Haematology Flashcards
haemostats
is the cessation of bleeding, has three stages:
Vascular
Platelet
Coagulation
These occur in conjunction with each other as a result of multiple cascades
Haemostasis requires interaction of platelets, coagulation and fibrinolytic factors, endothelium,
Proinflammatory and anti-inflammatory mediators and leukocytes
Clot formation is initiated by vascular injury, in which a platelet plug forms and is reinforced
With fibrin produced via the extrinsic pathway
coagulation cascade
At the site of vessel injury platelets will arrive at the site to begin the clotting cascade
Involves extrinsic and intrinsic pathway
Extrinsic pathway:
Begins with now exposed molecules of the tissue wall such as tissue factor (contact system initiated)
Forms a complex with factor VIIa leading to activation of factor Xa
Point of Xa activation is point at which the extrinsic and intrinsic pathway meet
Intrinsic pathway:
Various coagulation factors such as IXa, XIa, XIIa which activate in cascade
An additional cofactor (VIIIa and IXa) combine with Xa to activate factor Xa (where pathways merge)
Combined pathway:
Xa is pivotal factor of clotting cascade
Xa combines with Va and Prothrombin further down cascade, catalysing prothrombin and inducing the ‘thrombin burst’
One Xa factor can catalyse 10,000 prothrombin to thrombin reactions
These large amounts of thrombin induce further platelet action and enhanced formation of fibrin
Fibrin forms strands which form the mesh that stabilises the clot during an arterial clot and holds the RBC together in a venous clot
Xa is a viable target for therapeutics involving pathological coagulation cascades
RBCs
7um diameter
No nucleus
Life span 100-120 days
Consists of 640 million molecules of hemoglobin (Hgb)
RBC count = total number of Hgb
Transports oxygen and CO2
Each Hgb transports four O2 molecules (oxyhaemoglobin) which carries to individual cells
Also binds to CO2 (carboxyhemoglobin), presence of CHgb helps release O2 from Hgb molecules
Haematological investigations for surgeries
Haematology is the study of blood components form and function and the coagulation system
Pre-operative care:
Assessment, diagnosis, management of safety issues
Preparation of patient centred care and decision making: pre op blood ordering, anaemia management, diabetes management, anticoagulation therapy management
Perioperative haem Ix:
Diagnostic assessment: diagnosis of blood diseases and abnormalities (e.g. patients general health)
Check for existing anaemias: bone marrow cancers, chemotherapy, vit B12/iron deficiencies, malabsorption disorders, liver disease, renal disease, anaemias, blood loss etc.
Prognostic assessment: identifies possibility of developing abnormal functioning blood, effective oxygenation and coagulation (e.g. how patients respond to their operations)
FBC
RBC: haemoglobin and haematocrit (in total)
WBC: differential count
Platelet count
Indications: Measures total Hgb or Hb in blood Indirect RBC measure Assessment of ongoing bleeding Evaluation of anaemic patients Normal range:
Male - 14-18 g/dl or 8.7-11.2 mmol/l
Female - 12-16g/dl or 7.4-9.9 mmol/l
Pregnancy - 11g/dl
Newborn - 14-24 g/dl
0-2 weeks - 12-20 g/dl
2-6 months - 10-17 g/dl
6 months - 6 years - 9.5-14 g/dl
6-18 years - 10-15.5g/dl
Elderly - Slightly decreased
indications of increased and decreased Hb
Indication of increased Hgb: Erythrocytosis Congenital heart disease Severe COPD Polycythaemia vera Severe dehydration
Indication of decreased Hgb: Anaemia Haemoglobinopathy Cirrhosis Haemolytic anaemia Haemorrhage Dietary deficiency Bone marrow failure Renal disease Normal pregnancy Rheumatoid/collagen vascular disease Haemolytic cancer Splenomegaly
RBC indices
Mean cell/corpuscular volume (MCV): average RBC size (80-100fL in adults)
Mean cell haemoglobin (MCH): average weight of RBCs (26-32 picogram)
Mean cell haemoglobin concentration (MCHC): average concentration of Hgb in RBCs (32-36g/dL)
haematocrit
volume % of RBC in whole blood.
Indication of Ix: Indirect measure of RBC no. and volume Rapid indirect measure of RBC count Serial assessment in ongoing bleeding Integral part of anaemic patient evaluation
Normal range:
Male - 42-52% or 0.42-0.52
Female - 0.37-0.47
Pregnancy - >0.33
Newborn - 0.44-0.64
2-8 weeks - 0.39-0.59
2-6 months - 0.35-0.50
6 months - 1 year - 0.29-0.43
1-6 years - 30-40%
6-18 years - 32-44%
Elderly - Slightly decreased
HCT/interfering factors:
Abnormality in RBC size
Haemodilution and dehydration
Unreliable levels immediately after haemorrhage
Extremely elevated WBC gives a decreased HCT (false anaemia)
Pregnancy shows decreased HCT
Chloramphenicol and penicillin both decrease levels
Living at high altitude increases HCT levels
WBC tests
evaluate infection, neoplasm, allergy and immunosuppression
- Total WCC
- Differential WBC count (different proportions of various WBC types)
Normal ranges:
Adults and children 2+ - 500-10,000/mm3 or 5-10 x10(9)/L
Children <2 - 6200-17,000/mm3
Newborn - 9000-30,000/mm3
neutrophils:
Phagocytosis of pathogens
55-70% normal
Lymphocytes
Natural killer cells, T and B lymphocytes
20-40% normally
B lymphocytes
Make Ig antibodies
T lymphocytes
Cooperate antibody production and attack infected cells
Monocytes
Phagocytosis
2-8% normally
Eosinophils
Phagocytose antigen-antibody complexes
1-4% normally
Basophils
Immune response to parasites and allergic reactions (hay fever)
0.5-1% normally
leukocytosis and leukopenia indications
Increased WBC indications (leukocytosis): Infection Neoplasia Malignancy Trauma, stress, haemorrhage, tissue necrosis Inflammation Dehydration Thyroid storm Steroid use
Decreased WBC indications (leukopenia): Drug toxicity Bone marrow failure Overwhelming infection Dietary deficiency (B12/iron) Bone marrow infiltration Autoimmune disease Hypersplenism (spleen extracts WBC aggressively)
coagulation screen tests
Platelet count (thrombocyte count PLT)
Clotting tests: prothrombin time (PT), fibrinogen, activated partial thromboplastin time (APTT), thrombin time and D’DIMER
APTT, PLT, PT and fibrinogen are standard coagulation tests prior to CV operations
Clotting screen normal range: Hb (g/dl) - Male: 13.5-18 or Female: 11.5-16 PT (s) - 12-13 aPTT (s) - 30-40 aPTT ratio - 1 (normal patient aPTT:present patient aPTT) INR - 1 Platelets (L) - 150-400 x10 (9) Fibrinogen (g/l) - 1.5-3
platelets
Forms in bone marrow
Small, round, non nucleated
Main role is maintenance of vascular integrity
Primary phase of hemostasis involves platelet aggregation
Platelet aggregation initiates the coagulation factor cascade
Normal values:
Premature infant - 100,000-300,000/mm3
Newborn - 150,000-300,000mm/3
Infant - 200,000-475,000/mm3
Child, Adult and elderly - 150,000-400,000/mm3
Greater than (thrombocytosis)
Less than (thrombocytopenia) Symptoms: easy bruising and frequent bleeding from gums, nost, GIT Caused by medications, congenital, leukaemia or lymphomas, chemotherapy, kidney infection/disease, excessive alcohol intake
fibrinogen
Normal range 60-100mg/dl or 1.5-4g/l
Derived from PT reaction as it occurs
Primarily a screen: any low fibrinogen detected is substituted for clauss fibrinogen test which measure fibrinogen directly
In disseminated intravascular coagulation the derived fibrinogen may be misleading
D’DIMER
Most notable subtype of fibrin degradation products
Levels of FDPs rise after any thrombotic event
Fibrin and fibrinogen degradation product (FDP) testing is commonly used to diagnose disseminated intravascular coagulation (DIC), PE, DVT, pregnancy, malignancy
During formation of a stable clot, amino acids are excised by various enzyme cascade reactions
The D’DIMER peptide is excised from the D portion of fibrin as the clot hardens
Therefore it is a useful predictor of recent clot formation
normal value:
for DIC in adult - 0.08-0.18 ugFEU/mL
for DVT/PE in adult - cut off for exclusion of VTE: <0.35ugFEU/mL
prothrombin time and INR
PT: time taken in seconds for blood to clot. Measures vitamin K dependent clotting pathways (extrinsic) therefore particularly measures warfarin activity (vit K antagonist)
PT and INR are calculations that monitor effectiveness of warfarin anticoagulation therapy
INR shows required dosage of warfarin to maintain balance between preventing clots and causing excessive bleeds for patients (aim for 2.5; between 2-3 in patients on warfarin)
Normal PT: 11-12.5 seconds
Full anticoagulant therapy: >1.5-2 x control value; 20-30%
Normal INR: 0.8-1.1
partial thromboplastin time PTT and thrombin time TT
Normal PTT: 60-70 seconds. Measures intrinsic clotting pathway, time taken for blood to clot. Useful in monitoring heparin therapy
Normal aPTT: 30-40 seconds. Provides ratio of APTT:normal clotting time and is primary calculator used to monitor heparin therapy
Thrombin time (TT):
Normal TT: 12-15 seconds. Measures time taken for fibrinogen to form fibrin (later clotting common pathway stage)
Primarily requested in liver disease units
operative haemorrhage and blood products
Primary bleeding: occurs within the intraoperative period. Resolved within operation. Major haemorrhages are recorded and patient monitored closely post operatively
Reactive bleeding: occurs within 24 hours of operation. Mainly from ligature slips or missed vessels (due to hypotension and vasoconstriction during operation). Once BP normalises post op this bleeding will occur
Secondary bleeding: occurs within 7-10 days post op. Due to erosion of a vessel from a spreading infection. Often seen when heavily contaminated wound is closed primarily
Blood products: Whole blood Packed RBCs Fresh frozen plasma (FFP) Platelet concentrates Cryoprecipitate
Thromboelastography TEG
Test of whole blood coagulation
Been shown to decreased usage of blood products and mortality during procedures (good for trauma)
May be used to screen patients for coagulopathy in blunt/penetrating trauma with hemorrhagic shock, those receiving massive transfusion protocol (1:1:1) to evaluate for discontinuation or guided product therapy or clinical suspicion for haemorrhage or coagulopathy
blood transfusion complications
Immunological complications Wrong blood episodes/errors Infections Immunomodulation Litigation
Early complications are rare but tend to be much more severe:
Acute haemolytic transfusion reaction: incompatible RBCs transfused. May lead to DIC. ABO incompatible transfusion has 10% mortality while non-ABO is less severe usually but can still cause intravascular hemolysis
Infective shock: bacterial contamination is rare but can be fatal. Acute onset hypotension, rigors and collapse rapidly following transfusion. Platelets more likely to be contaminated than RBCs
Transfusion related acute lung injury: acute respiratory distress due to donor plasma containing antibodies against patients’ leukocytes. <6 hours onset nonproductive cough, SoB, hypoxia and frothy sputum. May have fever and rigors. CXR shows multiple perihilar nodules with lower lung infiltration. Usually from multiparous women who have become alloimmunized
Fluid overload: too much fluid leading to pulmonary oedema, acute respiratory failure. Those at particular risk have chronic anaemia (normovolaemic/hypervolemic) or symptoms of cardiac failure prior to transfusion
Non-haemolytic febrile reaction to transfusion of platelets and RBCs: fevers and rigors can develop due to patients’ antibodies to transfused white cells. Multiparous women who have received multiple previous transfusions are most at risk. Not life threatening reaction, treat by slowing transfusion and paracetamol
Anaphylaxis: antibodies react to proteins in transfused blood components, release IgE or IgG antibodies. Urticaria and itching common within minutes of transfusion starting
haemoglobin
Protein in RBCs that carries O2 from the lungs to body tissues and returns CO2 from tissues to lungs
Made of four protein molecules (globulin chains) that are each connected and a heme (Fe containing porphyrin) totalling 8 components
Also plays role in maintaining the shape of the RBCs and helping maintain acid-base balance within circulation
blood
8% body weight
Blood is a connective tissue: made of living cells suspended in a non-living matrix (plasma)
Main function: transportation of oxygen, nutrients, hormones and signalling molecules
Whole blood contains: Red cells Platelets Plasma Cryoprecipitate (protein for blood clotting)
Centrifuge separates whole blood into three distinct layers:
Erythrocyte layer on bottom (red)
White cell and platelets layer in middle
Yellow plasma (55% blood volume) full of proteins, waste products, electrolytes and plasma proteins (albumin, alpha/beta globulins) mostly made in the liver
blood types
O, A, B, AB refers to type of antigen present (O = none present). Each type can also be Rh +ve or -ve making 8 types of blood
Each has a different glycoprotein in plasma membrane (antigen) that immune system can recognise
In different blood types, enter circulation will trigger an immune response due to unrecognised antigen present in the system.
Often targets foreign body with agglutination (sticking the cells together) which can cause clots
AB: universal recipients due to having both antigens so will recognise ALL blood types (O, A and B)
O: universal donor due to lack of antigens meaning it can be given to anyone of any blood type and not be detected by the immune system. However they are ONLY able to receive O type blood as immune system will detect and respond to both A and B antigens
Rhesus antigens: either have (+ve) or don’t (-ve)
Rhesus positive: can accept either +/-ve blood as they will recognise (do NOT have antibodies against) rhesus protein
Rhesus negative: stick to -ve donor blood as +ve will trigger immune response. Negative types can actually tolerate Rh+ve ONCE but after this they will develop antigens and lead to never accepting +ve blood again. This can be a problem in -ve mothers giving birth to +ve children if there is blood exchange. Is okay for one pregnancy but for any subsequent births she will need rhogam serum injection containing anti-rh antigens to block the mother’s immune response to her baby
erythropoietin cell cycle
Develop from committed stem cells to mature RBCs in about 7 days
Megakaryocyte erythroid progenitor (MEP), proerythroblast, early erythroblast, intermediate erythroblast, late erythroblast, nuclear erythroblast, nuclear extrusion, reticulocyte then RBC; each stage differentiates more by losing nuclei and proteins etc.
When matured in healthy individuals circulate for around 100-120 days (and 80-90 days in full term infant)
The regulation of formation is mostly from erythropoietin (EPO) from the kidneys (some in liver too) which is produced when hypoxia or low O2 levels are detected in the kidneys using hypoxia inducible factor (oxygen used to degrade/inactivate HIF so when hypoxic HIF signalling increases)
Old erythrocytes get more rigid and more likely to get stuck in capillaries. There are many channels to collect these older RBCs especially around the spleen (RBC graveyard) trapping old RBCs where macrophages engulf and digest components, separating them all into individual components for recycling or waste removal (amino acids, Fe stored in liver or put into new erythrocytes and haem turned into bilirubin for bile)
destruction process is called eryptosis
sickle cell anaemia
Autosomal recessive
Most common in african descent; must screen all african origin people for SCD pre-op
1/700 incidence
HbSS - homozygotes (SS) symptomatic sickle cell anaemia
HbAS - heterozygous - sickle cell trait (no symptoms but falciparum malaria resistant) may still experience symptomatic sickling hypoxia
SCD is most common in patients of africam indian, middle east and carribean descent as single copy of gene increases malarial resistance and is a selective advantage.
Pathology:
Foetal Hb (HbF) is usually replaced by HbA at around 6 weeks of age. Patients with SCD have an abnormal amount of variant Hb (HbS) which causes abnormal sickle shaped erythrocytes
Results from three interconnected sequelae of SCD
Vaso-occlusive crisis results in bone infarcts and subperiosteal haemorrhages
Chronic anaemia resulting in expansion of medullary spaces
Infection
These predispose individuals to complications such as growth disturbance and pathological fractures
Pathogenesis: Hypoxia Deoxygenated HbS Polymerises Deformity of RBCs, sickle cells cannot travel normally or carry oxygen Haemolysis + blocked small vessels
SCD investigations
Bloods: Hb 60-90g/L, reticulocytes 10-20%, high bilirubin. Haemolysis variable
Film: sickle cell and target cells
Sickle solubility test +ve but doesn’t distinguish between types
Hb electrophoresis confirms diagnosis
Pregnant women at risk of being carriers are offered testing during pregnancy
Newborn screening heel prick test at 5 days of age
XR: vaso-occlusive crisis can shoe osteonecrosis, subperiosteal and epidural haemorrhage, hand-foot syndrome (dactylics), growth disturbance, osteomyelitis or marrow hyperplasia in anaemia
SCD complications
Anaemia Increase infection risk Stroke Avascular necrosis in large joints Pulmonary HTN Painful and persistent penile erection (priapism) CKD Sickle cell crisis Acute chest syndrome
sickle cell crises
Umbrella term for spectrum of acute crises related to condition. Range from mild to life threatening, can occur spontaneously or triggered by stresses such as infection, dehydration, cold or significant life events.
There is no specific treatment for sickle cell crises and they are managed supportively:
Have a low threshold for admission to hospital
Treat any infection
Keep warm
Keep well hydrated (IV fluids may be required)
Simple analgesia such as paracetamol and ibuprofen
Penile aspiration in priapism
Avoid NSAIDs (ibuprofen) in renal impairment
vaso-occlusive painful crisis (SCD)
Commonly occurs from microvascular occlusion causing distal ischaemia
Can be triggered by cold, dehydration, infection or hypoxia
Associated with dehydration and raised haematocrit
Symptoms typically include pain, fever, those of triggering infection
Bone marrow infarction causes severe skeletal pain; osteomyelitis presents with localised pain and systemic features of infection
Hands and feet show dactylitis (inflammation of finger or toes)
Mesenteric ischemia results in acute abdomen presentation
CNS infarction results in stroke, seizures, cognitive defects
Splenic infarction - susceptibility to infection (40% SCD childhood deaths)
Poor growth, chronic renal failure, gallstones, retinal disease, iron overload
Lung damage from hypoxia causing fibrosis and pulmonary HTN
Can cause priapism in men by trapping blood in penis causing painful and persistent erection (urological emergency treated with aspirin of blood from penis)
Management: no specific treatment are managed supportively
IV opiates, haematologist advice,
G+S bloods, FBC, reticulocyte count,
septic screen (Blood cultures, MSU + CXR),
Rehydrate (IV fluids) and keep warm,
NSAIDs and paracetamol analgesia
oxygen PRN,
consider empirical antibiotics if fever >38, unwell or chest signs
Penile aspiration if priapism (urological emergency)
splenic sequestration crisis (SCD)
Splenic sequestration crisis is caused by red blood cells blocking blood flow within the spleen. This causes an acutely enlarged and painful spleen. The pooling of blood in the spleen can lead to a severe anaemia and circulatory collapse (hypovolaemic shock).
Splenic sequestration crisis is considered an emergency. Management is supportive with blood transfusions and fluid resuscitation to treat anaemia and shock.
Splenectomy prevents sequestration crisis and is often used in cases of recurrent crises. Recurrent crises can lead to splenic infarction and therefore susceptibility to infections.
aplastic crisis and hand-foot syndrome (SCD)
Aplastic crisis describes a situation where there is a temporary loss of the creation of new blood cells. This is most commonly triggered by infection with parvovirus B19.
It leads to significant anaemia. Management is supportive with blood transfusions if necessary. It usually resolves spontaneously within a week.
Hand foot syndrome:
Occurs in 50% children with SCD
Most common between 6 months and 6 YO
Usually have systemic symptoms of fever, elevated WCC
Characterised by swelling of hands and feet (uni or bilateral)
Usually self limiting
acute chest syndrome (SCD)
A diagnosis of acute chest syndrome requires:
Fever or respiratory symptoms with
New infiltrates seen on a chest xray
This can be due to infection (e.g. pneumonia or bronchiolitis) or non-infective causes (e.g. pulmonary vaso-occlusion or fat emboli).
Is a medical emergency with a high mortality and requires prompt supportive management and treatment of the underlying cause:
Antibiotics or antivirals for infections
Blood transfusions for anaemia
Incentive spirometry using a machine that encourages effective and deep breathing
Artificial ventilation with NIV or intubation may be required
management of sickle cell
Cord blood taken at birth
Ensure vaccination up to date
Avoid dehydration and other triggers of sickle cell crisis
Pneumococcal prophylaxis (vaccine +/- penicillin V)
Hydroxycarbamide to stimulate HbF production which does not lead to sickling of RBCs (protective against sickle cell crisis and acute chest syndrome)
Blood transfusions for severe anaemia
Bone marrow transplant can be curative
Referral to hematologist for chronic management
Prevention: genetic counselling, parental tests and education can prevent 90% deaths form crisis
acute sickle cell crises protocol:
- analgesia
- haematologist early intervention
- septic screen: blood cultures, MSU, CXR
- rehydrate with IV fluids and keep warm
- oxygen PRN
- consider early empirical antibiotics if temperature, unwell or chest signs
aplastic anaemia
Condition where the body does not produce enough blood cells
Leaves the patient fatigued, prone to infection and uncontrolled bleeding
Rare and serious condition, can develop at any age, suddenly or gradually worsen over time, can be mild or severe
Can be short term or develop into chronic condition
Cause:
radio/chemotherapy
Exposure to toxic chemicals like pesticides, insecticides, benzene
Use of certain drugs (RA and some antibiotics)
Autoimmune disorders
Viral infection: hepatitis, epstein-barr, cytomegalovirus, parvovirus B19 and HIV
Pregnancy
Idiopathic
Associations:
Paroxysmal nocturnal hemoglobinuria: RBCs break down too soon which can lead to aplastic anaemia or vice versa
Fanconi’s anaemia (rare) inherited disease that leads to aplastic anaemia. Tend to have many birth defects
risk factors for aplastic anaemia and presentation
radio/chemotherapy Exposure to toxic chemicals Drugs Family history Pregnancy (rare)
Symptoms: Fatigue SOB Rapid irregular HR Pallor Frequent or prolonged infections Unexplained or easy bruising Nosebleeds or bleeding gums Prolonged clotting time Skin rashes Dizziness Headache Fevers
diagnosis of aplastic anaemia and management
Diagnosis:
Bloods: FBC (RBC, WCC, platelets all decreased)
Bone marrow biopsy (few blood cells present)
Management:
Depend on age and severity of condition
Anaemia caused by radio or chemotherapy may cease with treatment cessation
Pregnant women treated with blood transfusions and often improves once pregnancy ends
Severe is life threatening and needs immediate hospitalisation
Blood transfusion of RBC and platelets (complications can arise from multiple transfusions)
Stem cell transplant
Immunosuppressants (gengraf, noral, sandimmune), steroids (methylprednisolone)
Bone marrow stimulants: sargramostim, filgrastim, pegfilgrastim often used with immune suppressing drugs
Antibiotics and antivirals prophylaxis
coeliac disease
Multi Genetic disorder associated with HLA types DQ2 (90%) or DQ8, plus other genetic or environmental factors.
Family tendency 10-15%
Approx 1 in 100 people in the UK have coeliac disease, however only 10-20% will be diagnosed
Highest incidence in ages 50-69
coeliac disease presentation
wide variation of signs and symptoms, many cases are asymptomatic
Persistent unexplained abdominal or GI symptoms
Faltered growth
Unexpected weight loss
Severe or persistent mouth ulcers
Unexplained iron, vit B12 or folate deficiency
Type 1 diabetes
Autoimmune thyroid disease
IBS in adults
1st degree relatives of people with coeliac disease
Dermatitis herpetiformis (classic manifestations of CD)
Gluten sensitivity
NICE recommends serological testing for coeliac disease in people with the following:
Metabolic bone disorder
Unexplained neuro symptoms (ataxia, epilepsy, dementia, depression)
Unexplained subfertility or recurrent miscarriage
Persistently raised liver enzymes without known cause
Dental enamel defects
Down’s or Turner syndrome
All newly diagnosed type 1 diabetics are screened for coeliac disease*
coeliac disease investigations
only accurate if gluten diet is eaten during diagnostic process
Autoantibodies: total IgA and tTG 1st line. IgA EMAs if weakly positive.
For children: total TgA and IgA tTG 1st line. IgG EMA, IgG DGP or tTG if IgA is deficient
FBC: anaemia, iron and folate deficiency, B12, ferritin, LFTs (elevated transaminases which should return to normal on gluten free diet), Ca and albumin
Small bowel barium studies to exclude other causes of malabsorption
Biopsy needed for confirmation by GI endoscopy or suction capsule
coeliac disease referrals and management and complications
Referrals to GI specialist:
Young people with +ve serological tests for endoscopic biopsy
Children with +ve serology to paediatric specialist for further investigation
-Ve serology to gastro specialist if CD still suspected for further investigation
management:
Gluten free diet (no wheat, barely, rye, bread, cakes etc) seems to be only effective treatment
Refractory CD: consider prednisolone initial management while waiting specialist advice
If after GFD excluded but symptoms persist/serology is high for >12 months refer for endoscopic biopsy
Annual review to measure weight, height, review symptoms, assess diet and adherence, need for specialist dietitian or nutritional advice
Consider DEXA scan, regular bloods for long term complications monitoring
complications: Deficiencies eg vit D and iron Osteoporosis Cancer Ulcerative jejunitis Functional hyposplenism Anxiety, depression Male infertility Poor foetal outcome in UNDIAGNOSED pregnancy women, but not diagnosed
anaemias
Medical condition in which RBC count and/or Hgb is less than normal
Not a disease in itself instead may reflect underlying disease process and must be considered in relation to patients age and gender
Hb <13.5g/dl (adult male) or <11.5g/dl (adult female), varies in children based on age group
Aetiology:
Decrease in RBC production: iron & B12 deficiencies, aplastic anaemia, CKD (decreased erythropoiesis)
Increase in RBC destruction: sickle cell anaemia, G6PD deficiency, spherocytosis,
Increased RBC loss: bleeding (acute or chronic)
classification of anaemias
FBC: Hb level (men <13.0g/dl; female 11.5 g/dl; pregnancy - 11g/dl ((dilutional effect from increased circulating plasma making RBC % smaller in proportion)))
MCV (blood film): microcytic anaemia (MCV <80 femtolitres), normocytic (MCV 80-100 femtolitres), macrocytic anaemia (MCV >100 femtolitres); always look at these values when someone is presenting with anaemia (Low Hb); these values may vary based on labs so always look at reference ranges
Classification based on aetiology:
Nutrient deficiency or depletion (most common worldwide): iron Fe, folate def, B12 def.
Blood loss: acute (reticulocytosis (6hrs) causing normocytic anaemia) or chronic (ongoing iron loss causing microcytic anaemia)
Acquired bone marrow disease: aplastic anaemia (inherited bone marrow failure), autoimmune destruction of bone marrow cells
Chronic systemic disease: normocytic anaemia or in severe cases microcytic anaemia when coexisting with iron deficiency anaemia
Chronic kidney disease: main cause is decreased erythropoietin production leading to decrease RBC production causing norm/microcytic anaemia
Chronic liver disease: intravascular dilution leading to macrocytic anaemia
Autoimmune haemolytic anaemia: RBCs attacked by autoantibodies causing destruction (SLE, RA or scleroderma)
Genetic disorders (haemoglobinopathies): thalassaemias: group of autosomal recessive conditions resulting in decreased/absent alpha globin (alpha thalassaemia) or beta globin chains in the Hb molecule. Leads to RBC destruction and hemolytic anaemia. Sickle cell: haemolytic anaemia.
causes of microcytic anaemia
TAILS Thalassaemia Anaemia of chronic disease Iron deficiency anaemia Lead poisoning Sideroblastic anaemia
causes of normocytic anaemia
3As 2Hs: Acute blood loss Anaemia of chronic disease Aplastic anaemia Haemolytic anaemia Hypothyroidism
causes of macrocytic anaemia
(deficiencies)
B12 deficiency
Folate deficiency
Normoblastic macrocytic: DARHL Drugs such as azathioprine Alcohol Reticulocytosis (usually from haemolytic anaemia or blood loss) Hypothyroidism Liver disease
anaemia presentation
Very nonspecific pallor/jaundice Fatigue Dyspnea Palpitations Anorexia Headaches Features of underlying disease Pica: dietary craving for inedible things like clay, dirt etc. Hair loss - iron deficiency anaemia
Signs:
Koilonychia is spoon shaped nails and can indicate iron deficiency
Angular chelitis can indicate iron deficiency
Atrophic glossitis is a smooth tongue due to atrophy of the papillae and can indicate iron deficiency
Brittle hair and nails can indicate iron deficiency
Jaundice occurs in haemolytic anaemia
Bone deformities occur in thalassaemia
Oedema, hypertension and excoriations on the skin can indicate chronic kidney disease
anaemia investigations
Hb level
Blood film: MCV, MCH, MCHC
Haematocrit (Hct) aka packed cell volume (PCV): measures proportion of blood:other cells
Haemoglobin electrophoresis: screen test to identify normal and abnormal Hb and assess quantity
Coeliac serology: presence of anti-endomysial antibody or tissue transglutaminase antibody for patient with iron deficiency anaemia (IDA)
FIT for those >50, IDA, weight loss OR <60 with abdominal mass
Blood serum level of ferritin, total iron binding capacity (TIBC), iron, B12 and folate
Reticulocyte count: normal 2%: quantitative measure of concentration of immature RBC in circulation. If LOW: due to decreased production such as bone marrow disease (aplastic anaemia). If elevated: reflects bone marrow response to increased RBC destruction (haemolysis). Means the bone marrow producing RBCs too fast resulting in mass immature RBCs (reticulocytes)
OGD and colonoscopy to investigate for GI cause of unexplained iron deficiency anaemia (urgent referral)
Bone marrow biopsy is cause unclear
Target cells - abnormal RBC seen in liver disease, normal shape but abnormal centre. Nonspecific sign for abnormal RBC production
iron studies
serum iron: measures circulating iron most of which bound to transferrin. low in iron deficiency anaemia but also anaemia of chronic disease
total iron binding capacity TIBC: circulating transport protein for iron.
Low iron = high binding capacity due to need for it
High iron = low binding capacity
transferrin saturation (TSAT): ratio of serum iron to TIBC. decreased in iron deficiency anaemias
ferritin: circulating iron storage protein. also an acute phase reactant increases independently of iron storage in inflammatory disorders, infection, liver disease, heart failure and malignancy
Very low iron deficiency anaemias
can be normal in severely iron deficient patients who are very unwell
sickle cell and beta thalassaemia Hb electrophoresis
Foetal haemoglobin = HbF
Up to 6 months switches to HbA and HbA2 (adult Hb)
The majority is HbA; around 2% is HbF and HbA2
Sickle cell: presence of HbS cells instead of HbA as majority
Beta thalassaemia: majority of RBCs remains HbF with little HbA and HbA2
diagnostic pathway for anaemias
FBC and peripheral blood smear examinations:
MCV <80 - microcytic anaemia
Request serum iron studies - low iron and ferritin with high TIBC - iron deficiency anaemia.
If low/normal iron and low/normal ferritin with low TIBC - suggests component of anaemia of chronic disease with iron deficiency anaemia
MCV 80-100 - normocytic anaemia.
Request reticulocyte count - if <2% (hypoproliferative) - suggests leukaemia, aplastic anaemia, pure RBC aplasia or other bone marrow failure syndromes
If >2% (hyper proliferative) - suggests haemorrhage or haemolytic anaemias
MCV >100 (macrocytic anaemia) - are the cells megalocytes and segmented neutrophils on peripheral smear??
If present megablastic - suggests vitamin B12 and/or folate deficiency or drug induced anaemia
If absent: non-megaloblastic. suggests alcohol abuse, myelodysplastic syndrome, liver disease, congenital bone marrow failure syndromes
macrocytic anaemias
Megaloblastic:
B12 deficiency
Folate deficiency
Non-megaloblastic: Reticulocytes Liver disease Hypothyroid Pregnancy
vitamin B12 deficiency
Hydroxocobalamin
Vitamin B12 deficiency: causes macrocytosis. DNA synthesis requires B12 cofactor therefore deficiency leads to decreased erythrocyte DNA synthesis resulting in macrocytosis.
Hydroxocobalamin body stores are sufficient to last for anywhere between 2-5 years depending on need. Absorbed in the ileum after binding to intrinsic factor
Crohn’s disease is most likely IBD cause of B12 deficiency as this affects the entire GIT NOT ulcerative colitis as this is limited to the colon only
Serum cobalamin (B12) of <200nanograms/L (148 picomol/L)
In elderly B12 may be 10-160 picomol/L with no anaemia
Women taken OCPs may have lower B12 but no anaemia
causes of vit B12 deficiency
Dietary deficiency is rare and usually only occurs in elderly, those on strict vegan or vegetarian diets
Other causes of B12 deficiency: lack of intrinsic factor in patients who have undergone gastrectomy or have pernicious anaemia
Malabsorption of B12 secondary to small bowel bacterial overgrowth, tapeworm, ringworm, familial factors, Crohn’s, celiac or drugs like PPIs, metformin or H2 receptor antagonist.
Crohn’s disease is most likely IBD cause of B12 deficiency as this affects the entire GIT NOT ulcerative colitis as this is limited to the colon only
Pernicious anaemia: autoimmune condition affects the gastric mucosal lining leading to mucosal atrophy. Reduced number of parietal cells which secrete intrinsic factor (IF) which is essential for Vit B12 absorption. If +ve they definitely have anaemia, but if -ve recheck in 12 months or so to see if Abs have developed. Or anti parietal cell antibodies are present (can be present in elderly without pernicious anaemia)
People with pernicious anaemia are at increased risk of gastric cancer and thyroid disease so must be screened for thyroid function annually and have regular colonoscopy/any bowel red flags immediately investigated
vit B12 deficiency presentation
Fatigue Weakness Irritability Exercise intolerance Exertional dyspnoea (concerning at rest) Neuro involvement: Loss of cutaneous sensation Muscle weakness Optic neuropathy Vertigo Psychiatric disturbance: mild neurosis to severe dementia Symmetrical neuropathy, affecting legs more than arms Ataxia Paraesthesia
vit B12 deficiency investigations
FBC: macrocytic anaemia with hypersegmented neutrophils and/or oval macrocytes
Serum Vitamin B12 <200ng/L or high clinical suspicion on vit B12 deficiency. B12 acts as a coenzyme that converts MMA to other substances; therefore is increased in B12 def. And can indicate functional B12 deficiency. However in CKD this is always elevated so must only be used in renal functioning pts.
Non dietary cause suspected: intrinsic factor antibodies (IFAB)
vit B12 deficiency management and complications
Based on vit B12 level (<200ng/l) and presence/absence of neurological symptoms
No neurological symptoms: IM hydroxocobalamin 1mg 3 x weekly for 2 weeks
If dietary cause: oral cyanocobalamin 50-150mcg daily (OTC) and dietary advice for B12 rich foods (eggs, meat)
Non-dietary cause: IM hydroxocobalamin 1000mcg every 3 months for life
Neurological involvement: urgent referral to haematology, loading dose vit B12 (hydroxocobalamin 1mg IM STAT every other day)
Complications of Vit B12 deficiency:
Neurological symptoms: paraesthesia, ataxia, progressive symmetrical neuropathy which affects the legs more than the arms, numbness, poor motor coordination, memory lapses, age related impairment
Severe psychiatric symptoms (rare)
folate deficiency
Folate is also needed as a cofactor in DNA synthesis. Folate deficiency can be caused by: dietary deficiency, increased need in pregnancy, congenital deficiency, alcoholism, increased turnover in conditions like haemolysis or SCD etc.
Serum folate of <7 nanomol/L (3micrograms/L) is used as a guide to indicate folate deficiency. 7-10 is indicative of deficiency but not diagnostic of anaemia
Folate is absorbed through upper part of small intestine (again only crohn’s could cause not ulcerative colitis) and stores last around 4 months
Causes:
Pregnancy
Malignancy e.g. leukaemia, lymphoma
Blood disorders (SCD, haemolytic anaemia)
Drugs: nitrofurantoin/trimethoprim, anticonvulsants, methotrexate
Malabsorption: IBD (crohn’s only) and reduced dietary intake
folate deficiency investigations and management
Serum folate (only reflets recent stores) MUST test B12 levels also due to risk of subacute combined degeneration of spinal cord, secondary to vitamin B12 deficiency. Presents with weakness of legs, arms, tingling and numbness progressively worsen, visual changes, psychiatric changes.
management:
Folic acid 5mg PO OD for 4 months, reassess iron studies and reduce to maintenance dose of 5mg every 1-7 days
iron deficiency anaemia
Affects large portion of the population especially women of childbearing age and those in low/middle income countries
You can be iron deficiency without anaemia
Normally 4-5 g iron in the body with no mechanism to regulate its excretion
Can be toxic in excess so absorption is controlled
25% stored in reticuloendothelial systems as protein complexes, ferritin and hemosiderin
0.1% bound to transferrin in plasma
4.9% in myoglobin, cytochromes and other enzymes
Majority is used to make haemoglobin
Causes:
Blood loss: GI (malignancy, telangiectasia, gastritis), menorrhagia (common cause), pregnancy or haematuria
Reduced intake: unlikely in western world (neglect)
Reduced absorption: coeliac disease, autoimmune gastritis or H. pylori infection
always assess for malignancy to rule out first
iron deficiency anaemia pathology
Pathology:
Iron stores begin to deplete but no anaemia initially due to storage use. May show mild fatigue without any gross Hb changes. MCV and MCH normal
Ferritin (storage) begins to fall, Hb remains stable and MCV/MCH remain normal
Mild anaemia (Hb >100g/l) and mild hypochromia (reduced MCH - always look at this!)
Moderate anaemia and hypochromia (reduced MCH) and microcytic (reduced MCV)
iron deficiency anaemia presentation
Fatigue Weakness Irritability Exercise intolerance Exertional dyspnea Headache Vertigo Angina like symptoms Pica: compulsion to eat substances not fit as food (clay/dirt) or craving ice Conjunctival pallor Angular stomatitis Atrophic glossitis (red, shiny tongue) Koilonychia (spoon nails)
iron deficiency anaemia investigations
Bloods: FBC (MCH, MCV, MCHC) blood film Ferritin: low in iron deficiency anaemia but can be normal in SEVERELY iron deficient patients who are very unwell (acute phase reactant goes up in inflammatory condition; doesn’t stay raised in chronic disease). LOW = all stores depleted. CRP of >5 considered chronic inflammation. Must always get CRP done with ferritin to take the whole picture into account and work out if ferritin is reflective or inflammation or iron stores. Can also use ESR; if CRP normal but high clinical suspicion of infection Serum iron: can be normal or low in iron deficiency so not very reliable Total iron binding capacity/serum transferrin: high in iron deficiency (strong hold due to lack of Fe) and low in anaemia of chronic disease Transferrin saturation (TSAT): decreased in iron deficiency anaemia (<20% may respond to iron therapy) Staining shows small (microcytic) and oxygen deficient cells (light stain) OGD and colonoscopy to investigate for GI cause of unexplained iron deficiency anaemia (urgent referral)
red flags to rule out before diagnosing iron deficiency
Iron deficiency anaemia is a SIGN not diagnosis (at first):
MUST RULE OUT UNDERLYING CAUSES:
GI Red flags: New onset indigestion New change in bowel habit Blood in stool Melaena New IBS in elderly
Gynaecological
Menstrual history
Pregnancy
Urological
Haematuria
Other Anticoagulants Telangiectasia Coeliac disease IBD **if someone has recently started anticoagulant DOAC then has life threatening or sudden increase GI bleeding it can often be an early sign of bowel cancer!!**
NICE referrals guide:
urgent (2WW) referral 60 + with iron def. anaemia
aged 50+ in those with iron def. anaemia and rectal bleeding
urgent colonoscopy in 55+ YO iron def. anaemia newly diagnosed patient.
refer all men and postmenopausal women with IDA unless they have overt non-GI bleeding
All people 50+ with marked anaemia or significant family history of colorectal carcinoma
premenopausal women if <50 YO with colonic symptoms, strong family history of GI cancer or persistent IDA despite treatment
refer to gynaecology for menorrhagia unresponsive to medical management or any postmenopausal bleeding irrespective of age
management of iron deficiency anaemia
(BNF says 3x daily 200mg) but clinical practice: Ferrous sulphate 200mg one tablet every other day/daily for 3 months (better iron absorption as only 60mg can be absorbed in 24 hours with fewer side effects) OD for anaemic patients and every other day for non-anaemic patients but iron deficient. Side effects GI upset and nausea and vomiting. Do not take with food, take separately from Ca containing foods and drinks (milk), Ca supplements, cereals, dietary fibres, tea, coffee and eggs. Antacids/PPIs may reduce absorption. Ascorbic acid tablets (or half glass orange juice) with iron enhances absorption. Not suitable for those with inflammatory conditions or malabsorption conditions (RA, IBD etc.) or those genuinely intolerant of oral iron
1g IV ferric carboxymaltose on week 1, reassess Hb then 500mg IV week 3, reassess iron stored/ferritin on week 6. Side effects rash, anaphylaxis and skin staining
Follow up with underlying conditions and to assess medications (usually 1 week)
NEVER transfuse young females who are IRON DEFICIENT unless they are clinically compromised (vitals poor)/Hb <70g/L!!
Once transfused once in UK can no longer donate blood anywhere in the world
Coping with side effects of iron tablets:
N&V, stomach pain or heartburn: take ferrous sulfate with or just after meal or snack. Stick to simple meals no rich or spicy foods
Constipation: each high fibre foods, exercise regularly, talk to pharmacist/doctor about laxative options
Dark/black stool: normal and nothing to worry about. Safety net for black and sticky looking stool, red streaks in it or feel unwell in any other way
microcytic anaemias Ix ad how to differentiate between them
MCV low then also need:
Serum iron level
Serum ferritin: also acts as acute phase reactant protein and rises in malignancy, so is useful to assess iron storage in healthy patients but NOT sick patients
Total iron binding capacity (TIBC)
How to differentiate between microcytic anaemias:
Iron deficiency anaemia
TIBC - Increased
serum iron - reduced
serum ferritin - reduced
Chronic inflammation/malignancy
TIBC - reduced
iron - reduced
ferritin - normal/increased
Thalassemia (alpha or beta)
TIBC - normal
iron - normal/increased
ferritin - normal
thalassaemia
Inherited blood disorder characterised by abnormal hHb production
Patients have defect in either alpha or beta chain of Hb causing production of abnormal RBCs and resultant anaemia
Most common in mediterranean, middle east, southern china, south/central/southeast asia
Classification based on chain affected:
Alpha thalassaemia: mutation in alpha globulin on chromosome 16 results in reduced alpha chain production. Carriers of condition are more common. Mostly asymptomatic no treated needed however need to be aware for genetic testing for their children who may receive homozygous
Beta thalassaemia: from mutation in beta globulin on chromosome 11 reduced B chain production. Can be transfusion dependent or non transfusion dependent based on stage.
beta thalassaemia classification
minor (trait): carrier state, asymptomatic or mild well tolerated with Hb >90g/l
intermedia: mild symptoms if present, moderate intermittently tolerated Hb >80g/l
does NOT usually need transfusions to maintain Hb
major: severe and symptomatic. presents in first year of life with severe anaemia and failure to thrive
extramedullary haematopoiesis: splenomegaly and skull bruising
life long blood transfusions needed. iron overload can cause heart issues, pancreatic issues (diabetes) and endocrine dysfunction
sideroblastic anaemia
Anaemia where bone marrow produces ringed sideroblasts (erythroblasts with iron loaded mitochondria) therefore can only be seen in bone marrow biopsy
Body has enough iron but due to genetic or acquired defects is unable to incorporate the iron into RBCs leading to anaemia
Can be congenital or acquired
Congenital: X linked disorder, mitochondrial disorders, pearson syndrome
Acquired: myelodysplastic syndrome (MDS), copper deficiency, alcohol, TB treatment, idiopathic
haemolytic anaemia
Premature destruction of RBCs
Causes often overlap and can get acute and chronic forms of most causes (flare ups)
Pathology:
increased unconjugated bilirubin from increased breakdown of haem
Broken down globins mopped up by haptoglobin by binding
Measure haptoglobin levels (free unbound to RBCs) therefore decrease and become low in haemolytic anaemia
Raised LDH also sign of haemolytic anaemia
Increased count of reticulocytes due to needing to to replace cells faster
Causes: Inherited Defects of RBC membrane production: Hereditary spherocytosis Defects in haemoglobin production Thalassaemia Sickle cell anaemia Defective RC metabolism G6PD deficiency (can be triggered by drugs eg malarial) Pyruvate kinase deficiency
Acquired: Mechanical hemolytic anaemia: Mechanical heart valves Immune causes: Mycoplasma infection Autoimmune: SLE, RA, Hodgkin’s lymphoma, Chronic lymphocytic leukaemia (CLL)
Autoimmune (DAT +ve)
Extravascular
Intravascular
Non-autoimmune (DAT -ve)
Important to differentiate between auto and non-autoimmune as auto are more at risk of cancers
autoimmune haemolytic anaemia
Autoimmune haemolytic anaemia occurs when antibodies are created against the patient’s red blood cells. These antibodies lead to destruction of the red blood cells. There are two types based on the temperature at which the auto-antibodies function to cause the destruction of red blood cells.
warm AIHA due to AB that is active at normal body temperature - anti IgG
cold hemagglutinin disease (CHAD) is due to ABs that cause RBC agglutination and hemolysis at temperatures below body temp (extremities) - anti C3d AB
direct antiglobulin test (Coombe’s test) for ABs against RBC:
detects presence and strength of anti-IgG and anti-C3d to determine which autoimmune type they have
Need to assess for warm or cold as treatment varies massively depending on this.
Warm will respond to steroids while cold will not and needs rituximab immune suppressants instead
Warm type autoimmune haemolytic anaemia is the more common type. Haemolysis occurs at normal or above normal temperatures. It is usually idiopathic, meaning that it arises without a clear cause.
Cold Type Autoimmune Haemolytic Anaemia:
This is also called cold agglutinin disease. At lower temperatures (e.g. less than 10ºC) the antibodies against red blood cells attach themselves to the red blood cells and cause them to clump together. This is called agglutination. This agglutination results in the destruction of the red blood cells as the immune system is activated against them and they get filtered and destroyed in the spleen. Cold type AIHA is often secondary to other conditions such as lymphoma, leukaemia, systemic lupus erythematosus and infections such as mycoplasma, EBV, CMV and HIV.
Management of autoimmune haemolytic anaemia:
Blood transfusions
Prednisolone (steroids)
Rituximab (a monoclonal antibody against B cells)
Splenectomy
haemolytic anaemia investigations
Hb low MCV high reticulocytes elevated heptoglobin decreased bilirubin increased conjugated bilirubin low LDH raised (by-product of RBC breakdown)
Normocytic anaemia
Blood film shows schistocytes (fragments of RBCs)
Direct Coombes test is positive in autoimmune cause
normocytic anaemia (anaemic of chronic disease)
Underlying disease/chronic inflammation
Increases IL-6 and other Inflam cytokines in liver
Increases hepcidin production which prevents iron absorption in bowel and/or has an inhibitory effect reducing erythropoietin stimulation in bone marrow leading to decreased erythrocyte formation
Important to distinguish between which pathway is occurring as to know if patient will respond to iron replacement (IV iron in absorption problems) or if they need bone marrow stimulation
thrombocytopenia
Low platelets
Liver produces thrombopoietin which regulates platelets production
Travels to bone marrow and circulating TPO binds to TPO receptor which causes cells to absorb the TPO and remove it from the blood
There is no direct negative feedback on the liver so always produces at a steady rate
Therefore can have production problem if liver disease
Or bone disease can cause problem with TPO absorption
There is very little variation in platelet count in single individual (due to continuous liver production) therefore a change by 98 x10(9) should prompt investigation even if they’re still within the normal range
classification:
NORMAL range: 150-400
MILD: 100-149, can be managed without referral
MOD: 50-99, may same day need referral if signs of active bleeding
SEVERE: <50, same day referral
ITP: <30, medical emergency
thrombocytopenia causes
Chronic liver disease
Medications: Antibiotics (piperacillin, vancomycin, rifampicin,) Antiepileptics Quinine Metformin (causes vitamin B12 def.) PPI (reduced nutrient absorption) Heparin induced (HIT) Cytotoxics (chemotherapy)
Alcohol
Nutritional deficiencies
Bone marrow disorders: Leukaemia
Lymphoma
Myeloma
Myelodysplastic syndrome
Autoimmune
Infections: Viral: HIV, hepatitis B/C, CMV and EBV, MMR, parvovirus
thrombocytopenia by infection
Viral: HIV, hepatitis B/C, CMV and EBV, MMR, parvovirus cause megakaryocyte apoptosis, platelet activation and consumption and direct TPO reduction from liver injury
Acute: thrombocytopenia can resolve spontaneously after virus has cleared
Chronic: HIV directly toxic to megakaryocytes causes secondary ITP. primary HIV associated thrombocytopenia (PHAT)
Cytomegalovirus reactivation due to immune suppression
Hepatitis B same mechanism as liver disease
Bacterial: direct bone marrow suppression in severe sepsis (mycoplasma, H. pylori, tick borne infections)
heparin induced thrombocytopenia
Thrombocytopenia following exposure to heparin
Rapid production of IgG antibodies with ABSENCE of IgM ABs; suggesting secondary immune response (IgG - long term memory)
Anyone who goes into hospital gets put on heparin prophylaxis LMWH to avoid clotting and VTE/PE/DVT, these are considered never events in hospital so must be on anticoagulants
Some people respond very badly to heparin
IgG long term memory Ab suggesting overactivation of immune system triggered by heparin
Doesn’t really happen with fondaparinux and sometimes this can be treatment
HIT diagnosis
Received heparin within <100 days (typically 5-10 days)
Recent venous/arterial thrombosis
Recent orthopaedic/CV surgery (most commonly)
Absence of other cause: sepsis, medications
Absence of bleeding (no/minimal petechiae/ecchymosis)
+ Thrombocytopenia (50% drop in platelet count - does not need to be below limit)
Risk assessment: 4Ts score for HIT: Degrees of thrombocytopenia Timing of platelet count fall Thrombosis or other sequelae Other causes for thrombocytopenia
bleeding history taking
Gum bleeding: active or stopped?
Epistaxis: bi or unilateral? Unilateral suggests the bleed is probably small, more proximal bleed (vessel) pressure likely to stop. Bilateral suggests more distal source of bleed and likely more sinister cause
Skin: petechiae/bruising? Was the bruising spontaneous or traumatic? (safeguard abuse)
GI: upper or lower GI bleed signs? Upper GI: normal creatinine or raised? (breaking down muscle)
CNS: new headache or seizure?
Anaemia: acute or chronic?
coagulation status and referrals
Mild: 149-100
Moderate: 99-50: not bleeding actively then refer to haematology (send first line of bloods and coagulation screen). If actively bleeding signs present then same day referral with haematology
Platelet count >50 then bleed probably not caused by platelets so check other coagulation factors: INR, aPTTr and fibrinogen
Severe - <50; platelets are potential cause of bleeding and platelet transfusion may be indicated. Needs a same day referral for review by haematology
blood film results for thrombocytopenia, MDS and AML,ALL,
True thrombocytopenia: anisocytosis/clumping is seen
MDS myelodysplastic syndrome: shows hypogranular platelets, dysplastic neutrophils and macrocytosis
Acute leukaemia (AML/ALL): shows circulating peripheral blasts, auer rods/promyelocytes
thrombocytopenia investigations
blood film
Haematinics:
Iron studies: iron level, TIBCm TSat and ferritin
Vitamin B12: serum +/- MMA
Serum folate
Liver and bone profile:
LFTs: raised ALP, ALT and GGT
Calcium: raised calcium can indicate malignancy
Virology: HIV Hepatitis B/C antigens and ABs EBV IgG, IgM CMV IgG, IgM
Specialist tests:
Myeloma screen: serum protein electrophoresis, serum free light chains
Hep2ANA (autoimmune screen): Particularly SLE autoimmune screening
Always look for blood tests done previously to use as a baseline
Normal for reticulocytes to increase in anaemia as this is to compensate in anaemic patients
Severe decreased platelets and signs of active bleeding - super concerning
In absence of active bleeding then they’re not dying but still need urgent referral
immune throbocytopenia and diagnosis
Isolated thrombocytopenia (without clear cause)
Presents with tiny, circular non-raised patches that appear on skin or mucosal membranes <5mm (PETECHIAE)
Wet petechiae seen on soft palate
Purpura: tiny circular non-raised patches on skin or mucous membranes 5-9mm
Mucosal bleeding from nose or gums
Diagnosis of exclusion based on finding no other cause for low platelets
Add in childrens management from ppt
ITP adult management
Acute setting:
High dose steroids (dexamethasone 40mg PO OD for 4 days
OR prednisolone 1mg/kg taper off for four weeks. Problem with prednisolone is usually symptoms come back during weaning process so can be on steroids for months instead of weeks so more likely to have long term steroid effects
IV Igs if steroids CI or not tolerated. Risk of transmittable disease/reaction (same as blood transfusion and can no longer ever donate blood products. Used if steroids don’t work/aren’t tolerated
If platelet count is not rising within 3 days then challenge with alternative therapies or another round of same therapy
Is possible after multiple therapies to lose responsiveness to treatment therefore is not good for chronic cases to receive multiple acute setting managements
Patients with ITP will never have normal platelet count as long as above 30 that’s good
Only below 30 will they use acute treatment because of the risk of losing response to therapies
Long term therapies:
Azathioprine OR mycophenolate mofetil (MMF)
TPO agonists (eltrombopag daily tablet or romiplostim weekly injection). Still only aiming for platelet target of 50-100 in these patients not normal amount
Immunomodulatory medications like rituximab can help put people into remission for several years, need special funding for it due to expense and length of treatment
Emergency:
Platelet transfusion if major active bleed
Patient will have destroyed all platelets given within 6-8 hours so very important to also establish acute setting management to follow up and ensure bleeding doesn’t resume
thrombotic thrombocytes purpura (TTP)
Medical emergency
Very rare, more common in females, statin use and pregnancy
Often screen for cancers as well as can be associated with some cancers
Pathophysiology:
Von Willebrand factor increases clot formation
ADAMTS13 responsible for splitting von Willebrand factor
In TTP there is an ADAMTS13 deficiency meaning there is inappropriate intravascular clot formation causing thrombosis AND thrombocytopenia
Causes multi organ failure from clot formation
Microtears of vessels and bleeding symptoms develop once platelets have been used up
WORST OF BOTH
TTP investigations and management
Investigation:
CT exclude haemorrhagic stroke, consider ischaemic if no sign of haemorrhage
Bloods
Management:
Immediate transfer to critical care/ICU at a TTP centre; avoid delaying for further ix unless life threatening
DO NOT give platelets - causes increased clotting and more ischaemia and DO NOT transfuse TTP patients unless there is active haemorrhage/life threatening - seek haematologist 222 crash call
Gain central venous access (very large bore) give daily plasma exchange (until platelets are >150 for 2 consecutive days)
Immunosuppression: high dose steroids (methylprednisolone) or MMF
Anticoagulation once platelets reach >50 with LMWH or aspirin
platelet targets for platelet transfusions and procedures
> 10 - all patients; routine dentistry
> 20 - sepsis/acutely unwell (incl. T. 38+)
> 30 - dental extraction
> 50 - surgery/invasive procedure. anticoagulation of any kind
> 80 (>100) - ocular or neurosurgery
As long as there’s no signs of active bleeding: ALWAYS CHECK
ocular/neuro guideline is 80 but clinical practice is >100 to ensure they don’t fall below 80 as once below 80 is irreversible
myelodysplastic syndrome
bone marrow disease in elderly
Rare group of disorders where the body no longer produces enough healthy RBCs/produces dysplastic and ineffective RBCs
Can cause cytopenia, bicytopenia or pancytopenia
Sometimes called bone marrow failure disorder and is a type of cancer
Most patients are >65 YO and is more common in men
Can range from mild-severe presentations varying on type, individual etc.
May be asymptomatic in early stages or progress to fatigue and dyspnea
Stem cell transplants is only curative treatment but many treatments to improve symptoms, quality of life and life expectancy
In some types of MDS only one type of blood cell is affected but in other multiple can be affected
Some MDS types will develop into acute myeloid leukaemia
Risk factors: Chemotherapy Acute lymphocytic leukaemia in childhood Hodgkin's disease Non-hodgkin lymphoma Smoking Benzene contact (in plastics, dyes, detergents etc) Down’s syndrome, fanconi anemia, bloom syndrome, ataxia telangiectasia
MDS presentation and diagnosis
Presentation: Constant fatigue Unusual bleeding Bruising and red marks under skin Pallor Dyspnoea Macrocytic anaemia and mild thrombocytopenia that progresses
Diagnosis:
Physical exam
Blood sample: FBC, MCV, ferritin, iron studies
Bone marrow biopsy/sample and genetic analysis
MDS management
Observations and monitoring condition
Chemotherapy drugs for leukaemia
Immunosuppressive therapy
Blood transfusions
Iron chelation to reduce excess mineral
Growth factors to encourage natural bone marrow erythropoiesis
Stem cell transplant is only curative treatment
leukaemia
Group of blood cancers which are characterised by accumulation of malignant WBCs in bone marrow often spill out into peripheral blood
Acute leukaemia: aggressive forms. Damage to immature (blasts) WBCs either the haematopoietic stem cells itself or one of it’s early progenitors. Often present with patients acutely unwell.
4 main types: All Cell Mates have Common Ambitions
AML: acute myeloid leukaemia
ALL: acute lymphoblastic leukaemia
CLL: chronic lymphoblastic leukaemia
CML: chronic myeloid leukaemia
Pathology:
Leukaemia is a form of cancer of the cells in the bone marrow. A genetic mutation in one of the precursor cells in the bone marrow leads to excessive production of a single type of abnormal white blood cell.
The excessive production of a single type of cell can lead to suppression of the other cell lines causing underproduction of other cell types. This results in a pancytopenia, which is a combination of low red blood cells (anaemia), white blood cells (leukopenia) and platelets (thrombocytopenia).
acute myeloid leukaemia (AML)
Acute myeloid leukaemia is the most common acute leukaemia in adults. There are many different types of acute myeloid leukaemia all with slightly different cytogenetic differences and differences in presentation.
It can present at any age but normally presents from middle age onwards. It can be the result of a transformation from a myeloproliferative disorder such as polycythaemia ruby vera or myelofibrosis.
A blood film will show a high proportion of blast cells. These blast cells can have rods inside their cytoplasm that are named Auer rods.
AML presentation
pancytopenia (anaemia, thrombocytopenia and leucopenia)
anaemia: SOB, fatigue, palpitations, chest pain, paraesthesia
thrombocytopenia: petechaie, purpuric rash, easy bruising, bleeding
leucopenia: recurrent infections, sepsis, very low WCC OR really high WCC from machine misreading blasts as mature WCs
Most common symptoms in the lead up to diagnosis: seeing more than one of these in same patient think of FBC investigations to look for decreasing no. of cells and look into underlying cause before they present septic into A+E : fatigue fever bruising or bleeding repeated infections feeling weak or SOB joint or bone pain
AML investigations
FBC: cytopenias (reduction in one of 3 cell lines eg low Hb) or pancytopenia (reduction in all 3 cell lines) - anaemia, thrombocytopenia and neutropenia
Blood film: circulating peripheral blasts
Biochemistry: elevated LDH (increased RBC breakdown) +/- elevated uric acid
diagnosis:
Pancytopenia with circulating peripheral blasts
Myeloid or lymphoid blasts?
Morphology of cells will determine between myeloid or lymphoid
auer rods are ONLY seen in AML (super tiny purple line)
Also look at CD markers using flow cytometry
Diagnosis confirmed only with bone marrow biopsy (aspirate and trephine (BMAT):
Bone marrow blasts >20%: normal bone marrow blasts % is 1-2%
Can be diagnosed with blasts <20% IF cytogenetic or molecular genetic abnormalities are present.
AML management
Induction treatment:
Aim to reduce cell burden with chemotherapy; can be curative or life prolonging. Complete remission = <5% blasts in bone marrow, normal blood counts
Consolidation treatment:
Once remission achieved aim to maintain absence: chemo if BMAT <5% blast cells (high dose cytarabine) OR if >5% blast cells re-induction chemotherapy +/-
intensification
HSCT for poor risk cytogenetics; aim for stem cell transplant once in complete remission
Haematopotic stem cell transplant:
Patients with intermediate or poor risk cytogenetics or relapsed disease
Significant morbidity and mortality associated with stem cell replacement so is last resort management
Allogeneic HSCT = someone else’s stem cells given to the patient
Supportive care:
Packed RBCs: target Hb >70 (unwell), >80 (well), >90 (symptomatic patients)
Platelets: target >10 (all), >20 (unwell/sepsis), >50 (for anticoagulation), >100 (for brain haemorrhage)
Prophylactics: antivirals (aciclovir 400mg PO BD), antifungals (posaconazole 300mg PO OD), antibacterial (neutrophil <1 ciprofloxacin 500mg PO BD; neutrophils >1 none needed)
Do not stop prophylaxis unless haematologist has been consulted
acute lymphoblastic leukaemia (ALL)
Blood cancer of children (ALL children get ALL)
Cancer of lymphoid WBCs
Single lymphoblast undergoes genetic changes which prohibit differentiation coupled with mutations affecting cellular proliferation
Most common form of acute leukaemia in children typically presents at ages 3-7, then >40 YO
90% cure rate
Want to avoid LP for diagnosis due to risk of bleed (low platelet count), also very small risk of giving the patient CNS leukaemia (very difficult to treat and pushed from vessel to CNS)
LP must only be done by haematologists (they administer chemo into the spinal cord after LP!!)
Acute lymphoblastic leukaemia is where there is malignant change in one of the lymphocyte precursor cells. It causes acute proliferation of a single type of lymphocyte, usually B-lymphocytes. Excessive proliferation of these cells causes them to replace the other cell types being created in the bone marrow, leading to a pancytopenia.
This is the most common cancer in children and peaks around 2-4 years. It can also affect adults over 45. It is often associated with Downs syndrome.
Blood film shows blast cells.
It is associated with the Philadelphia chromosome (t(9:22) translocation) in 30% of adults and 3-5% of children with ALL.
ALL diagnosis
Blood film:
Immunophenotype seen by flow cytometry (which cell surface receptors are present)
Cytogenetic gene mutations on philadelphia chromosome = poor prognosis
must differentiate from acute lymphoblastic lymphoma which has lymph node involvement or extra nodal masses and has worse prognosis
chronic myeloid leukaemia (CML) and presentation
Myeloproliferative neoplasm (MPN) characterised by dysregulated production and uncontrolled proliferation of mature and granulocytes (neutrophil, basophil, eosinophil) with fairly normal cellular differentiation
Presentation:
20-50% asymptomatic and picked up on routine blood tests
Fatigue
Malaise
Weight loss
Excessive swelling
Abdominal pain: Splenomegaly, Hepatomegaly (from taking up role of making WBCs as bone marrow is not doing the job)
CML investigations and management
Investigations:
WCC: 90-100
Blood film: predominantly neutrophils (myelocytes) and low level peripheral blasts <2%
Philadelphia chromosome: BCR-ABL mutation translocation between chromosomes 9 and 22 associated with CML, take tablet OD for life and same life expectancy as everyone else
Management:
TKIs e.g. imatinib
Hydroxycarbamide
chronic lymphocytic leukaemia (CLL) and presentation
Mature B cell neoplasm characterised by progressive accumulation of monoclonal B lymphocytes
Presentation: Elderly patient Often detected on routine test for something else; autoimmune haemolytic anaemia (AIHA) or hypogammaglobulinemia Low level LAP Splenomegaly Hepatomegaly
CML diagnosis and management
Diagnosis:
If well; repeat FBC in 2-3 months time to reassess lymphocyte count
Investigate lymphocytosis in mean time (HIV, HBV, HCV, EBV)
Refer to haematology if repeat lymphocyte count is raised or severe infection/anaemia present
Don’t usually need treatment
Watch and wait, often die WITH CLL however not FROM CLL
Prognosis still roughly the same even with later presentation however treatment cannot reverse damaged done in symptomatic patients (hyperviscosity can cause blindness or other systemic symptoms)
lymphoma
Blood cancers characterised by accumulation of malignant lymphocytes in lymph nodes and lymphoid tissues, classically presenting with LAP
types:
hodgkin lymphoma: classical (nodular scleorsis, mixed cellularity, lymphocyte rich, lymphocyte depleted)
or nodular lymphocyte-Predominant
Non-hodgkin’s lymphoma: high grade - diffuse large B cell lymphoma (mantle cell lymphoma, peripheral T cell lymphoma, angioimmunoblastic lymphoma, Burkitt’s lymphoma)
or low grade - follicular lymphoma
High grade lymphoma will always need treatment will die because of if untreated
Low grade lymphomas can be present asymptomatically with no problems often need no treatment just need lifelong monitoring in case it develops into high grade lymphoma
hodgkin lymphoma
Blood cancer that arises from the germinal centre or pot germinal centre, B lymphocytes
Formed of minority of malignant cells that are surrounded by an inflammatory background of cells
Primary lymphoid organs: bone marrow and thymus.
Secondary lymphoid organs: lymph nodes, spleen (germinal centre)
10% of all lymphomas, patients are usually young (20 YO) slightly more common in men
Types: Nodular sclerosis Mixed cellularity Lymphocyte rich Lymphocyte depleted Nodular lymphocyte predominant
Pathophysiology
Classical Reed-Sternberg cells on a background of inflammatory cells (lymphocytes, eosinophils, neutrophils, macrophages, plasma cells, fibroblasts)
Often associated with collagen deposition and fibrosis
Reed-sternberg cells: biobed, double or multiple nuclei, two or more prominent, eosinophilic, inclusion like nuclei
hodgkin lymphoma presentation and diagnosis
Painless LAP: cervical or supraclavicular, non tender, rubber consistency
Non productive cough/gradually worsening SOB: mediastinal mass
B symptoms: night sweats (drenching 3+ x weekly), weight loss, fevers
Pruritus months or years prior to diagnosis
Fevers in absence of infection
diagnosis
Clinical symptoms and tissue biopsy (excisional biopsy)
Cannot use FNA as may miss diagnosis/miss malignant cells, need much larger samples
Routine light microscopy and immunophenotype with immunohistochemistry
PETCT scan for staging
hodgkin lymphoma staging
stage 1: lymphoma in single lymph node or one group of lymph nodes or an organ of the lymphatic system (such as the thymus)
stage 2: lymphoma is in two or more groups of lymph nodes, on same side of the diaphragm
stage 3: lymphoma on both sides of the diaphragm
stage 4: lymphoma is in an extra nodal site and lymph nodes are affected above and below diaphragm or is in more than one extra nodal site
Most patients present at stage 3 or 4
Stage 4 most common presentation and survival rate is 85% so prognosis is very good. Curative often, don’t shove them onto palliative care
lymphoma management
stage 1/2 disease: ABVD - doxorubicin, bleomycin, vinblastine and dacarbazine +/- intense field radiotherapy
stage 3/4: escalated BEACOPP. bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisolone. higher rates of toxicity including reversible bone marrow suppression, secondary malignancies, sterility and rare cases of fatal sepsis
relapsed/refractory disease: brentuximab
ICE: ifosfamide, carboplatin and etoposide
GDP: gemcitabine, dexamethasone, cisplatin
once/if in remission - aim to autologous stem cell transplant
prognosis:
80% 10 year survival rate, better in <40 YO and female
very few people have relapses or need stem cell transplants
non-hodgkin lymphoma
Blood cancer arising from B or T lymphocytes
80% of all lymphomas
Predominantly in later life >70
Slightly more common in men
Types:
High grade: diffuse large B cell, burkitt lymphoma, angioimmunoblastic lymphoma. These are fast growing, have acute presentation onset with rapid deterioration and will always need treatment
Low grade: follicular or splenic marginal zone lymphoma. Indolent, often use watch and wait management
non-hodgkin lymphoma presentation and investigations
Painless LAP: cervical, axillary or inguinal, non tender, rubber consistency, rapidly growing
Abdominal symptoms: abdominal LAP, abdominal pains/change in bowel habit
B symptoms: night sweats (drenching 3x weekly), weight loss, fevers without infection
if you feel cervical enlarged lymph nodes MUST check armpits and inguinal lymph nodes in absence of systemic illness should not all be enlarged
Diagnosis:
Clinical symptoms and URGENT tissue biopsy to confirm
LAP show significant enlargement, persist for more than 4-6 weeks with progressive increase in size
Light microscopy and immunophenotype with immunohistochemistry
PETCT for staging
management of non hodgkin lymphoma
high grade:
Chemotherapy
low grade: (follicular lymphoma)
watch and wait
radiotherapy
plasma cell disorders
Monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma
Monoclonal gammopathy of undetermined significance (MGUS) and presentation/investigations
Premalignant clonal plasma cell disorder
Presence of monoclonal protein (M protein or paraprotein)
With NO evidence of multiple myeloma, amyloidosis or Waldenstrom macroglobulinemia (WM)
Investigations:
Presents to GP with nonspecific symptoms
Back pain
SOB
Raised globulin noticed on routine bloods and requests serum protein electrophoresis (SPEP), serum free light chains (SFLC) and paraprotein quantitation (PP)
Urine symptoms indicate end organ failure
MGUS criteria
M protein <30 g/l
Bone marrow clonal plasma cells <10% and low level of plasma cell infiltration in a trephine biopsy
No myeloma related organ or tissue impairment (ROTI)
Calcium levels increased: corrected serum Ca >0.25mmol/l above upper limit of normal or >2.75mmol/l
Renal insufficiency attributable to myeloma
Anaemia: Hb 20g/l below the lower limit of normal or Hb <100g/l
Bone lesions: lytic lesions or osteoporosis with compression fractures (MRI or CT scan)
multiple myeloma and investigations
Malignant blood cancer of plasma cells leading to: CRAB symptoms. Calcium, renal failure, anaemia and bone pain as well as cytopenias (pancytopenia: anaemia, thrombocytopenia and neutropenia)
Multiple myeloma is terminal diagnosis however chemotherapy can prolong life. Causes may bony metastases which severely disables individual and leads to death
Paraprotein quantitation will be >30 OR presence of CRAB symptoms
Ix:
Raised globulin noticed on routine bloods and requests serum protein electrophoresis (SPEP), serum free light chains (SFLC) and paraprotein quantitation (PP)
Urine symptoms indicate end organ failure
management of multiple myeloma
chemotherapy
radiotherapy
autologous stem cell transplant (auto-HSCT): aim upfront chemotherapy followed by transplant
followed by close observation and chemotherapy when relapses occur
MGUS vs myeloma
MGUS: - monoclonal paraprotein <30 - no renal issues - no anaemia - no calcium issues - no bony lesions needs annual monitoring FBC, renal profile, bone profile and history
myeloma:
- monoclonal paraprotein present
- renal impairment
- anaemia (hb <100)
- Hypercalcaemia
- bony lesions
myeloproliferative neoplasms (MPNs) types
Polycythaemia vera (PV) Essential thrombocythemia (ET) Chronic myeloid leukaemia (CML) Primary myelofibrosis (MF) Chronic neutrophilic leukaemia (CNL) Chronic eosinophilic leukaemia (CEL)
erythrocytosis: polycythaemia
Elevation of red cell mass (RCM), part of blood occupied by RBCs
Detected by abnormal elevation of Hb and/or haematocrit (Hct)/packed cell volume (PCV)
Hb and Hct are concentrations of components of peripheral blood rather than absolute numbers
types/cause:
- Relative: just due to reduced plasma volume is normal physiological response will self correct
- absolute: primary or secondary
Regulation of RBC:
Blood loss stimulates RBC production detected by hypoxia in kidneys stimulating EPO production and subsequent erythropoiesis
Renal cell carcinomas can increase EPO resulting in too much RBC production
CNS tumours can also cause increased erythropoiesis
Hepatocellular carcinoma can also make too much EPO and RBCs
secondary causes of polycythaemia and investigations
Hypoxia: pO2, carboxyhemoglobin % (3-4% = smoker; any higher ask to have their boiler checked), sleep studies, smoking history, CXR
Renal cell carcinoma, stenosis or adrenal carcinoma: renal bloods (creatinine, urea, K+, U+Es, eGFR), urine dip (haematuria), urological history, USS abdomen/renal tract
Hepatic (HCC): liver bloods (ALT, ALP, GGT) and alcohol history
Neurological (hemangioblastoma): headaches, changes in behaviour, nausea and vomiting - MRI of head (diagnosis of brain tumour)
eGFR only to be used in primary/non-acute setting as takes awhile to show acute changes
polycythaemia vera and presentation
Clonal proliferation of myeloid cells, with variable maturity and hematopoietic efficiency, resulting in raised red cell mass
Intrinsic defect within the bone marrow JAK-STAT signalling pathway (JAK2 V617F exon 14 mutation)
JAK2 activates EPO, GSCF and TPO downstream regulation
Mutation makes haematopoietic stem cells more sensitive to growth factors causing increased proliferation (of potentially all 3 cell lines)
presentation
Raised Hb and Hct/PCV
Associated with iron deficiency (using up the iron so not enough present)
Reduced EPO level is very suggestive (body trying to stop EPO due to increased sensitivity however symptoms still persist as EPO sensitivity so increased)
Erythromelalgia (burning pain in hands and feet)
Pruritus +/- skin excoriation from scratching
Facial plethora (red face)
Gouty arthritis and tophi from increased RBC destruction increased uric acid = gout
Thrombocytosis (platelet >450)
Leukocytosis (>11.0)
thrombocytosis overview
Raised platelet count (>450,000 microL) Normal between 150-400 Primary (haematological) Or secondary (reactive) Secondary reactive causes: Acute blood loss: increased proliferation of progenitor cells
Iron deficiency: megakaryocytic erythroid progenitor cells increased
Acute haemolytic anaemia: increased proliferation of progenitor cells and increased cytokine release
Infections: acute and chronic infectious TB
Inflammatory: RA, IBD, nephrotic syndrome
Tissue damage: MI, acute pancreatitis, severe trauma, burns, post-surgical
Ovarian cancer: IL-6 producing cancers increase TPO production
Lung cancers Colorectal cancers Prostate cancers Breast cancers *always screen patients with isolated raised platelet count for cancers*
Investigation:
TPO, IL-11 and IL-6 inflammatory markers all increase with thrombocytosis
Management:
Treating underlying cause
essential thrombocythemia
Clonal stem cell disorder resulting in excessive platelet production
Causes: JAK2 V617F mutation (65%) causes haematopoietic SCs more sensitive to growth factors
CALR mutation (25%) leads to cytokine independent growth and activation of JAK/STAT signalling. Mutated CARL interacts with MPL and activates MPL directly
MPL mutation (5%): encodes for TPO receptor mutation and activates TPO-R
essential thrombocythemia presentation and management
Around 50% asymptomatic just incidental finding on routine tests
Vasomotor symptoms (microvascular disturbances) Headache Lightheadedness Syncope Atypical chest pain Livedo reticularis Transient visual disturbances
Thrombotic/hemorrhagic event CVA MI SVT DVT PE
First trimester pregnancy loss
management:
Hydroxyurea and aspirin for primary thrombocythemia and high risk of blood clots
ALL management
Stage 1 is remission induction. The aim of remission induction is to kill the leukaemia cells in your bone marrow, restore the balance of cells in your blood, and relieve your symptoms. Involves regular blood transfusions and antibiotic prophylaxis alongside chemotherapy, steroid therapy and other targeted therapies
Stage 2 is consolidation. This aims to kill any remaining leukaemia cells. Regular chemotherapy injections
Stage 3 is maintenance. This involves taking regular doses of chemotherapy medicines to stop leukaemia coming back, can last for around 2 years
Summary of four leukaemia types and how to differentiate
ALL CeLL mates have CoMmon AMbitions
<5 and >45 - acute lymphoblastic leukaemia (ALL)
>55 - chronic lymphocytic leukaemia (CLL)
>65 -chronic myeloid leukaemia (CML)
>75 acute myeloid leukaemia (AML)
Summary to differentiate:
Acute lymphoblastic leukaemia: Most common leukaemia in children. Associated with Down syndrome.
Chronic lymphocytic leukaemia: Most common leukaemia in adults overall. Associated with warm haemolytic anaemia, Richter’s transformation into lymphoma and smudge / smear cells.
Chronic myeloid leukaemia: Has three phases including a 5 year “asymptomatic chronic phase”. Associated with the Philadelphia chromosome.
Acute myeloid leukaemia: Most common acute adult leukaemia. It can be the result of a transformation from a myeloproliferative disorder. Associated with Auer rods.
leukaemia investigations
FBC initial Ix within 48 hours if leukaemia is suspected Blood film Lactate dehydrogenase (LDH) often raised but non-specific Bone marrow biopsy CXR for infection/LAP Lymph node biopsy to assess for lymphoma LP if CNS involvement CT, MRI, PET scan for staging
Von Willebrand disease and presentation
The most common inherited cause of abnormal bleeding (haemophilia) Many genetic causes most are autosomal dominant Causes involve a deficiency, absence or malfunctioning of the glycoprotein von Willebrand factor (VWF). Three types (1-3) ranging in severity, type 3 being the most severe
Presentation: Easy, prolonged or heavy bleeding Bleeding gums with brushing teeth Epistaxis Menorrhagia Heavy bleeding with injury, surgery Family history
Von Willebrand disease diagnosis and management
Diagnosis:
Clinical history
Family history
Bleeding assessments: coagulation status and bloods
Management:
Does not need day to day management; only needed in response to a major bleed or trauma to stop the bleeding or in preparation for operations to prevent bleeding
Desmopressin stimulates release of VWF
VWF can be infused
Factor VIII often infused with plasma derived VWF to help coagulation
Women with menorrhagia can try a combination of: tranexamic acid, mefenamic acid, norethisterone, COC, mirena coil.
Hysterectomy may be needed in severe cases
haemophilia A and B
Inherited severe bleeding disorders
Haemophilia A is caused by a deficiency in factor VIII
Haemophilia B (Christmas disease) is caused by a deficiency in factor IX, tends to be less severe
They are X linked recessive disorders, in order to have the condition you must have an X chromosome with the abnormal gene (must be homozygous in women but only heterozygous in men due to only one X chromosome)
Women can be carriers of the disease while men are almost exclusively affected due to only needing one recessive gene
Haemophilia A and B presentation
Bleed excessively in response to minor trauma
Spontaneous haemorrhage
Often present in neonates or early childhood
Can present in infants with intracranial haemorrhage, haematomas and cord bleeding
Haemarthrosis (bleeding in joints) - mostly in haemophilia A
Bleeding in muscles
Bleeding in gums, GIT, retroperitoneal space, following procedures - mostly from haemophilia A
Haematuria
diagnosis and management of haemophilia A and B
Diagnosis:
Bleeding scores
Coagulation factor assays: in female carriers of haemophilia A you are likely to see prolonged APTT with normal PT and normal fibrinogen
Genetic testing
Management:
Specialist haematology referral
Clotting factors XII or IX can be replaced via IV infusions
Can be done prophylactically or in response to bleeding
Complication of this is formation of antibodies again the clotting factor resulting in treatment becoming ineffective
Acute episodes of bleeding or prevention of excessive bleeding during surgery involve: infusions of clotting factor, desmopressin to stimulate VWF and antifibrinolytics like tranexamic acid
haemophilia C and presentation
AKA plasma thromboplastin antecedent deficiency or Rosenthal syndrome, is a clotting disorder is a deficiency in factor XI
Most commonly seen in Ashkenazi jewish populations
Factor XI is important for producing thrombin protein that converts fibrinogen to fibrin during the clotting cascade
Autosomal recessive disorder
Presentation: Easy, prolonged or heavy bleeding Bleeding gums with brushing teeth Epistaxis Menorrhagia Heavy bleeding with injury, surgery Family history
haemophilia C diagnosis and management
Diagnosis:
Genetic testing in pregnancy
Clotting tests
Antibodies against XI to assess risk for developing defence against treatment
Management:
Tend to be treated on presentation of bleed rather than prophylaxis
Can inject plasma factor XI
Infusions of fresh frozen plasma PRN in operations or after traumas
Fibrin glue to treat injuries
Tranexamic acid (oral, IV or topical)
Women with menorrhagia can consider mirena coil or COC
People with severe disorder should NOT use NSAIDs as this increases bleed risk
G6PD Deficiency
X linked autosomal recessive disorder so mostly affects males while females are often carriers of the disorder
Genetic abnormality that results in a deficiency of G6PD (glucose-6-phosphate dehydrogenase) in the blood
It is responsible for keeping RBCs healthy and without enough the RBCs breakdown prematurely (increased haemolysis) eventually leading to haemolytic anaemia
Haemolytic anaemia can be induced in those with the disorder by eating fava beans, certain legumes, infections or drugs (antimalarials, sulfonamides, aspirin and NSAIDs)
Most prevalent in Africa (up to 20% population)
Risk factors: Male African Middle eastern Family history
G6PD deficiency presentation, diagnosis and management
Presentation:
Mostly asymptomatic
When triggered shows symptoms of haemolytic anaemia: tachycardia, dyspnea, dark yellow/orange urine, fever, fatigue, dizziness, pallor, jaundice of skin and eyes
Once cause (infection, medications, foods etc.) has been removed then symptoms tend to resolve
Diagnosis:
Blood tests for G6PD, FBC, serum Hb and reticulocyte count
Management:
Avoid triggering foods, medications and prevent infection where possible
Prompt treatment of infections
Haemolytic anaemia: oxygen, blood transfusions likely to be needed
antiphophsolipid syndrome overview
Disorder characterised by antiphospholipid antibodies where the blood becomes prone to clotting
The patient is in a hypercoagulable state
Main associations are with thrombosis and pregnancy, particularly recurrent miscarriage
Can occur in isolation (primary) or secondary to an autoimmune condition, particularly SLE
Associated with AP antibodies: lupus anticoagulant, anticardiolipin and anti-B2 glycoprotein I antibodies
These antibodies interfere with coagulation and create a hypercoagulable state
Complications/presentation:
Venous thrombosis (DVT, PE)
Arterial thrombosis (stroke, MI, renal thrombosis)
Pregnancy complications (recurrent miscarriage, stillbirth, preeclampsia)
Livedo reticularis: purple lace like rash giving mottled appearance to skin
Libman-sacks endocarditis: non-bacterial endocarditis with vegetations on valves of heart. Mitral valve most often affected.
Thrombocytopenia
Diagnosis: History of thrombosis or pregnancy complication plus persistent antibodies Lupus anticoagulant Anticardiolipin antibodies Anti-beta-2 glycoprotein I antibodies
Management:
Referral to rheumatology, haematology and obstetrics (if pregnant)
Long term warfarin with INR 2-3 to prevent thrombosis (3-4 INR with recurrent thrombosis)
haemochromatosis overview
Iron storage disorder resulting in excessive total body iron and deposition of iron in tissues
The human haemochromatosis protein HFE gene is often mutated causing this condition (autosomal recessive mutation)
Presentation:
Usually present after age 40 when iron overload becomes symptomatic
Presents later in females due to menstruation acting to eliminate iron from the body
Fatigue
Joint pain
Pigmentation (bronze or slate grey)
Hair loss
Erectile dysfunction
Amenorrhea
Cognitive symptoms (memory and mood disturbance)
Diagnosis: Serum ferritin Iron studies - transferrin saturation Genetic testing (GOLD STANDARD) Liver biopsy (perl’s stain) to establish iron in parenchymal cells CT abdomen MRI
Complications:
Type 1 Diabetes (iron affects the functioning of the pancreas)
Liver Cirrhosis
Iron deposits in the pituitary and gonads lead to endocrine and sexual problems (hypogonadism, impotence, amenorrhea, infertility)
Cardiomyopathy (iron deposits in the heart)
Hepatocellular Carcinoma
Hypothyroidism (iron deposits in the thyroid)
Chrondocalcinosis / psedogout (calcium deposits in joints) causing arthritis
Management:
Venesection (weekly removal of blood to decrease total iron)
Monitor serum ferritin
Avoid alcohol
Genetic counselling
Monitoring and treatment of complications
haemolytic anaemias management
Dependent on cause; hereditary spherocytosis (most common type) treated with folate supplements and splenectomy (+ cholecystectomy if gallstones are a problem)
Autoimmune haemolytic anaemia treated by blood transfusions, prednisolone, rituximab and splenectomy
Prosthetic valve haemolysis treated with monitoring, oral iron, blood transfusions (severe) or revision surgery (severe)
iron overload
Iron overload occurs in thalassaemia as a result of faulty creation of red blood cells, recurrent transfusions and increased absorption of iron in response to the anaemia.
Patients with thalassaemia have serum ferritin levels monitored to check for iron overload. Management involves limiting transfusions and iron chelation.
Iron overload in thalassaemia causes effects similar to haemochromatosis:
Fatigue Liver cirrhosis Infertility and impotence Heart failure Arthritis Diabetes Osteoporosis and joint pain
Thalassaemia management
Alpha thalassaemia:
more commonly carriers of condition, asymptomatic and no treatment however need to be aware of genetic testing of children who may be homozygous.
Must monitor FBC and complications.
Blood tranfusion PRN, splenectomy, bone marrow transplant can be curative
Beta thalassaemia:
Can be transfusion or non-transfusion dependent based on stage
Minor: FBC monitoring
Intermedia: monitoring FBC, transfusions PRN, iron chelation to prevent iron overload
Major: regular transfusions, iron chelation and splenectomy, bone marrow transplant can be curative (potentially)
