Haematology Flashcards
What is contained within plasma?
RBCs
WBCs
Clotting factors
What is serum?
Blood after clotting factors removed
Contains:
Glucose
Electrolytes
Proteins
Where do blood cells develop?
Bone marrow
Bone marrow mostly found in pelvis/vertebrae/ribs/sternum
What are pluripotent haematopoietic stem cells?
Undifferentiated cells that can transform into various blood cells
What do pluripotent haematopoietic stem cells differentiate into?
Myeloid stem cells- Megakaryocyte (platelet), Erythrocyte (RBC), Myeloblast (basophil, neutrophil, eosinophil, macrophage)
Lymphoid stem cells- B cell, T cell, natural killer cell
Dendritic cells
What is the role of platelets?
Lifespan 10d
Clump together (platelet aggregation) and plug gaps where blood clots form
Outline the development of RBCs
Develop from reticulocytes- Immature RBCs
RBCs survive 120d
What do B lymphocytes differentiate into?
Mature in bone marrow
Plasma cells
Memory B cells
What do T lymphocytes differentiate into?
Mature in thymus gland
CD4 cells (T helper cells)
CD8 (cytotoxic T cells)
Natural killer cells
What is anisocytosis?
Variation in size of RBCs
Seen in myelodysplastic syndrome and anaemia (iron deficiency, pernicious, AI haemolytic anaemia)
What are spherocytes?
Sphere-shaped RBCs w/o bi-concave disk shape
Indicate AI haemolytic anaemia or hereditary spherocytosis
What are smudge cells?
Ruptured WBCs that occur when cells aged or fragile
Associated with chronic lymphocytic leukaemia
What are sideroblasts?
Immature RBCs with nucleus surrounded by iron blobs
Sideroblastic anaemia- Bone marrow cannot incorporate iron into Hb molecules- Either due to genetic defect or myelodysplastic syndrome
What are schistocytes?
Fragments of RBCs
Indicate RBCs physically damaged during journey through circulation
Microangiopathic haemolytic anaemia (MAHA)- When small thrombi obstruct small vessels- Churns RBCs causing haemolysis
Metallic heart valve replacement (metallic valves damage RBCs)
List key causes of MAHA
HUS
DIC
Thrombocytopenic purpura (TTP)
What are target cells?
RBCs with central pigmented area surrounded by pale area surrounded by ring of thicker cytoplasm on outside
Seen in iron deficiency anaemia and post-splenectomy
What are Heinz bodies?
Individual blobs (inclusions) seen inside RBCs
Blobs are denatured (damaged) Hb
Seen in G6PD deficiency and alpha-thalassaemia
What are Howell-Jolly bodies?
Individual blobs of DNA material inside RBCs
Spleen normally removes RBCs with this DNA
Seen after a splenectomy or with a non-functioning spleen (SCA), or severe anaemia where body regenerating RBCs very fast
What is anaemia?
Low conc. Hb in blood
Consequence of underlying disease
What is the role of Hb?
Protein found in RBCs
Responsible for picking up oxygen in lungs and transporting it to cells
Iron essential in creating Hb
What is mean cell volume (MCV)?
Size of RBCs
Women- Hb 120-165g/l- MCV 80-100 femtolitres
Men- 130-180g/l- MCV 80-100 femtolitres
List the causes of microcytic anaemia
T- Thalassaemia
A- Anaemia of chronic disease
I- Iron deficiency anaemia
L- Lead poisoning
S- Sideroblastic anaemia
What is the association between anaemia of chronic disease and CKD?
Often occur together due to reduced production of erythropoietin by kidneys- Hormone responsible for stimulating RBC production
How is anaemia of chronic disease associated with CKD treated?
Give erythropoietin
List causes of normocytic anaemia
A- Acute blood loss
A- Anaemia of chronic disease
A- Aplastic anaemia
H- Haemolytic anaemia
H- Hypothyroidism
What are the 2 types of macrocytic anaemia?
Normoblastic or megaloblastic
What are the causes of megaloblastic anaemia?
Results from impaired DNA synthesis, prevents cells dividing normally- Grow into large abnormal cells
B12 deficiency
Folate deficiency
List causes of normoblastic macrocytic anaemia
Alcohol
Reticulocytosis (usually from haemolytic anaemia or blood loss)
Hypothyroidism
Liver disease
Drugs- Azathioprine
What is reticulocytosis?
Increased conc. of reticulocytes- Happens when rapid turnover of RBCs- Haemolytic anaemia or blood loss
List generic symptoms of anaemia
Tiredness
SOB
Headaches
Dizziness
Palpitations
Worsening of other conditions
What are the symptoms specific to iron deficiency anaemia?
Pica (dietary cravings for dirt/soil)
Hair loss
What are the generic signs of anaemia?
Pale skin
Conjunctival pallor
Tachycardia
Raised RR
List the signs specific of iron deficiency anaemia
Koilonychia (spoon shaped nails)
Angular cheilitis
Atrophic glossitis (smooth tongue due to atrophy of papillae)
Brittle hair and nails
What is the sign specific to haemolytic anaemia?
Jaundice
What is the sign specific to thalassaemia?
Bone deformities
List the signs specific to anaemia associated with CKD
Oedema
HTN
Excoriations on skin
What investigations are done to determine cause of anaemia?
FBC- For Hb and MCV
Reticulocyte count- Indicates RBC production
Blood film- For abnormal cells and inclusions
Renal profile- For CKD
LFTs- For liver disease and bilirubin (raised in haemolysis)
Ferritin- Iron
B12 and folate
Intrinsic factor antibodies- Pernicious anaemia
TFTs- Hypothyroidism
Coeliac disease serology- Anti-tissue transglutaminase antibodies
Myeloma screening- Serum protein electrophoresis
Direct Coombs test- AI haemolytic anaemia
Colonoscopy and oesophagogastroduodenoscopy (OGD)- Indicated for unexplained iron deficiency anaemia to exclude GI cancer as source of bleeding
Bone marrow biopsy- Indicated for unexplained anaemia/possible malignancy (eg: Leukaemia or myeloma)
List causes of iron deficiency anaemia
Insufficient dietary iron (eg: Restrictive diets)
Reduced iron absorption (eg: Coeliac disease)
Increased iron requirements (eg: Pregnancy)
Loss of iron through bleeding (eg: From peptic ulcer or bowel cancer)
What is the most common cause of iron deficiency anaemia in adults?
Blood loss:
Menstruation
GI tract- Cancer (eg: Stomach or bowel), oesophagitis and gastritis, peptic ulcer, IBD, angiodysplasia (abnormal vessels in wall)
What is the most common cause of iron deficiency anaemia in children?
Dietary insufficiency
Pica a common presentation in children
Outline absorption of iron
Absorbed in duodenum and jejunum
Requires acid from stomach to keep iron in soluble ferrous (Fe2+) form
When stomach contents less acidic- Changes to insoluble ferric (Fe3+) form
PPIs reduce stomach acid- Interfere with iron absorption
Inflammation of duodenum or jejunum (eg: Coeliac pr Crohn’s) can reduce iron absorption
Outline testing of iron deficiency anaemia
What is total iron-binding capacity (TIBC)?
Space for iron to attach to on transferrin molecules combined
Directly related to amount of transferrin in blood
What is transferrin?
Iron travels around in blood bound to carrier protein transferrin
What is transferrin saturation?
Refers to proportion of transferrin molecules bound to iron- Expressed as a percentage
What is the formula for transferrin saturation?
Transferrin saturation = Serum ion/TIBC
What is ferritin?
A protein that stores iron inside cells
Acute-phase protein released with inflammation (eg: Infection or cancer)
What are the causes of changes in ferritin levels?
Low ferritin- Iron deficiency
Normal ferritin doesn’t exclude iron deficiency
Raised ferritin- Difficult to interpret- Inflammation (infection/cancer), liver disease, iron supplements, haemochromatosis
How does TIBC change with iron levels?
Marker for how much transferrin is in the blood
Iron deficiency- TIBC and transferrin increase
Iron overload- TIBC and transferrin decrease
How does transferrin saturation change with iron levels?
Transferrin saturation- Indicates total iron in body
Less iron= Transferrin less saturated
Increased iron in body= Transferrin more saturated
Can increase after eating a meal or taking iron supplements- Fasting gives more accurate results
List causes of iron overload
Haemochromatosis
Iron supplements
Acute liver damage (liver contains lots of iron)
Iron overload causes raised serum ferritin, serum iron, and iron saturation (doesn’t increase TIBC)
Outline investigations of new iron deficiency in an adult w/o a clear cause
Colonoscopy and oesophagogastroduodenoscopy (OGD) for malignancy
What are the 3 options for treating iron deficiency anaemia?
Oral iron (eg: Ferrous sulphate or ferrous fumarate)- Works slowly
Iron infusion (eg: IV CosmoFer)
Blood transfusion (in severe anaemia)
What are the common SEs of oral iron?
Constipation
Black stools
What are the risks of iron infusions?
Small risk allergic reactions and anaphylaxis
Avoid during infections- Can feed the bacteria
What is pernicious anaemia?
Caused by Vit D 12 deficiency
A macrocytic anaemia
Autoimmune involving antibodies against parietal cells or intrinsic factor= Lack of absorption of Vit B12
What are the causes of low Vit B12?
Pernicious anaemia
Insufficient dietary B12 (vegan diet)
Meds- Reduce B12 absorption (PPIs and metformin)
What are parietal cells?
In stomach
Produce intrinsic factor
What are intrinsic factors?
Essential for absorption of Vit B12 in distal ileum
List the neurological symptoms of B12 deficiency
Peripheral neuropathy- Numbness or paraesthesia
Loss of vibration sense
Loss of proprioception
Visual changes
Mood and cognitive changes
Which antibodies are used to diagnose pernicious anaemia?
Intrinsic factor antibodies (1st line)
Gastric parietal cell antibodies (less helpful)
Outline initial management of pernicious anaemia
Intramuscular hydroxycobalamin:
No neuro symptoms- 3x/wk for 2wks
Neuro symptoms- Alternate days until no further improvement in symptoms
Outline maintenance of management of Vit B12 deficiency
Pernicious anaemia- 2-3mthly injections for life
Diet-related- Oral cyanocobalamin or twice-yrly injections
How are patients managed with B12 and folate deficiency together?
Treat B12 deficiency first, then correct folate
If give folic acid to Vit b12 deficiency- Leads to subacute combined degeneration of cord- Demyelination in spinal cord and severe neuro problems
List the inherited conditions that can cause chronic haemolytic anaemia
Hereditary spherocytosis
Hereditary elliptocytosis
Thalassaemia
SCA
G6PD deficiency
List acquired conditions that can lead to haemolytic anaemia
AI haemolytic anaemia
Alloimmune haemolytic anaemia (eg: Transfusion reactions and haemolytic disease of newborn)
Paroxysmal nocturnal haemoglobinuria
Microangiopathic haemolytic anaemia
Prosthetic valve-related haemolysis
What are the features of haemolytic anaemia?
Anaemia
Splenomegaly (spleen becomes filled with destroyed RBCs)
Jaundice (bilirubin released during destruction of RBCs)
Outline investigations of haemolytic anaemia
FBC- Normocytic anaemia
Blood film- Schistocytes (fragments of RBCs)
Direct Coombs test- Positive in autoimmune haemolytic anaemia
What is hereditary spherocytosis?
Autosomal dominant
Causes fragile, sphere-shaped RBCs that easily breakdown when passing through spleen
How does hereditary spherocytosis present?
Anaemia
Jaundice
Gallstones
Splenomegaly
Aplastic crisis in presence of parvovirus
Likely to be a positive FHx
What are the key findings of hereditary spherocytosis on bloods?
Raised mean corpuscular Hb conc. on FBC
Raised reticulocyte count due to rapid turnover of RBCs
Spherocytes on blood film
How is hereditary spherocytosis managed?
Folate supplementation
Blood transfusions when required
Splenectomy
Gallbladder removal (cholecystectomy) required if gallstones a problem
What is hereditary elliptocytosis?
RBCs are ellipse-shaped
Autosomal dominant
Presentation and management same as hereditary spherocytosis
What is G6PD deficiency?
Defect in gene coding for glucose-6-phosphate dehydrogenase- An enzyme responsible for protecting cells from oxidative damage
X-linked recessive (males more often affected and females are carriers)
Common in Mediterranean, Asian and African patients
Results in acute episodes of haemolytic anaemia triggered by infections/drugs/fava beans
What are the key medication triggers of G6PD deficiency?
Ciprofloxacin
Sulfonylureas (eg: Gliclazide)
Sulfasalazine
How does G6PD deficiency present?
Jaundice (often in neonatal period)
Gallstones
Anaemia
Splenomegaly
Heinz bodies on blood film
How is G6PD deficiency diagnosed?
G6PD enzyme assay
List the triggers of G6PD deficiency acute episodes of haemolytic anaemia
Infection
Drugs (ciprofloxacin, sulfonylureas, sulfasalazine)
Fava beans
Outline autoimmune haemolytic anaemia
Antibodies created against patient’s RBCs- Lead to RBC destruction
2 types- Warm and cold- Based on temperature at which auto-antibodies destroy RBCs
Outline warm AI haemolytic anaemia
More common than cold
Haemolysis occurs at normal/above normal temperatures
Usually idiopathic
Outline cold-reactive AI haemolytic anaemia
Cold agglutinin disease
At lower temperatures, antibodies attach to RBCs and cause agglutination
Immune system activated, RBCs destroyed
Can be secondary to lymphoma/leukaemia/SLE/infections (eg: Mycoplasma, EBV, CMV, HIV)
Outline management of AI haemolytic anaemia
Blood transfusions
Prednisolone
Rituximab (monoclonal antibody against B cells)
Splenectomy
Outline alloimmune haemolytic anaemia
Occurs due to foreign RBCs or foreign antibodies
Transfusion reactions or haemolytic disease of the newborn
What is a haemolytic transfusion reaction?
RBCs transfused into patient- Immune system produces antibodies against antigens on foreign RBCs- New RBCs destroyed
What is haemolytic disease of the newborn?
Maternal antibodies cross placenta from mother to fetus
Maternal antibodies target antigens on RBCs of fetus and are destroyed
Occurs when fetus is rhesus D positive, and mother rhesus D negative
During sensitisation event, mother exposed to fetal RBCs and produces anti-D antibodies
Antibodies can cross to baby and cause haemolysis
Sensitisation prevented in rhesus -ve women using anti-D prophylaxis
What is paroxysmal nocturnal haemoglobinuria?
Caused by genetic mutation in haematopoietic stem cells in bone marrow
Not inherited- Mutation occurs during lifetime
Results in loss of proteins on surface of RBCs that inhibit complement cascade on RBCs and their destruction
What is the characteristic presenting symptom of paroxysmal nocturnal haemoglobinuria?
Red urine in the morning- Contains haemoglobin and haemosiderin
Anaemia
Thrombosis
Smooth muscle dystonia (oesophageal spasm and ED)
How is paroxysmal nocturnal haemoglobinuria managed?
Eculzumab
Bone marrow transplantation (can be curative)
What is microangiopathic haemolytic anaemia (MAHA)?
Destruction of RBCs as they travel through circulation
Most often caused by abnormal activation of clotting system- Blood clots partially obstruct small blood vessels- Thrombotic microangiopathy
Obstructions churn RBCs causing haemolysis
What are the causes of microangiopathic haemolytic anaemia (MAHA)?
HUS
DIC
TTP
SLE
Cancer
What are the key findings on blood film of MAHA?
Schistocytes
What is prosthetic valve haemolysis?
Haemolytic anaemia= Key complication of prosthetic valves
Caused by turbulent flow around valve and shearing of RBCs
Outline management of prosthetic valve haemolysis
Monitoring
Oral iron and folic acid supplementation
Blood transfusions if severe
Revision surgery if severe
What is thalassaemia?
Genetic defect in protein chains that make up Hb
What chains does normal Hb consist of?
2 alpha-globin chains
2 beta-globin chains
What is the inheritance of thalassaemia?
Autosomal recessive
Outline the features of thalassaemia
Microcytic anaemia (low MCV)
Fatigue
Pallor
Jaundice
Gallstones
Splenomegaly
Poor growth and development
Which type of anaemia is caused by thalassaemia?
Haemolytic anaemia- RBCs more fragile and breakdown easily
Spleen acts as a sieve and collects destroyed RBCs= Splenomegaly
Outline investigations of thalassaemia
Microcytic anaemia (low MCV)
Raised ferritin suggests iron overload
Hb electrophoresis used to diagnose globin abnormalities
DNA testing can look for genetic abnormality
All pregnant women offered screening test
What is the link between iron overload and thalassaemia?
Iron overload may occur due to:
Increased iron absorption in GI tract
Blood transfusions
List symptoms and complications of iron overload in thalassaemia
Liver cirrhosis
Hypogonadism
Hypothyroidism
HF
Diabetes
Osteoporosis
Outline management of iron overload in thalassaemia
Serum ferritin levels monitored
Limit transfusions and iron chelation
Outline alpha-thalassaemia
Gene for alpha-globin on Chr 16
Asymptomatic as carrier
Hb H disease- Moderate anaemia
Alpha-thalassaemia major- Intrauterine death due to severe fatal anaemia
Outline management of alpha-thalassaemia
Monitoring
Blood transfusions
Splenectomy
Bone marrow transplant
Outline beta-thalassaemia
Defects in gene coding for Chr 11
Split into 3 different types
Outline thalassaemia minor
Carriers of abnormally functioning beta-globin gene
1 abnormal and 1 normal gene
Causes mild microcytic anaemia
Requires monitoring only
Outline thalassaemia intermedia
2 abnormal copies of beta-globin gene
Can be either:
2 defective genes
1 defective gene and 1 deletion gene
Causes more significant microcytic anaemia
Outline management of thalassaemia intermedia
Require monitoring and may need occasional blood transfusions
May require iron chelation to prevent iron overload
Outline beta thalassaemia major
Homozygous for deletion genes
No functioning beta-globin genes
Most severe form- Presents with severe anaemia and failure to thrive
List presentation of beta thalassaemia major
Bone marrow under increased strain= Expands= Increases risk of fractures and changes appearance
Frontal bossing
Enlarged maxilla
Depressed nasal bridge
Protruding upper teeth
Outline management of beta thalassaemia major
Regular transfusions
Iron chelation
Splenectomy
Bone marrow transplant- Curative
How can a DVT cause a stroke?
Atrial septal defect- Passes through to L side of heart and into systemic circulation to brain
List the RFs for VTE
Immobility
Recent surgery
Long haul travel
Pregnancy
Hormone therapy with oestrogen
Malignancy
Polycythaemia
SLE
Thrombophilia
What is a common presentation of antiphospholipid syndrome?
Recurrent miscarriage and recurrent DVT
List examples of thrombophilias
Antiphospholipid syndrome
Factor V Leiden
Antithrombin deficiency
Protein C or S deficiency
Hyperhomocysteinaemia
Prothrombin gene variant
Activated protein C resistance
Outline VTE prophylaxis
LMWH- Enoxaparin
Anti-embolic compression stockings
What are the CIs of compression stockings?
Peripheral artery disease
What are the CIs to enoxaparin?
Active bleeding
Existing anticoagulation- With warfarin or DOAC
Outline presentation of DVT
Unilateral
Calf or leg swelling
Dilated superficial veins
Tenderness to calf
Oedema
Colour change to leg
What could be diagnosis of a patient presenting with symptoms of DVT in both legs?
Bilateral DVT (rare)
Chronic venous insufficiency
Heart failure
When is calf circumference measured?
To check for unilateral calf swelling in a DVT
Measure 10cm below ischial tuberosity
>3cm difference is significant
Outline how Wells score can influence management of VTE
VTE likely- Perform leg vein US
Unlikely- Perform d-dimer, if +ve, perform leg vein US
Outline D-dimer
Sensitive but not specific for VTE- Helps for exclusion
What are the causes of a raised d-dimer?
VTE
Pneumonia
Malignancy
HF
Surgery
Pregnancy
What is the 1st line investigation of PE?
CT pulmonary angiogram (CTPA)
Outline initial management of VTE
Initial anticoagulant- Apixaban or rivaroxaban
Alternative- LMWH
Start anticoagulation immediately if VTE suspected and delay in scan
Consider catheter-directed thrombolysis if symptomatic iliofemoral DVT and symptoms <14d
Outline options for long term anticoagulation in VTE
Options- DOAC, warfarin or LMWH
DOACs- Don’t require monitoring
Warfarin- 1st line in antiphospholipid syndrome- Target INR between 2 and 3
LMWH- 1st line in pregnancy
How long should patients be on anticoagulation after a VTE?
3mths- Reversible cause (then review)
3-6mths- Active cancer (then review)
Long term- Unprovoked VTE/recurrent VTE/irreversible underlying cause (eg: Thrombophilia)
What are the exceptions to using DOAC as long term anticoagulation?
Severe renal impairment (creatinine clearance <15ml/min)
Antiphospholipid syndrome
Pregnancy
What is an inferior vena cava filter?
Devices inserted into IVC to filter blood and catch blood clots travelling from venous system towards heart and lungs
Used as anticoagulation for those unsuitable for meds/PE occurred whilst on anticoagulation
How is an unprovoked DVT investigated?
Review history, baseline bloods and physical exam for evidence of cancer
If patients not going to continue anticoagulation beyond 3-6mths- Consider testing for antiphospholipid syndrome and hereditary thrombophilias (if FHx +ve for VTE)
What is Budd-Chiari syndrome?
Obstruction to outflow of blood from liver caused by thrombosis is hepatic vein/IVC
Associated with hypercoagulable states
What is the classic triad of Budd-Chiari syndrome?
Abdo pain
Hepatomegaly
Ascites
How is Budd-Chiari syndrome diagnosed?
Doppler ultrasonograohy
How is Budd-Chiari Syndrome managed?
Anticoagulation
Endovascular procedures (eg: Thrombolysis or angioplasty)
Transjugular intrahepatic portosystemic shunt (TIPS)
Liver transplant
What deficiency is haemophilia A?
Factor VIII
What deficiency is haemophilia B?
Factor IX
What is the inheritance pattern of haemophilia?
X-linked recessive
More common in males
What are the features of haemophilia?
Excessive bleeding in response to minor trauma
Risk of spontaneous bleeding w/o trauma
Neonates- Intracranial haemorrhage, haematomas, cord bleeding
Haemarthrosis- Can lead to joint damage and deformity
Bleeding into muscles- Compartment syndrome
Areas of bleeding:
Oral mucosa
Epistaxis
GI tract
Urinary tract- Haematuria
ICH
Surgical wounds
How is haemophilia diagnosed?
Bleeding score
Coagulation factor assays
Genetic testing
How is haemophilia managed?
Affected clotting factors (VIII, or IX) IV infusion
What is a complication of haemophilia treatment?
Giving clotting factors can form antibodies against treatment- Become ineffective
What is Von Willebrand Disease?
Most common inherited cause of abnormal and prolonged bleeding
What is the inheritance of Von Willebrand Disease?
Most common autosomal dominant:
Deficiency/absence of glycoprotein VWF
What is the role of VWF?
Platelet adhesion and aggregation in damaged vessels
Outline the types of VWD
Type 1: Partial deficiency VWF- Most common- Mildest
Type 2: Reduced function VWF
Type 3: Complete deficiency VWF- Most rare and severe
Outline presentation of VWD
History of unusually easy, prolonged, heavy bleeding
Bleeding gums with brushing
Epistaxis
Easy bruising
Menorrhagia
Heavy bleeding during/after surgery
Family history heavy bleeding or VWD
Outline diagnosis of VWD
History
FHx
Bleeding assessment
Various underlying causes and types means no single VWD test
Outline management of VWD
Management only at times of severe bleeding/trauma or in [reparation for surgery
Desmopressin (stimulates VWF release from endothelial cells)
TXA
VWF infusion
Factor VIII plus VWF infusion
What causes reduced platelets?
EBV, CMV, HIV
B12 deficiency
Folic acid deficiency
Liver failure- Reduced thrombopoietin production by liver
Leukaemia
Myelodysplastic syndrome
Chemotherapy
What can platelet destruction occur with?
Meds- Sodium valproate, methotrexate
Alcohol
Immune thrombocytopenic purpura (ITP)
Thrombotic thrombocytopenic purpura (TTP)
Heparin-induced thrombocytopenia (HIT)
Haemolytic uraemic syndrome (HUS)
What is thrombocytopenia?
Low platelet count
Outline presentation of thrombocytopenia
<50 x 10^9/L = Easy bruising and prolonged bleeding times
Epistaxis
Bleeding gums
Heavy periods
Easy bruising
Haematuria
Rectal bleeding
What can occur if platelet count <10 x 10^9/L?
Intracranial haemorrhage
GI bleeding
List the differential diagnoses of abnormal bleeding
Thrombocytopenia
VWD
Haemophilia A or B
Disseminated Intravascular Coagulation (DIC)- Usually secondary to sepsis
What is ITP?
Antibodies created against platelets- Thrombocytopenia
How does ITP present?
Purpura- Non-blanching lesions caused by bleeding under skin
Outline management of ITP
Monitor platelet count, control BP and suppress periods
Prednisolone
IV immunoglobulins
Thrombopoietin receptor agonists (eg: Avatrombopag)
Rituximab (targets B cells)
Splenectomy
Outline rituximab
Monoclonal AB
Targets CD20 proteins on surface of B cells
Reduces production of ABs responsible for AI disease
What is Thrombotic Thrombocytopenic Purpura?
Tiny thrombi develop throughout small vessels, using up platelets
Deficiency in ADAMTS13
Causes thrombocytopenia, purpura, tissue ischaemia and end-organ damage
What is the role of ADAMTS13?
Inactivates VWF
Reduces platelet adhesion to vessel walls
Reduces clot formation
What can cause an ADAMTS13 deficiency?
Hereditary
AI diseases
How is TTP managed?
Plasma exchange
Steroids
Rituximab
What is Heparin-Induced Thrombocytopenia?
Antibodies against platelets in response to heparin (usually unfractionated)
Target protein on platelets- PF4
Usually starts 5-10d after starting treatment with heparin
Causes hypercoagulable state and thrombosis
Outline diagnosis of HIT
Test for HIT antibodies in blood
Outline management of HIT
Stop heparin
Use alternative anticoagulant- Fondaparinux or argatroban
What is myelodysplastic syndrome?
Cancer caused by mutation in myeloid cells of bone marrow
Results in inadequate production of blood cells (ineffective haematopoiesis)
What does myelodysplastic syndrome have the potential to turn into?
Acute myeloid leukaemia
What are the features on blood count of myelodysplastic syndrome?
Anaemia
Neutropenia
Thrombocytopenia
Pancytopenia- Low RBCs, WBCs and platelets
What are the risk factors for myelodysplastic syndrome?
Old age
Previous chemo/radiotherapy
Outline diagnosis of myelodysplastic syndrome
Abnormal FBC
May have blasts on blood film
Bone marrow biopsy- Confirms diagnosis
Outline management of Myelodysplastic syndrome
Watchful waiting
Supportive treatment- Blood or platelet transfusions
Erythropoietin- Stimulates RBC production
Granulocyte colony-stimulating factor- Stimulates neutrophil production
Chemo and targeted therapies (eg: Lenalidomide)
Allogenic stem cell transplantation (risky but potentially curative)
What are myeloproliferative disorders?
Uncontrolled proliferation of a single type of stem cell
Form of cancer occurring in bone marrow
Develop and progress slowly
What do myeloproliferative disorders have the potential to develop into?
Acute myeloid leukaemia
What is the proliferating cell line of primary myelofibrosis?
Haematopoietic stem cells
What are the blood findings in primary myelofibrosis?
Low Hb
High or low white cell count
High or low platelet count
What is the proliferating cell line in polycythaemia vera?
Erythroid cells
What are the blood findings in polycythaemia vera?
Megakaryocyte
What are the blood findings in essential thrombocythaemia?
High platelet count
Which gene mutations are associated with myeloproliferative disorders?
JAK2
What is Myelofibrosis?
Can result from primary myelofibrosis/polycythaemia vera/essential thrombocythaemia
Proliferation of single cell line leads to bone marrow fibrosis
Is a response to cytokines released from proliferating cells (fibroblast growth factor)
What is the effect of bone marrow fibrosis in myelofibrosis?
Anaemia
Low WBCs
Low Platelets
As progresses- Production of blood cells happens in other areas (extramedullary haematopoiesis)- Liver and spleen- Hepatomegaly, splenomegaly, portal HTN- If occurs around spine can compress SC
What can a blood film in myelofibrosis show?
Teardrop-shaped RBCs
Anisocytosis (varying sizes of RBCs)
Blasts (immature red and white cells)
Outline presentation of myeloproliferative disorders
Fatigue
Weight loss
Night sweats
Fever
Underlying complications:
Anaemia- Tired, SOB, dizziness
Splenomegaly- Abdo pain
Portal HTN- Ascites, varices abd abdo pain
Low platelets- Bleeding and petechiae
Raised Hb- Itching, headaches, red face
Low WBCs- Infections
Gout- Complication of polycythaemia
What is a common complication of polycythaemia and thrombocythaemia?
Thrombosis- Leads to MI/stroke/VTE
What are the clinical signs of polycythaemia?
Red face
Conjunctival plethora (opposite of conjunctival pallor)
Splenomegaly
HTN
Outline diagnosis of myeloproliferative disorders
Bone marrow biopsy
Myelofibrosis- Bone marrow aspiration dry- Turned to scar tissue
Test genes- JAK2, MPL, CALR
Outline management of primary myelofibrosis
No active treatment for mild disease with minimal symptoms
Supportive management complications
Chemotherapy (eg: Hydroxycarbamide)
Targeted therapy- JAK2 inhibitors (ruxolitinib)
Allogenic stem cell transplantation (risky but potentially curative)
Outline management of polycythaemia vera
Venesection
Aspirin- Reduce risk thrombus formation
Chemotherapy- Hydroxycarbamide
Outline management of essential thrombocythaemia
Aspirin- Reduce risk thrombus formation
Chemo- Hydroxycarbamide
Anagrelide- Platelet lowering agent
What is sickle cell anaemia?
Genetic condition causing sickle shaped RBCs
Makes RBCs more fragile and easily destroyed- Haemolytic anaemia
Patients prone to sickle cell crises
Outline pathophysiology of Sickle Cell Disease (SCD)
HbS
Autosomal recessive
Affects gene for beta-globin on Chr11
Outline SCD and malaria
SCD more common in patients from areas traditionally affected by malaria
Having sickle cell trait reduces severity of malaria
Selective advantage
Outline screening of SCD
Newborn blood spot at 5d
Pregnant at high risk of being carriers offered testing
List complications of SCD
Anaemia
Increased risk of infection
CKD
Sickle cell crises
Acute chest syndrome
Stroke
Avascular necrosis in large joints (hip)
Pulmonary HTN
Gallstones
Priapism
Outline sickle cell crisis
Spectrum of acute exacerbations caused by SCD
Can occur spontaneously or specific triggers
What are the potential triggers of sickle cell crisis?
Dehydration
Infection
Stress
Cold weather
Outline management of sickle cell crisis
Low threshold admission to hospital
Treat infections
Keep warm
Good hydration
Analgesia (avoid NSAIDs if renal impairment)
Outline vaso-occlusive crisis
Painful crisis
Most common type of sickle cell crisis
Sickle-shaped RBCs clog capillaries and cause distal ischaemia
How does a vaso-occlusive crisis present?
Pain and swelling in hands or feet- Can affect chest and back
Fever
Priapism
How is priapism managed in a vaso-occlusive crisis?
Aspirate blood from penis
What is a splenic sequestration crisis?
RBCs block flow within spleen
Causes acutely enlarged, painful spleen
Blood pooling in spleen- Severe anaemia and hypovolaemic shock
EMERGENCY
How is a splenic sequestration crisis managed?
Blood transfusions
Fluid resuscitation
Splenectomy in recurrent cases
What are the complications of splenic sequestration crisis?
Splenic infarction- Hyposplenism, susceptibility to infections (Strep and Haemophilus influenzae)
Outline aplastic crisis
A type of sickle cell crisis
Temporary absence of creation of new RBCs
Triggered by Parvovirus B19
Leads to significant aplastic anaemia
Outline management of aplastic crisis
Usually resolves spontaneously within a week
May require blood transfusions
Outline acute chest syndrome
Type of Sickle cell crisis
Vessels supplying lungs become clogged with RBCs
Vaso-occlusive crisis, fat embolism or infection can trigger this
How does acute chest syndrome present?
Fever
SOB
Chest pain
Cough
Hypoxia
CXR- Pulmonary infiltrates
How is acute chest syndrome managed?
Analgesia
Good hydration
Antibiotics or antivirals if infection
Blood transfusions if anaemia
Incentive spirometry- Machine that encourages effective and deep breathing
Respiratory support- Oxygen
Outline general management of SCD
Avoid triggers
Up to date vaccines
Antibiotic prophylaxis- Pen V
Hydroxycarbamide- Stimulates HbF
Crizanlizumab
Blood transfusions- Severe anaemia
Bone marrow transplant- Can be curative
How does Hydroxycarbamide help in SCD?
Stimulates production of HbF- Doesn’t sickle
Reduces frequency of vaso-occlusive crises, improves anaemia, may extend lifespan
How does Crizanlizumab help in SCD?
Monoclonal AB- Targets P-selectin (adhesion molecule on endothelial cells inside walls of blood vessels and platelets)
Prevents RBCs sticking to blood vessel wall, reduces frequency of vaso-occlusive crises
What is leukaemia?
Cancer of a particular line of stem cells in bone marrow
Causes unregulated production of specific type of blood cell
What is AML?
Acute myeloid leukaemia
Rapidly progressing cancer of myeloid cell line
Transformation from myeloproliferative disorder
Auer rods
What is ALL?
Acute lymphoblastic leukaemia
Rapidly progressing cancer of lymphoid cell line- Usually B-lymphocytes
Most common leukaemia in children
Associated with Down syndrome
What is CML?
Chronic myeloid leukaemia
Slowly progressing cancer of myeloid cell line
3 phases- Including long chronic
Philadelphia chromosome
What is CLL?
Chronic lymphocytic leukaemia
Slowly progressing cancer of lymphoid cell line- Usually B-lymphocytes
Warm haemolytic anaemia
Richter’s transformation and smudge cells
>60y
Outline pathophysiology of leukaemia
Genetic mutation in one of precursor cells in bone marrow leads to excessive production of single type abnormal WBC
Suppresses other cell lines- Pancytopenia
What is pancytopenia?
Combination of low RBCs (anaemia), WBCs (leukopenia) and platelets (thrombocytopenia)
Outline presentation of leukaemia
Non-specific:
Fatigue
Fever
Pallor due to anaemia
Petechiae or bruising due to thrombocytopenia
Abnormal bleeding
Lymphadenopathy
Hepatosplenomegaly
Failure to thrive
What are the differentials of non-blanching rash?
Leukaemia
Meningococcal septicaemia
Vasculitis
Henoch-Schonlein purpura (HSP)
ITP
TTP
Traumatic or mechanical (eg: Severe vomiting)
Non-accidental Injury (NAI)
Outline investigations of leukaemia
FBC within 48h if suspected
Blood film
LDH- Raised in leukaemia (non-specific)
Bone marrow biopsy
CT and PET scans (staging)
Lymph node biopsy (assess abnormal lymph nodes)
Genetic tests and immunophenotyping
What is Richter’s transformation?
Rare transformation of CLL into high-grade B-cell lymphoma
What are smear/smudge cells?
Ruptured WBCs that occur whilst preparing blood film- Cells aged/fragile
Associated with CLL
Outline general management of leukaemia
Targeted therapy:
Tyrosine kinase inhibitors (ibrutinib)
MA (rituximab- Targets B-cells)
Chemotherapy
Radiotherapy
Bone marrow transplant
Surgery
List complications of chemotherapy
Failure to treat cancer
Stunted growth and development in children
Infections due to immunosuppression
Neurotoxicity
Infertility
Secondary malignancy
Cardiotoxicity
Tumour lysis syndrome
What is tumour lysis syndrome?
Result of chemotherapy
High uric acid
High potassium
High phosphate
Low calcium
Uric acid can cause AKI
Hyperkalaemia- Cardiac arrhythmias
Release of cytokines- Systemic inflammation
How is the risk of tumour lysis syndrome managed?
Good hydration and urine output before chemotherapy
Allopurinol or rasburicase- Suppress uric acid levels
What is lymphoma?
Cancer affecting lymphocytes inside lymphatic system
Cancer cells proliferate inside lymph nodes- Lymphadenopathy
Outline Hodgkin’s lymphoma
Most common specific type of lymphoma
Bimodal age distribution 20-25y and 80y
What are the RFs for Hodgkin’s lymphoma?
HIV
EBV
AI conditions- RA and sarcoidosis
FHx
List types of Non-Hodgkin lymphoma
Diffuse large B cell lymphoma
Burkitt lymphoma
MALT lymphoma
What is Diffuse large B cell lymphoma?
NHL
Rapidly growing painless mass in older patients
What is Burkitt lymphoma?
NHL
Associated with EBV and HIV
What is MALT lymphoma?
NHL
Affects mucosa-associated lymphoid tissue- Usually around stomach
List RFs for NHL
HIV
EBV
H. pylori- MALT lymphoma
Hep B or C infection
Exposure to pesticides
Exposure to trichloroethylene
FHx
Outline presentation of lymphoma
Lymphadenopathy- Non-tender, feel firm and rubbery
Hodgkin’s- Lymph node pain after drinking alcohol
B symptoms:
Fever
Weight loss
Night sweats
Fatigue
Itching
Cough
SOB
Abdo pain
Recurrent infections
Outline investigations of lymphoma
Lymph node biopsy
Hodgkin’s- Reed-Sternberg cells- Large B lymphocytes with 2 nuclei and prominent nucleoli
CT, MRI, PET scans- Staging
Which condition are Reed-Sternberg cells found in?
Hodgkin’s lymphocytes
Which condition are Auer rods found in?
AML
Outline Lugano classification
Staging Hodgkin’s and NHL
Stage 1: Confined to one node/group of nodes
Stage 2: >1 group of nodes but on same side of diaphragm
Stage 3: Affects lymph nodes above and below diaphragm
Stage 4: Widespread involvement, including non-lymphatic organs (eg: Lungs/liver)
Outline management of Hodgkin’s lymphoma
Chemo/radiotherapy
Usually curable, though risk of relapse and SEs
What are the risks of chemotherapy in Hodgkin’s lymphoma?
Infections
Cognitive impairment
Secondary cancers (eg: Leukaemia)
Infertility
What are the risks of radiotherapy in Hodgkin’s lymphoma?
Tissue fibrosis
Secondary cancers
Infertility
How is NHL managed?
Watchful waiting
Chemo/radiotherapy
MA- Eg: Rituximab
Stem cell transplantation
What is myeloma?
Type of cancer affecting plasma cells in bone marrow
Cancer in a specific type of plasma cell results in production of large quantities paraprotein (or M protein)- Abnormal antibody/part of antibody
What are plasma cells?
B lymphocytes that produce antibodies
What is multiple myeloma?
Myeloma affects multiple bone marrow areas in body
What is MGUS?
Monoclonal gammopathy of undetermined significance
Production of specific paraprotein w/o other features of myeloma or cancer
Incidental finding in otherwise healthy person
Small risk progression to myeloma (1%/y)
What is smouldering myeloma?
Abnormal plasma cells and paraproteins but no organ damage or symptoms
10% risk/y developing into myeloma
List complications of myeloma
Infection
Bone pain
Fractures
Renal failure
Anaemia
Hypercalcaemia
Peripheral neuropathy
SC compression
Hyperviscosity syndrome
Venous thromboembolism
Outline management of myeloma bone disease
Bisphosphonates- Suppress osteoclast activity
Radiotherapy for bone lesions- Improve bone pain
Orthopaedic surgery- Stabilise bones/treat fractures
Cement augmentation- Improve spine stability and pain
Outline management of myeloma
Chemo:
Bortezomib
Thalidomide
Dexamethasone
High-dose chemo followed by stem cell transplant- Option for fitter patients:
Autologous (uses patient’s stem cells)
Allogenic (stem cells from healthy donor)
Outline prognosis of myeloma
Relapsing-remitting
Never fully cured
Outline xray findings in myeloma
Well-defined lytic lesions (look ‘punched out’
Diffuse osteopenia
Abnormal fractures
Raindrop skull- Multiple lytic lesions seen in skull
What are Bence Jones proteins?
Free light chains (antibodies) in urine
Found in urine in myeloma
What are the 4 key features of myeloma?
C- Calcium elevated
R- Renal failure
A- Anaemia
B- Bone lesions and bone pain
Outline anaemia in myeloma
Most common complication
Cancerous plasma cells invade bone marrow- Suppresses other blood cell lines- Anaemia, leukopenia, thrombocytopenia
Normocytic and normochromic
Outline myeloma bone disease
Increased osteoclast activity and suppressed osteoblast activity
Osteoclasts- Absorb bone
Osteoblasts- Deposit bone
Metabolism of bone imbalanced- More bone reabsorbed than constructed
Abnormal bone areas patchy- Some very thin, others normal= OSTEOLYTIC LESIONS- Weak points lead to pathological fractures
What are the common sites of myeloma bone disease?
Skull
Long bones
Ribs
Spine
Outline presentation of myeloma bone disease
Abnormal bone areas patchy- Some very thin, others normal= OSTEOLYTIC LESIONS- Weak points lead to pathological fractures
Increased osteoclast activity- Calcium reabsorption from bone into blood- Hypercalcaemia
Plasmacytomas- Individual tumours formed by cancerous plasma cells- Occur in bones, replacing normal bone tissue or in soft tissues
Outline renal disease and myeloma
Causes are:
Paraproteins- Deposit in kidneys
Hypercalcaemia- Affect kidney function
Dehydration
Glomerulonephritis
Meds used to treat condition
Outline hyperviscosity syndrome and myeloma
Plasma viscosity increases when more proteins in blood- Paraproteins
EMERGENCY
What are the complications of hyperviscosity syndrome in myeloma?
Bleeding- Nosebleeds and bleeding gums
Visual symptoms and eye changes (eg: Retinal haemorrhages)
Stroke
HF
What are the risk factors for myeloma?
Older age
Male
Black ethnic origin
FHx
Obesity
Outline presentation of myeloma
Persistent bone pain
Pathological fractures
Unexplained fatigue
Unexplained weight loss
Fever of unknown origin
Hypercalcaemia
Anaemia
Renal impairment
Outline investigations of myeloma
FBC- Anaemia or leukopenia
Calcium- Raised
ESR- Increased
Plasma viscosity- Increased
U&Es- Renal impairment
Serum protein electrophoresis- Detect paraproteinaemia
Serum-free light-chain assay- Detect abnormally abundant light chains
Urine protein electrophoresis- Detect Bence-Jones protein
Bone marrow biopsy- Confirms diagnosis
Imaging:
1. Whole body MRI
2. Whole body low-dose CT
3. Skeletal survey (Xray)
