basophilic stippling?
lead poisoning
thalassaemia
sideroblastic anaemia
myelodysplasia
Blood films- pathological red cell forms: Howell-Jolly bodies?
hyposplenism
Blood films- pathological red cell forms: Heinz bodies?
G6PD def
alpha-thalassaemia
Blood films- pathological red cell forms: schistocytes (helmet cells)?
intravascular haemolysis
mechanical heart valve
disseminated intravascular coagulation
Blood films- pathological red cell forms: pencil poikilocytes?
iron def anaemia
Blood films- pathological red cell forms: burr cells (echinocytes)?
uraemia
pyruvate kinase def
Blood films- pathological red cell forms: ancathocytes?
abetalipoproteinemia
Typical blood film in hyposplenism eg. post-splenectomy, coeliac disease (30% pts)?
target cells
Howell-Jolly bodies
Pappenheimer bodies
siderotic granules
acanthocytes
Typical blood film in iron def anaemia?
target cells
‘pencil’ poikilocytes
if combined with B12/folate deficiency a ‘dimorphic’ film occurs with mixed microcytic and macrocytic cells
Typical blood film in myelofibrosis?
tear drop poikilocytes
Typical blood film in intravascular haemolysis?
schistocytes
Typical blood film in megaloblastic anaemia?
hypersegmented neutrophils
Blood products- whole blood fractions?
packed red cells
platelet rich plasma
platelet concentrate
fresh frozen plasma
cryoprecipitate
SAG-Mannitol Blood
Blood products- whole blood fractions: packed red cells?
Used for transfusion in chronic anaemia and cases where infusion of large volumes of fluid may result in cardiovascular compromise. Product obtained by centrifugation of whole blood.
Blood products- whole blood fractions: platelet rich plasma?
Usually administered to patients who are thrombocytopaenic and are bleeding or require surgery. It is obtained by low speed centrifugation.
Blood products- whole blood fractions: platelet concentrate
Prepared by high speed centrifugation and administered to patients with thrombocytopaenia.
Blood products- whole blood fractions: fresh frozen plasma?
Prepared from single units of blood.
Contains clotting factors, albumin and immunoglobulin.
Unit is usually 200 to 250ml.
Usually used in correcting clotting deficiencies in patients with hepatic synthetic failure who are due to undergo surgery.
Usual dose is 12-15ml/Kg-1.
It should not be used as first line therapy for hypovolaemia.
Blood products- whole blood fractions: cryoprecipitate
Formed from supernatant of FFP.
Rich source of Factor VIII and fibrinogen.
Allows large concentration of factor VIII to be administered in small volume.
Blood products- whole blood fractions: SAG-Mannitol Blood?
Removal of all plasma from a blood unit and substitution with:
Sodium chloride
Adenine
Anhydrous glucose
Mannitol
Up to 4 units of SAG M Blood may be administered. Thereafter whole blood is preferred. After 8 units, clotting factors and platelets should be considered.
What blood products must be cross matched?
Packed red cells
Fresh frozen plasma
Cryoprecipitate
Whole blood
What blood products can be ABO incompatible in adults?
platelets
What are cell saver devices?
These collect patients own blood lost during surgery and then re-infuse it. There are two main types:
- Those which wash the blood cells prior to re-infusion. These are more expensive to purchase and more complicated to operate. However, they reduce the risk of re-infusing contaminated blood back into the patient.
- Those which do not wash the blood prior to re-infusion.
Their main advantage is that they avoid the use of infusion of blood from donors into patients and this may reduce risk of blood borne infection. It may be acceptable to Jehovah’s witnesses.
It is contraindicated in malignant disease for risk of facilitating disease dissemination.
In some surgical pts the use of what can pose specific problems and may require the use of specialised blood products?
warfarin
Blood products used in warfarin reversal: immediate or urgent surgery in pts taking wardarin?
- Stop warfarin
- Vitamin K (reversal within 4-24 hours)
IV takes 4-6h to work (at least 5mg)
Oral can take 24 hours to be clinically effective - Fresh frozen plasma
Used less commonly now as 1st line warfarin reversal
30ml/kg-1
Need to give at least 1L fluid in 70kg person (therefore not appropriate in fluid overload)
Need blood group
Only use if human prothrombin complex is not available - Human Prothrombin Complex (reversal within 1 hour)
Bereplex 50 u/kg
Rapid action but factor 6 short half life, therefore give with vitamin K
CMV is transmitted in what?
leucocytes
Irradiated blood products?
depleted of T-lymphocytes and used to avoid transfusion-associated graft versus host disease (TA-GVHD) caused by engraftment of viable donor T lymphocytes.
Indications for CMV negative blood?
Granulocyte transfusions
Intra-uterine transfusions
Neonates up to 28 days post expected date of delivery
Pregnancy: Elective transfusions during pregnancy (not during labour or delivery)
Indications for irradiated blood?
Granulocyte transfusions
Intra-uterine transfusions
Neonates up to 28 days post expected date of delivery
Bone marrow / stem cell transplants
Immunocompromised (e.g. chemotherapy or congenital)
Patients with/previous Hodgkin lymphoma
Fresh frozen plasma? (FFP)
most suited for ‘clinically significant’ but without ‘major haemorrhage’ in patients with a prothrombin time (PT) ratio or activated partial thromboplastin time (APTT) ratio > 1.5
typically 150-220 mL
can be used prophylactically in patients undergoing invasive surgery where there is a risk of significant bleeding
In contrast to red cells, the universal donor of FFP is AB blood because it lacks any anti-A or anti-B antibodies
Cryoprecipitate?
contains concentrated Factor VIII:C, von Willebrand factor, fibrinogen, Factor XIII and fibronectin, produced by further processing of Fresh Frozen Plasma (FFP). Clinically it is most commonly used to replace fibrinogen
much smaller volume than FFP, typically 15-20mL
most suited for patients for ‘clinically significant’ but without ‘major haemorrhage’ who have a fibrinogen concentration < 1.5 g/L
Cryoprecipitate example use cases?
example use cases include disseminated intravascular coagulation, liver failure and hypofibrinogenaemia secondary to massive transfusion. It may also be used in an emergency situation for haemophiliacs (when specific factors not available) and in von Willebrand disease
can be used prophylactically in patients undergoing invasive surgery where there is a risk of significant bleeding where the fibrinogen concentration < 1.0 g/L
Prothrombin complex concentrate?
used for the emergency reversal of anticoagulation in patients with either severe bleeding or a head injury with suspected intracerebral haemorrhage
can be used prophylactically in patients undergoing emergency surgery depending on the particular circumstance
Recommended thresholds for transfusion and target after transfusion?
Pts without acute coronary syndrome:
- threshold: 70g/L
- target after transfusion: 70-90g/L
With ACS:
- threshold= 80g/L
- target= 80-100g/L
When should transfusion thresholds not be used?
in patients with ongoing major haemorrhage or patients who require regular blood transfusions for chronic anaemia.
RBC transfusion?
red blood cells should be stored at 4°C prior to infusion
in a non-urgent scenario, a unit of RBC is usually transfused over 90-120 minutes
Cryoglobulinaemia?
rare blood disorder in which abnormal proteins called cryoglobulins become insoluble and precipitate (solidify) at low temperatures, typically below normal body temperature. These precipitated proteins can cause blood vessel inflammation and blockages, particularly in small to medium-sized blood vessels, leading to a condition known as vasculitis.
Cryoglobulinemia can cause a wide range of symptoms, often affecting the skin, kidneys, nerves, and joints.
Cryoglobulinaemia
Immunoglobulins which undergo:
reversible precipitation at 4 deg C, dissolve when warmed to 37 deg C. One-third of cases are idiopathic
3 types of cryoglobinaemia?
type I (25%):
- monoclonal - IgG or IgM
- associations: multiple myeloma, Waldenstrom macroglobulinaemia
type II (25%)
- mixed monoclonal and polyclonal: usually with rheumatoid factor
- associations: hepatitis C, rheumatoid arthritis, Sjogren’s, lymphoma
type III (50%)
- polyclonal: usually with rheumatoid factor
- associations: rheumatoid arthritis, Sjogren’s
Possible features of cryoglobinaemia?
Raynaud’s only seen in type I
cutaneous:
vascular purpura, distal ulceration, ulceration
arthralgia
renal involvement:
diffuse glomerulonephritis
Cryoglobinaemia Ix?
low complement (esp. C4)
high ESR
Cryoglobinaemia Mx?
treatment of underlying condition e.g. hepatitis C
immunosuppression
plasmapheresis
Summary of cryoprecipitate?
Blood product made from plasma
Usually transfused as 6 unit pool
Indications include massive haemorrhage and uncontrolled bleeding due to haemophilia
Composition of cryoprecipitate?
Agent Quantity
Factor VIII 100IU
Fibrinogen 250mg
von Willebrand factor
Variable
Factor XIII Variable
Factor V Leiden?
activated protein C resistance) is the most common inherited thrombophilia, present in around 5% of the UK
What is factor V Leiden due to?
gain of function mutation in the Factor V Leiden protein. The result of the mis-sense mutation is that activated factor V (a clotting factor) is inactivated 10 times more slowly by activated protein C than normal. This explains the alternative name for factor V Leiden of activated protein C resistance,
Factor V Leiden: heterozygotes vs homozygotes risk?
Heterozygotes have a 4-5 fold risk of venous thrombosis.
Homozygotes have a 10 fold risk of venous thrombosis but the prevalence is much lower at 0.05%.
Why is screening for factor V LeideFann not recommended, even after VTE?
a previous thromboembolism itself is a risk factor for further events and this should dictate specific management in the future, rather than the particular thrombophilia identified.
Fanconi anaemia inheritance?
autosomal recessive
Fanconi anaemia features?
haematological:
aplastic anaemia, increased risk of AML
neurological
skeletal abnormalities:
- short stature
- thumb/radius abnormalities
cafe au lait spots
What does G6PD deficiency stand for?
Glucose-6-phosphate dehydrogenase (G6PD) deficiency
What is G6PD def?
commonest red blood cell enzyme defect.
It is more common in people from the Mediterranean and Africa
Inherited in an X-linked recessive fashion.
Many drugs can precipitate a crisis as well as infections and broad (fava) beans
Pathophysiology of G6PD def?
G6PD is the first step in the pentose phosphate pathway, which converts glucose-6-phosphate→ 6-phosphogluconolactone
this reaction also results in nicotinamide adenine dinucleotide phosphate (NADP) → NADPH
i.e. glucose-6-phosphate + NADP → 6-phosphogluconolactone + NADPH
NADPH is important for converting oxidizied glutathine back to it’s reduced form
reduced glutathine protects red blood cells from oxidative damage by oxidants such as superoxide anion (O2-) and hydrogen peroxide
↓ G6PD → ↓ reduced NADPH → ↓ reduced glutathione → increased red cell susceptibility to oxidative stress
Features of G6PD def?
neonatal jaundice
intravascular haemolysis
gallstones are common
splenomegaly may be present
Heinz bodies on blood films.
Bite and blister cells may also be seen
Diagnosis of G6PD def?
G6PD enzyme assay:
levels should be checked around 3 months after an acute episode of hemolysis, RBCs with the most severely reduced G6PD activity will have hemolysed → reduced G6PD activity → not be measured in the assay → false negative results
Some drugs causing haemolysis in G6PD def?
anti-malarials: primaquine
ciprofloxacin
sulph- group drugs: sulphonamides, sulphasalazine, sulfonylureas
Some drugs thought to be safe in G6PD def?
penicillins
cephalosporins
macrolides
tetracyclines
trimethoprim
Mx of G6PD def?
- avoid triggers: fava beans, infections, drugs
- hydration, O2, IV fluids, blood transfusion if anaemia severe
What happens in G6PD def?
genetic disorder affecting the enzyme G6PD, which plays a key role in protecting red blood cells from oxidative damage. Without sufficient G6PD, red blood cells can break down prematurely, leading to hemolytic anemia.
G6PD def vs hereditary spherocytosis?
G6PD def:
- gender= male (X-linked recessive)
- ethnicity= african, mediterranean
- Hx= neonatal jaundice, infection/drugs precipitate haemolysis, gallstones
- blood film= Heinz bodies
- diagnostic test= measure enzyme activity of G6PD
HS:
- gender= male and female (autosomal dominant)
- ethnicity= northern european
- Hx= neonatal jaundice, chronic symptoms although haemolytic crisis may be precipitated by infection, gallstones, splenomegaly
- blood film= spherocytes (round, lack of central pallor)
- diagnostic test= EMA binding
Graft versus host disease (GVHD)?
multi-system complication of allogeneic bone marrow transplantation. Less frequently, it may also occur following solid organ transplantation or transfusion in immunocompromised patients.
poor prognosis
When does graft vs host disease occur? (GVHD)
when T cells in the donor tissue (the graft) mount an immune response toward recipient (host) cells. It is not to be confused with transplant rejection (in which recipient immune cells activate an immune response toward the donor tissue).
3 conditions required for GVHD?
Billingham criteria:
The transplanted tissue contains immunologically functioning cells
The recipient and donor are immunologically different
The recipient is immunocompromised
RFs for GVHD
Poorly matched donor and recipient (particularly HLA)
Type of conditioning used prior to transplantation
Gender disparity between donor and recipient
Graft source (bone marrow or peripheral blood source associated with higher risk than umbilical cord blood)
Acute and chronic GVHD are considered…
separate syndromes
Acute GVHD?
Is classically defined as onset is classically within 100 days of transplantation
Usually affects the skin (>80%), liver (50%), and gastrointestinal tract (50%)
Multi-organ involvement carries a worse prognosis
Chronic GVHD?
May occur following acute disease, or can arise de novo
Classically occurs after 100 days following transplantation
Has a more varied clinical picture: often lung and eye involvement in addition to skin and GI, although any organ system may be involved
diagnosis of GVHD?
clinical and diagnosis of exclusion
S&S of acute GVHD?
Painful maculopapular rash (often neck, palms and soles), which may progress to erythroderma or a toxic epidermal necrolysis-like syndrome
Jaundice
Watery or bloody diarrhoea
Persistent nausea and vomiting
Can also present as a culture-negative fever
S&S of chronic GVHD?
Skin: Many manifestations including poikiloderma, scleroderma, vitiligo, lichen planus
Eye: Often keratoconjunctivitis sicca, also corneal ulcers, scleritis
GI: Dysphagia, odynophagia, oral ulceration, ileus. Oral lichenous changes are a characteristic early sign (2)
Lung: my present as obstructive or restrictive pattern lung disease
Mx of GVHD?
immunosuppression and supportive measures.
IV steroids are the mainstay of immunosuppressive treatment in severe cases of acute GVHD. Extended courses of steroid therapy are often needed in chronic GVHD and dose tapering is vital.
Second-line therapies include anti-TNF, mTOR inhibitors and extracorporeal photopheresis.
Excessive immunosuppression may predispose patients to infection, and also limit the beneficial graft-versus-tumour effect of the transplant.
Topical steroid therapy may be sufficient in mild disease with limited cutaneous involvement.
Hereditary angioedema (HAE)?
autosomal dominant condition associated with low plasma levels of the C1 inhibitor (C1-INH, C1 esterase inhibitor) protein.
C1-INH is a multifunctional serine protease inhibitor - the probable mechanism behind attacks is uncontrolled release of bradykinin resulting in oedema of tissues.
HAE Ix?
C1-INH level is low during an attack
low C2 and C4 levels are seen, even between attacks. Serum C4 is the most reliable and widely used screening tool
Symptoms of HAE?
attacks may be proceeded by painful macular rash
painless, non-pruritic swelling of subcutaneous/submucosal tissues
may affect upper airways, skin or abdominal organs (can occasionally present as abdominal pain due to visceral oedema)
urticaria is not usually a feature
Mx of HAE?
acute:
- HAE does not respond to adrenaline, antihistamines, or glucocorticoids
- IV C1-inhibitor concentrate, fresh frozen plasma (FFP) if this is not available
prophylaxis: anabolic steroid Danazol may help
ITP in adults is more common in what gender?
females
Presentation of ITP in adults?
may be detected incidentally following routine bloods
symptomatic patients may present with:
- petechiae, purpura
- bleeding (e.g. epistaxis)
- catastrophic bleeding (e.g. intracranial) is not a common presentation
Ix of ITP in adults?
full blood count: isolated thrombocytopenia
blood film
a bone marrow examination is no longer used routinely
antiplatelet antibody testing has poor sensitivity and doesn’t affect clinical management so is not commonly done
Mx of ITP in adults?
oral prednisolone
pooled normal human immunoglobulin (IVIG) may also be used:
it raises the platelet count quicker than steroids, therefore may be used if active bleeding or an urgent invasive procedure is required
splenectomy is now less commonly used
immunosuppressive drugs e.g. cyclophosphamide
Evan’s syndrome?
ITP in association with autoimmune haemolytic anaemia (AIHA)
Decreased haptoglobin (remember haptoglobin binds to free Hb)?
intravascular haemolysis
Increased and decreased MCHC?
Increased:
- hereditary spherocytosis
- autoimmune haemolytic anemia (associated with spherocytosis)
Decreased:
- microcytic anaemia (e.g. iron deficiency)
What is MCHC?
mean corpuscular Hb conc
measures average amount of Hb in single RBC
When to consider lead posioning?
abdo symptoms and neuro signs
also consider acute intermitted porphyria
What does lead poisoning result in?
defective ferrochelatase and ALA dehydratase function
Features of lead posioning?
abdominal pain
peripheral neuropathy (mainly motor)
neuropsychiatric features
fatigue
constipation
blue lines on gum margin (only 20% of adult patients, very rare in children)
Ix for lead poisoning?
> 10 mcg/dl significant
- FBC= microcytic anaemia
- Blood film= basophilic stippling and clover-leaf morphology
raised serum and urine levels of delta aminolaevulinic acid may be seen making it sometimes difficult to differentiate from acute intermittent porphyria
urinary coproporphyrin is also increased (urinary porphobilinogen and uroporphyrin levels are normal to slightly increased)
in children, lead can accumulate in the metaphysis of the bones although x-rays are not part of the standard work-up
Mx of lead poisoning?
various chelating agents are currently used:
dimercaptosuccinic acid (DMSA)
D-penicillamine
EDTA
dimercaprol
Lymphatic drainage of ovaries?
The ovaries drain to the para-aortic lymphatics via the gonadal vessels.
Lymphatic drainage of the uterus?
The uterine fundus has a lymphatic drainage that runs with the ovarian vessels and may thus drain to the para-aortic nodes. Some drainage may also pass along the round ligament to the inguinal nodes.
The body of the uterus drains through lymphatics contained within the broad ligament to the iliac lymph nodes.
Lymphatic drainage of cervix?
cervix drains into three potential nodal stations; laterally through the broad ligament to the external iliac nodes, along the lymphatics of the uterosacral fold to the presacral nodes and posterolaterally along lymphatics lying alongside the uterine vessels to the internal iliac nodes.
Any of the following features in pt aged 0-24yrs should prompt v urgent FBC (within 48hrs) to Ix for leukaemia…
Pallor
Persistent fatigue
Unexplained fever
Unexplained persistent infections
Generalised lymphadenopathy
Persistent or unexplained bone pain
Unexplained bruising
Unexplained bleeding
Methaemoglobinaemia?
describes Hb which has been oxidised from Fe2+ to Fe3+. This is normally regulated by NADH methaemoglobin reductase, which transfers electrons from NADH to methaemoglobin resulting in the reduction of methaemoglobin to haemoglobin. There is tissue hypoxia as Fe3+ cannot bind oxygen, and hence the oxidation dissociation curve is moved to the left
Methaemoglobinaemia congenital causes?
haemoglobin chain variants: HbM, HbH
NADH methaemoglobin reductase deficiency
Methaemoglobinaemia acquired causes?
drugs: sulphonamides, nitrates (including recreational nitrates e.g. amyl nitrite ‘poppers’), dapsone, sodium nitroprusside, primaquine
chemicals: aniline dyes
Methaemoglobinaemia features?
‘chocolate’ cyanosis
dyspnoea, anxiety, headache
severe: acidosis,
arrhythmias, seizures, coma
normal pO2 but decreased oxygen saturation
Methaemoglobinaemia Mx?
NADH methaemoglobinaemia reductase deficiency: ascorbic acid
IV methylthioninium chloride (methylene blue) if acquired
MGUS?
Monoclonal gammopathy of undetermined significance (MGUS, also known as benign paraproteinaemia and monoclonal gammopathy) is a common condition that causes a paraproteinaemia and is often mistaken for myeloma.
Around 10% of patients eventually develop myeloma at 10 years, with 50% at 15 years
MGUS features?
usually asymptomatic
no bone pain or increased risk of infections
around 10-30% of patients have a demyelinating neuropathy
MGUS differentiating features from myeloma?
normal immune function
normal beta-2 microglobulin levels
lower level of paraproteinaemia than myeloma (e.g. < 30g/l IgG, or < 20g/l IgA)
stable level of paraproteinaemia
no clinical features of myeloma (e.g. lytic lesions on x-rays or renal disease)
Myelodysplastic syndromes (MDS)?
encompass a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, peripheral blood cytopenias, and a risk of progression to acute myeloid leukaemia (AML). These disorders predominantly affect older adults, with a median age at diagnosis of 70-75 years.
Myelodysplastic syndromes (MDS) aetiology and pathophysiology?
MDS arises from genetic mutations in hematopoietic stem cells.
Around 90% of cases are primary with the remaining 10% secondary to causes such as chemotherapy and radiotherapy. Secondary MDS typically develops around 5 years post-treatment.
The key pathophysiological feature of MDS is ineffective hematopoiesis leading to peripheral cytopenias despite a typically hypercellular bone marrow. The exact mechanisms are still not entirely understood, but they likely involve a combination of increased apoptosis, abnormal differentiation, and immune dysregulation.
Myelodysplastic syndromes (MDS) clinical features?
MDS can present with various symptoms related to the underlying cytopenias. Common presentations include fatigue, weakness, and pallor due to anaemia; recurrent infections due to neutropenia; and easy bruising or bleeding due to thrombocytopenia. Some patients may be asymptomatic and are diagnosed incidentally on routine blood counts.
Myelodysplastic syndromes (MDS) diagnosis?
The diagnosis of MDS is based on peripheral blood counts, bone marrow examination, and cytogenetic analysis. Bone marrow biopsy typically shows dysplastic changes in hematopoietic cells and a varying degree of blasts. Cytogenetic analysis can identify specific chromosomal abnormalities that may have prognostic implications.
Myelodysplastic syndromes (MDS) Tx?
depends on the subtype of MDS, the patient’s age and overall health, and the severity of symptoms. Options include supportive care (e.g., blood transfusions, growth factors), disease-modifying therapy (e.g., hypomethylating agents, lenalidomide), immunosuppressive therapy, and hematopoietic stem cell transplantation. The latter is the only potentially curative option but is limited by the patient’s age and comorbidities.
Neutropaenia?
low neutrophil counts, < 1.5 * 10^9
Normal neutrophil count?
2-7.5 * 10^9
Why is neutropaenia important to recognise?
as it predisposes to severe infection
Mild, moderate and severe neutropaenia?
Mild= 1-1.5
Moderate= 0.5-1.0
Severe= <0.5
(all * 10^9)
Causes of neutropaenia?
viral=HIV, EBV, hepatitis
drugs
benign ethnic neutropaenia:
common in people of black African and Afro-Caribbean ethnicity; requires no treatment
haematological malignancy=
myelodysplastic malignancies, aplastic anemia
rheumatological conditions
SLE: mechanisms include circulating antineutrophil antibodies
rheumatoid arthritis: e.g. hypersplenism as in Felty’s syndrome
severe sepsis
haemodialysis
What drugs cause neutropaenia?
cytotoxics
carbimazole
clozapine
Paroxysmal nocturnal haemoglobinuria (PNH)?
acquired disorder leading to haemolysis (mainly intravascular) of haematological cells. It is thought to be caused by increased sensitivity of cell membranes to complement (see below) due to a lack of glycoprotein glycosyl-phosphatidylinositol (GPI). Patients are more prone to venous thrombosis
Paroxysmal nocturnal haemoglobinuria (PNH) pathophysiology?
GPI can be thought of as an anchor which attaches surface proteins to the cell membrane
complement-regulating surface proteins, e.g. decay-accelerating factor (DAF), are not properly bound to the cell membrane due a lack of GPI
thrombosis is thought to be caused by a lack of CD59 on platelet membranes predisposing to platelet aggregation
Paroxysmal nocturnal haemoglobinuria (PNH) features?
haemolytic anaemia
red blood cells, white blood cells, platelets or stem cells may be affected therefore pancytopaenia may be present
haemoglobinuria: classically dark-coloured urine in the morning (although has been shown to occur throughout the day)
thrombosis e.g. Budd-Chiari syndrome
aplastic anaemia may develop in some patients
Paroxysmal nocturnal haemoglobinuria (PNH) diagnosis?
flow cytometry of blood to detect low levels of CD59 and CD55 has now replaced Ham’s test as the gold standard investigation in PNH
Ham’s test: acid-induced haemolysis (normal red cells would not)
Paroxysmal nocturnal haemoglobinuria (PNH) Mx?
blood product replacement
anticoagulation
eculizumab, a monoclonal antibody directed against terminal protein C5, is currently being trialled and is showing promise in reducing intravascular haemolysis
stem cell transplantation
What types of blood product in transfusions have the highest risk of bacterial contamination?
platelet transfusion
Platelet transfusion in active bleeding?
Offer platelet transfusions to patients with a platelet count of <30 x 10 9 with clinically significant bleeding (World Health organisation bleeding grade 2- e.g. haematemesis, melaena, prolonged epistaxis)
Platelet thresholds for transfusion are higher (maximum < 100 x 10 9) for patients with severe bleeding (World Health organisation bleeding grades 3&4), or bleeding at critical sites, such as the CNS.
Platelet transfusion pre-invasive procedure (prophylactic)?
Platelet transfusion for thrombocytopenia before surgery/ an invasive procedure.
Aim for plt levels of:
> 50×109/L for most patients
50-75×109/L if high risk of bleeding
> 100×109/L if surgery at critical site
Platelet transfusion for planned invasive procedure or no active bleeding?
A threshold of 10 x 109 except where platelet transfusion is contradindicated or there are alternative treatments for their condition
For example, do not perform platelet transfusion for any of the following conditions:
- Chronic bone marrow failure
- Autoimmune thrombocytopenia
- Heparin-induced thrombocytopenia, or
- Thrombotic thrombocytopenic purpura.
Post-thrombotic syndrome?
pts may develop Cx following DVT
Venous outflow obstruction and venous insufficiency result in chronic venous hypertension. The resulting clinical syndrome is known as post-thrombotic syndrome.
Features of post-thrombotic syndrome?
painful, heavy calves
pruritus
swelling
varicose veins
venous ulceration
Tx for post-thrombotic syndrome?
- compression stockings
- keep leg elevated
How may primary immunodeficiency disorders be classified?
according to which component of immune system they affect
Primary immunodeficiency disorders- neutrophil disorders?
- chronic granulomatous disease
- Chediak-Higashi syndrome
- Leukocyte adhesion def
Primary immunodeficiency disorders- neutrophil disorders: chronic granulomatous disease?
Lack of NADPH oxidase reduces ability of phagocytes to produce reactive oxygen species
Causes recurrent pneumonias and abscesses, particularly due to catalase-positive bacteria (e.g. Staphylococcus aureus and fungi (e.g. Aspergillus)
Negative nitroblue-tetrazolium test
Abnormal dihydrorhodamine flow cytometry test
Primary immunodeficiency disorders- neutrophil disorders: Chediak-Higashi syndrome?
Microtubule polymerization defect which leads to a decrease in phagocytosis
Affected children have ‘partial albinism’ and peripheral neuropathy. Recurrent bacterial infections are seen
Giant granules in neutrophils and platelets
Primary immunodeficiency disorders- neutrophil disorders: Leukocyte adhesion deficiency?
Defect of LFA-1 integrin (CD18) protein on neutrophils
Recurrent bacterial infections.
Delay in umbilical cord sloughing may be seen
Absence of neutrophils/pus at sites of infection
Primary immunodeficiency disorders- B cell disorders?
- common variable immunodef
- Bruton’s (x-linked) congenital agammaglobulinaemia
- Selective immunoglobulin A deficiency
Primary immunodeficiency disorders- B cell disorders: common variable immunodeficiency?
Many varying causes
Low antibody levels, specifically in immunoglobulin (Ig) types IgG, IgM and IgA. Recurrent chest infections. May also predispose to autoimmune disorders and lymphona
Primary immunodeficiency disorders- B cell disorders: Bruton’s (x linked) congenital agammaglobulinaemia?
Defect in Bruton’s tyrosine kinase (BTK) gene that leads to a severe block in B cell development
X-linked recessive. Recurrent bacterial infections are seen
Absence of B-cells with reduced immunoglogulins of all classes
Primary immunodeficiency disorders- B cell disorders: selective immunoglobulin A deficiency?
Maturation defect in B cells
Most common primary antibody deficiency. Recurrent sinus and respiratory infections
Associated with coeliac disease and may cause false negative coeliac antibody screen
Severe reactions to blood transfusions may occur (anti-IgA antibodies → analphylaxis)
Primary immunodeficiency disorders- T cell disorders?
DiGeorge syndrome?
Primary immunodeficiency disorders- T cell disorders: DiGeorge syndrome?
22q11.2 deletion, failure to develop 3rd and 4th pharyngeal pouches
Common features include congenital heart disease (e.g. tetralogy of Fallot), learning difficulties, hypocalcaemia, recurrent viral/fungal diseases, cleft palate
Primary immunodeficiency disorders- combines B and T cell disorders?
- severe combined immunodef
- ataxic telangiectasia
- Wiskott-Aldrich syndrome
- Hyper IgM syndromes
Primary immunodeficiency disorders- combines B and T cell disorders: severe combined immunodeficiency?
Many varying causes. Most common (X-linked) due to defect in the common gamma chain, a protein used in the receptors for IL-2 and other interleukins. Other causes include adenosine deaminase deficiency
Recurrent infections due to viruses, bacteria and fungi.
Reduced T-cell receptor excision circles
Stem cell transplantation may be successful
Primary immunodeficiency disorders- combines B and T cell disorders: ataxic telangiectasia?
Defect in DNA repair enzymes
Autosomal recessive. Features include cerebellar ataxia, telangiectasia (spider angiomas), recurrent chest infections and 10% risk of developing malignancy, lymphoma or leukaemia
Primary immunodeficiency disorders- combines B and T cell disorders: Wiskott-Aldrich syndrome?
Defect in WASP gene
X-linked recessive. Features include recurrent bacterial infections, eczema, thrombocytopaenia.
Low IgM levels
Increased risk of autoimmune disorders and malignancy
Primary immunodeficiency disorders- combines B and T cell disorders: Hyper IgM syndromes?
Mutations in the CD40 gene
Infection/Pneumocystis pneumonia, hepatitis, diarrhoea
Sideroblastic anaemia?
condition where red cells fail to completely form haem, whose biosynthesis takes place partly in the mitochondrion. This leads to deposits of iron in the mitochondria that form a ring around the nucleus called a ring sideroblast. It may be congenital or acquired.
Congenital causes of sideroblastic anaemia?
delta-aminolevulinate synthase-2 deficiency
Acquired causes of sideroblastic anaemia?
myelodysplasia
alcohol
lead
anti-TB medications
Ix for sideroblastic anaemia?
FBC:
hypochromic microcytic anaemia (more so in congenital)
iron studies: high ferritin, high iron, high transferrin saturation
blood film:
basophilic stippling of red blood cells
bone marrow:
Prussian blue staining will show ringed sideroblasts:
Mx for sideroblastic anaemia?
supportive
TUC
pyridoxine may help
Sideroblasts?
immature RBCs (erythroblasts)
Causes of severe thrombocytopenia?
ITP
DIC
TTP
haem malignancy
Causes of moderate thrombocytopenia?
heparin induced thrombocytopenia (HIT)
drug-induced (e.g. quinine, diuretics, sulphonamides, aspirin, thiazides)
alcohol
liver disease
hypersplenism
viral infection (EBV, HIV, hepatitis)
pregnancy
SLE/antiphospholipid syndrome
vitamin B12 deficiency
Pseudothrombocytopenia has been reported in association with the use of what?
EDTA as an anticoag
Inherited causes of thrombophilia?
Gain of function polymorphisms:
- factor V Leiden (activated protein C resistance): most common cause of thrombophilia
- prothrombin gene mutation: second most common cause
Deficiencies of naturally occurring anticoagulants:
- antithrombin III deficiency
- protein C deficiency
- protein S deficiency
Acquired causes of thrombophilia?
- antiphospholipid syndrome
- COCP
Thrombophilia?
blood has increased tendency to form clots
What does TTP stand for?
thrombotic thrombocytopenic purpura
TTP?
rare, life-threatening blood disorder. In TTP, blood clots form in small blood vessels throughout your body.
abnormally large and sticky multimers of von Willebrand’s factor cause platelets to clump within vessels
in TTP there is a deficiency of ADAMTS13 (a metalloprotease enzyme) which breakdowns (‘cleaves’) large multimers of von Willebrand’s factor
overlaps with haemolytic uraemic syndrome (HUS)
TTP features?
rare, typically adult females
fever
fluctuating neuro signs (microemboli)
microangiopathic haemolytic anaemia
thrombocytopenia
renal failure
TTP causes?
post-infection e.g. urinary, gastrointestinal
pregnancy
drugs: ciclosporin, oral contraceptive pill, penicillin, clopidogrel, aciclovir
tumours
SLE
HIV
Thymoma?
most common tumour of the anterior mediastinum and is usually detected between the sixth and seventh decades of life.
Thymoma associated with what?
myasthenia gravis (30-40% of patients with thymoma)
red cell aplasia
dermatomyositis
also : SLE, SIADH
Thymoma causes of death?
compression of airway
cardiac tamponade
Tranexamic acid?
synthetic derivative of lysine.
Its primary mode of action is as an antifibrinolytic that reversibly binds to lysine receptor sites on plasminogen or plasmin. This prevents plasmin from binding to and degrading fibrin.
What is tranexamic acid used for?
menorrhagia
IV bolus followed by infusion in cases of major haemorrhage
Around 40% pts with PE have no…
major risk factors
VTE common predisposing factors?
malignancy, pregnancy, period following operation
General RFs for VTE?
increased risk with advancing age
obesity
family history of VTE
pregnancy (especially puerperium)
immobility
hospitalisation
anaesthesia
central venous catheter: femoral»_space; subclavian
Underlying conditions that are RFs for VTE?
malignancy
thrombophilia: e.g. Activated protein C resistance, protein C and S deficiency
heart failure
antiphospholipid syndrome
Behcet’s
polycythaemia
nephrotic syndrome
sickle cell disease
paroxysmal nocturnal haemoglobinuria
hyperviscosity syndrome
homocystinuria
Medications that are RFs for VTE?
- COCP
- HRT (O&P)
- raloxifen and tamoxifen
- antipsychotics esp olanzapine
Prevalence and relative risk of VTE of different inherited thrombophilias?
1) Condition 2) Prevalence 3) Relative risk of VTE
Factor V Leiden (heterozygous) 5% 4
Factor V Leiden (homozygous) 0.05% 10
Prothrombin gene mutation (heterozygous) 1.5% 3
Protein C deficiency 0.3% 10
Protein S deficiency 0.1% 5-10
Antithrombin III deficiency 0.02% 10-20
Most common inherited bleeding disorder?
Von Willebrand’s disease
Inheritance of Von Willebrand’s disease?
autosomal dominant
Von Willebrand’s disease?
most common inherited bleeding disorder
The majority of cases are inherited in an autosomal dominant fashion
Characteristically behaves like a platelet disorder i.e. epistaxis and menorrhagia are common whilst haemoarthroses and muscle haematomas are rare
Role of von Willebrand factor?
large glycoprotein which forms massive multimers up to 1,000,000 Da in size
promotes platelet adhesion to damaged endothelium
carrier molecule for factor VIII
Types of von Willebrand’s disease?
type 1: partial reduction in vWF (80% of patients)
type 2: abnormal form of vWF
type 3: total lack of vWF (autosomal recessive)
Ix for von Willebrand’s disease?
prolonged bleeding time
APTT may be prolonged
factor VIII levels may be moderately reduced
defective platelet aggregation with ristocetin
Mx for von Willebrand’s disease?
tranexamic acid for mild bleeding
desmopressin (DDAVP)
factor VIII concentrate
How does desmopressin (DDAVP) work in the Mx of von Willebrand’s disease?
raises levels of vWF by inducing release of vWF from Weibel-Palade bodies in endothelial cells
How is type 3 von Willebrand’s disease (most severe form) inherited?
autosomal recessive trait
Type 2 von Willebrand’s disease (vWD)?
type 2A VWD is caused by defective platelet adhesion due to decreased high molecular weight VWF multimers (i.e. the VWF protein is too small).
Type 2B is characterised by a pathological increase of VWF-platelet interaction.
Type 2M is caused by a decrease in VWF-platelet interaction (not related to loss of high molecular weight multimers).
Type 2N is caused by abnormal binding of the VWF to Factor VIII.
There is no clear correlation between symptomatic presentation and type of VWD however common themes amongst patients include excessive mucocutaneous bleeding, bruising in the absence of trauma and menorrhagia in females.
Symptoms of vWD?
- epistaxis
- easy bruising
- menorrhagia
- bleeding gums
- prolonged bleeding after cuts or minor trauma
- GI bleeding
- heavy or prolonged bleeding post childbirth
- hemarthrosis and hematomas in severe cases
Waldenstrom’s macroglobulinaemia?
uncommon condition seen in older men. It is a lymphoplasmacytoid malignancy characterised by the secretion of a monoclonal IgM paraprotein
Waldenstrom’s macroglobulinaemia features?
systemic upset: weight loss, lethargy
hyperviscosity syndrome e.g. visual disturbance;
the pentameric configuration of IgM increases serum viscosity
hepatosplenomegaly
lymphadenopathy
cryoglobulinaemia e.g. Raynaud’s
Waldenstrom’s macroglobulinaemia Ix?
monoclonal IgM paraproteinaemia
bone marrow biopsy is diagnostic= infiltration of the bone marrow with lymphoplasmacytoid lymphoma cells
Waldenstrom’s macroglobulinaemia Mx?
rituximab-based combination chemotherapy
Wiskott-Aldrich syndrome?
Causes primary immunodeficiency due to a combined B- and T-cell dysfunction. It is inherited in a X-linked recessive fashion and is thought to be caused by mutation in the WASP gene.
Wiskott-Aldrich syndrome features?
recurrent bacterial infections (e.g. Chest)
eczema
thrombocytopaenia
low IgM levels
