Haematology P3 Flashcards
What qualifies as neutropenia?
< 1.5x10^9
Causes of neutropenia:
- viral: HIV, EBV, hepatitis
- drugs: cytotoxics, carbimazole, clozapine
- benign ethnic neutropenia: black African and Afro-Caribbean, no Tx
- haematological malignancy: myelodysplastic, aplastic anaemia
- rheumatological
- SLE
- RA (hypersplenism in Felty’s)
- severe sepsis
- haemodialysis
What causes neutropenic sepsis and what are the features? (how can you prevent)
- 7-14 days post chemotherapy
- neutrophil count <0.5x10^9
- temp >=38 degrees
- sepsis signs
- prophylaxis: fluoroquinolone
Management of neutropenic sepsis:
- Abx immediately
- piperacillin with tazobactam
- if still unwell after 48 hours, meropenem (+vancomycin)
Causes of normocytic anaemia:
- anaemia of chronic disease
- chronic kidney disease
- aplastic anaemia
- haemolytic anaemia
- acute blood loss
Whats is paroxysmal nocturnal haemoglobinuria:
- acquired disorder leading to haemolysis (mainly intravascular)
- caused by increased sensitivity of cell membranes to complement due to lack of glycoprotein glycosyl-phosphatidylinositol (GPI)
- patients more prone to venous thrombosis
Features of paroxysmal nocturnal haemoglobinuria:
- haemolytic anaemia
- pancytopaenia may be present
- haemoglobinuria: dark urine in morning
- thrombosis e.g. Budd-Chiari syndrome
- aplastic anaemia in some patients
Diagnosis of paroxysmal nocturnal haemoglobinuria:
Ham’s test: acid induced haemolysis (not with normal red cells)
Management of paroxysmal nocturnal haemoglobinuria:
- blood product replacement
- anticoagulation
- eculizumab, monoclonal antibody directed against terminal protein C5
- stem cell transplant
When is platelet transfusion offered to a patient with active bleeding?
- platelet count <30x10^9 with bleeding e.g. haematemesis, melaena, prolonged epistaxis
- transfusion thresholds are higher: max <100x10^9 with severe bleeding or bleeding at critical sites e.g. CNS
Platelet transfusions have the highest risk of what compared to other types of blood product:
bacterial contamination
When would platelet transfusions be used prophylactically?
-pre-invasive procedure
-for thrombocytopenia before surgery
-aim for platelet levels of >50x10^9/L for most patients
50-75x10^9/L if high risk bleeding
>100x10^9 if surgery at critical site
When would platelet transfusions be use without active bleeding or planned invasive procedure?
threshold of 10x10^9
CONTRA for platelet transfusions:
- chronic bone marrow failure
- autoimmune thrombocytopenia
- heparin induced thrombocytopenia
- thrombotic thrombocytopenia purpura
What is polycythaemia caused by?
- relative: dehydration, stress (Gaisbock syndrome)
- primary (rubra vera)
- secondary: COPD, altitude, OSA, excessive erythropoietin ( cerebellar haemangioma, hypernephroma, hepatoma, uterine fibroids)
How do you differentiate between the different causes of polycythaemia?
red cell mass studies
-true polycythaemia: >35ml/kg in men and >32ml/kg in women
What is polycythaemia rubra vera?
- myeloproliferative disorder
- clonal proliferation of marrow stem cells leading to increased RCV
- overproduction of neutrophils and platelets
- mutation of JAK2 in 95% of patients
Features of polycythaemia rubra vera:
- hyperviscosity
- pruritus, typically after hot bath
- splenomegaly
- haemorrhage
- plethoric appearance
- HTN
- low ESR
Criteria for JAK2 positive polycythaemia vera:
A1 - high haematocrit or raised red cell mass
A2 - mutation in JAK2
Criteria for JAK2 negative polycythaemia vera:
requires A1, 2 and 3 with either another A or 2 B criteria
A1 - raised red cell mass or haematocrit
A2 - absence of JAK2 mutation
A3 - no cause of secondary erythrocytosis
A4 - palpable splenomegaly
A5 - presence of acquired genetic abnormality in haematopoietic cells
B1 - thrombocytosis
B2 - neutrophil leucocytosis
B3 - radiological evidence of splenomegaly
B4 - endogenous erythroid colonies or low serum erythropoietin
Management of polycytheamia vera:
- aspirin
- venesection - first line
- hydroxyurea - slightly increased risk of secondary leukaemia
- phosphorus-32 therapy
Prognosis of polycytheamia vera:
- thrombotic events
- 5-15% myelofibrosis
- 5-15% acute leukaemia
Post-thrombotic syndrome symptoms and management:
- painful heavy calves
- pruritus
- swelling
- varicose veins
- venous ulceration
- compression stocking once syndrome has developed and keep leg elevated
How do DVT/PE come about in pregnancy?
- hypercoagulable state
- majority in last trimester
- increase in VII, VIII, X and fibrinogen
- decrease in protein S
- uterus presses on IVC causing venous stasis in legs
Treatment of DVT/PE in pregnancy:
- warfarin contraindicated
- LMWH preferred to IV
Neutrophil disorders:
- chronic granulomatous disease
- Chediak-Higashi syndrome
- Leukocyte adhesion deficiency
What happens in chronic granulomatous disease:
- lack of NADPH oxidase reduces ability of phagocytes to produce ROS
- recurrent pneumonias and abscesses (esp catalase positive bacteria e.g. staph aureus and fungi e.g. aspergillus)
- negative nitro blue tetrazolium test
- abnormal dihydrorhodamine flow cytometry test
What happens in Chediak-Higashi syndrome:
- microtubule polymerisation defect which leads to decrease in phagocytosis
- partial albinism and neuropathy
- recurrent bacterial infections
- giant granules in neutrophils and platelets
What happens in leukocyte adhesion deficiency:
- defect of LFA-1 intern (CD18) protein on neutrophils
- recurrent bacterial infections
- delay in umbilical cord sloughing may be seen
- absence of neutrophils/pus at sites of infections
B cell disorders:
- common variable immunodeficiency
- Bruton’s (x-linked) congenital agammaglobulinaemia
- Selective immunoglobulin A deficiency
Common variable immunodeficiency:
- many causes
- hypogammaglobulinaemia
- predisposes to autoimmune disorders and lymphoma
Bruton’s congenital agammaglobulinaemia:
- defect in Bruton’s tyrosine kinase (BTK) gene that leads to severe block in B cell development
- x-linked recessive
- recurrent bacterial infections
- absence of B cells with reduced immunoglobulins
Selective immunoglobulin A deficiency:
- maturation defect in b cells
- most common primary Ab deficiency
- recurrent sinus and respiratory infections
- associated with coeliac disease and may cause false negative coeliac Ab screen
DiGeorge syndrome:
- T cell disorder
- 22q11.2 deletion
- failure to develop 3rd and 4th pharyngeal pouches
- congenital heart disease (e.g. tetralogy of fallot), learning difficulties, hypocalcaemia, recurrent viral/fungal diseases, cleft palate
Combined B and T cell disorders:
- severe combined immunodeficiency
- ataxic telangiectasia
- Wiskott-Aldrich syndrome
- Hyper IgM syndromes
Severe combined immunodeficiency:
- most common x-linked due to defect in common gamma chain, protein in receptors for IL-2
- also due to adenosine deaminase deficiency
Ataxic telangiectasia:
- defect in DNA repair enzymes
- autosomal recessive
- cerebellar ataxia, telangiectasia, recurrent chest infections
- 10% risk malignancy, lymphoma or leukaemia
Wiskott-Aldrich syndrome:
- WASP gene
- x-linked recessive
- recurrent bacterial infections, eczema, thrombocytopenia
- low IgM levels
- increased risk of autoimmune disorders and malignancy
Hyper IgM syndromes:
- mutations in CD40 gene
- infection/pneumocystis pneumonia
- hepatitis
- diarrhoea
What is sickle cell anaemia?
- auotosomal recessive
- synthesis of abnormal haemoglobin chain HbS
- more common in African descent (heterozygous condition offers protection against malaria)
- only symptomatic if severely hypoxic
- symptoms in homozygotes not until 4-6 months when HbS takes over from foetal haemoglobin
- sickle cells are fragile and haemolyse; block small blood vessels
Investigations for sickle cell anaemia:
haemoglobin electrophoresis
Sickle cell crisis management:
- analgesia
- rehydrate
- oxygen
- Abx if evidence of infection
- blood transfusion
- exchange transfusion e.g. if neurological complications
Longer term management of sickle cell anaemia:
- hydroxyurea - increases HbF levels
- receive pneumococcal polysaccharide vaccine every 5 years
Types of sickle cell crises:
- thrombotic (painful)
- sequestration
- acute chest syndrome
- aplastic
- haemolytic
Sickle cell thrombotic crisis:
- painful/vaso-occlusive crisis
- precipitated by infection, dehydration, deoxygenation
- diagnosed clinically
- e.g. avascular necrosis of hip, hand-foot syndrome in children, lungs, spleen and brain
Sequestration crisis in sickle cell:
sickling within organs such as spleen or lungs causes pooling of blood with worsening of anaemia
Acute chest syndrome in sickle cell:
- dyspnoea
- chest pain
- pulmonary infiltrates
- low pO2
- most common cause of death after childhood
Aplastic crisis in sickle cell:
- caused by infection with parvovirus
- sudden all in Hb
- low reticulocyte
Haemolytic crises in sickle cell:
- rare
- fall in Hb due to increased rate of haemolysis
- high reticulocyte
What is sideroblastic anaemia?
- red cells fail to completely form haem
- deposits of iron in mitochondria; ring around nucleus called ring sideroblast
- congenital or acquired
Congenital cause of sideroblastic anaemia:
delta -aminolevulinate synthase-2 deficiency
Acquired causes of sideroblastic anaemia:
- myelodysplasia
- alcohol
- lead
- anti-TB meds
Investigations for sideroblastic anaemia:
- hypochromic microcytic anaemia
- bone marrow: sideroblasts and increased iron stores
Management of sideroblastic anaemia:
- supportive
- treat any underlying cause
- pyridoxine may help
Causes of massive splenomegaly:
- myelofibrosis
- chronic myeloid leukaemia
- visceral leishmaniasis
- malaria
- Gaucher’s syndrome
Other causes of splenomegaly:
- portal HTN
- lymphoproliferative disease
- haemolytic anaemia
- infection: hepatitis, glandular fever
- infective endocarditis
- sickle cell, thalassaemia
- RA (Felty’s)
Causes of severe thrombocytopenia:
- ITP
- DIC
- TTP
- haematological malignancy
Causes of moderate thrombocytopenia:
- heparin induced thrombocytopenia
- drug induced (quinine, diuretics, sulphonamides, aspirin, thiazides)
- alcohol
- liver disease
- hypersplenism
- viral infection
- pregnancy
- SLE/antiphospholipid syndrome
- vit B12 deficiency
What is pseudothrombocytopenia associated with?
EDTA as anticoagulant
What qualifies as thrombocytosis:
> 400x10^9/L
Causes of thrombocytosis:
- reactive e.g. infection, surgery, iron def anaemia
- malignancy
- essential thrombocytosis
- hyposplenism
Essential thrombocytosis:
- one of myeloproliferative disorders
- overlaps with chronic myeloid leukaemia, polycythaemia rubra vera and myelofibrosis
- megakaryocyte proliferation results in overproduction of platelets
Features of essential thrombocytosis:
- platelet >600x10^9/L
- both thrombosis and haemorrhage can be seen
- burning sensation in hands
- JAK2 mutation in 50% patients
Management of essential thrombocytosis:
- hydroxyurea to reduce platelet count
- interferon alpha in younger patients
- low dose aspirin to reduce thrombotic risk
Thrombophilia inherited causes:
Gain of function polymorphisms:
- factors V Leiden (activated protein C resistance) - most common
- prothrombin gene mutation - second most common
- antithrombin III def
- protein C def
- protein S def
Which thrombophilias have the highest relative risk of VTE?
- Factor V Leiden homozygous
- Protein C def
- antithrombin III def
Causes of acquired thrombophilia:
- antiphospholipid syndrome
- COCP
What is TTP?
- abnormally large and sticky multimers of VWF
- clumps in vessels
- deficiency of ADAMTS13 (metalloprotease enzyme)
- overlaps with HUS
Features of TTP:
- rare, typically adult females
- fever
- fluctuating neuro signs (micro emboli)
- microangiopathic haemolytic anaemia
- thrombocytopenia
- renal failure
Causes of TTP:
- post infection
- pregnancy
- drugs: ciclosporin, COCP, penicillin, clopidogrel, acyclovir
- tumours
- SLE
- HIV
What is a thymoma?
- most common tumours of anterior mediastinum
- assoc: myasthenia gravis (30-40%), red cell aplasia, dermatomyositis, SLE, SIADH
- causes of death: compression of airway, cardiac tamponade
What is tranexamic acid used for?
- synthetic derivation of lysine
- antifibrinolytic that reversibly binds to lysine receptor site on plasminogen or plasmin
- commonly for menorrhagia
- IV bolus followed by infusion for major haemorrhage
What is tumour lysis syndrome:
- related to high grade lymphomas and leukaemias
- usually with chemotherapy (occasionally with steroids)
- prophylaxis: IV allopurinol or IV rasburicase
- lower risk: oral allopurinol
- breakdown of tumour cells leads to hyperkalaemia and hyperphosphataemia with hypoclacaemia
- present with AKI and hyperuricaemia
- clinical tumour lysis syndrome: lab tumour lysis syndrome with either increased creatinine (1.5 times) or cardiac arrhythmia/sudden death or seizure
General risk factors for VTE:
- increased risk with advancing age
- obesity
- family history of VTE
- pregnancy
- immobility
- hospitalisation
- anaesthesia
- central venous catheter: femoral»subclavian
Underlying condition risk factors for VTE:
- malignancy
- thrombophilia
- heart failure
- antiphospholipid
- Behcet’s
- polycythaemia
- nephrotic syndrome
- sickle cell
- paroxysmal nocturnal haemoglobinuria
- hyperviscosity syndrome
- homocystinuria
Medication risk factors for VTE:
- COCP
- HRT: higher with oestrogen and progesterone combined
- raloxifene and tamoxifen
- antipsychotics especially onlanzapine
What is B12 used for and how is it absorbed?
- red blood cell development and maintenance of nervous system
- absorbed after binding to IF secreted from parietal cells in stomach
- absorbed in terminal ileum
- small amount absorbed passively
Causes of vitamin B12 deficiency:
- pernicious anaemia: most common
- post gastrectomy
- vegan/poor diet
- disorders of terminal ileum (Crohn’s)
- metformin (rare)
Features of vit B12 deficiency:
- macrocytic anaemia
- sore throat and mouth
- neurological symptoms: dorsal column affected first prior to distal paraesthesia
- neuropsychiatric symptoms
Management of vit B12 deficiency:
- if no neurological involvement 1mg of IM hydroxocobalamin 3 times each week for 2 weeks then every 3 months
- if also deficient in folic acid, treat B12 first to avoid precipitating subacute combined degeneration of cord
What is VW disease?
-most common inherited bleeding disorder
-autosomal dominant
-vWF is carrier molecule for factor VIII, promotes platelet adhesion to damaged endothelium, large glycoprotein which forms massive multimers
type I: partial reduction in vWF (most common)
type II: abnormal form of vWF
type III: total lack of vWF (autosomal recessive)
Investigations for VW disease:
- prolonged bleeding time
- APTT may be prolonged
- factor VIII levels may be moderately reduced
- defective platelet aggregation with ristocetin
Management of VW disease:
- tranexamic acid for mild bleeding
- desmopressin: raised levels of vWF by inducing release of vWF from Weibel-Palade bodes in endothelial cells
- factor VIII concentrate
What is Waldenstrom’s macroglobulinaemia?
- in older men
- lymphoplasmacytoid malignancy characterised by secretion of monoclonal IgM paraprotein
Features of Waldenstrom’s macroglobulinaemia:
- monoclonal IgM paraproteinaemia
- systemic upset: weight los, lethargy
- hyperviscosity syndrome e.g. visual disturbances (pentameric configuration of IgM increases serum viscosity)
- hepatosplenomegaly
- lymphadenopathy
- cryoglobulinaemia e.g. Raynaud’s
What is Wiskott-Aldrich syndrome and what are the features:
- primary immunodeficiency due to combined B and T cell dysfunction
- inherited in X-linked recessive fashion
- mutation in WASP gene
- recurrent bacterial infections e.g. chest, eczema, thrombocytopaenia, low IgM levels
Complication of ileocaecal resection in Crohn’s:
vit B12 def
What is disproportionate microcytic anaemia?
- microcytic anaemia
- drop in MCV much more than Hb
- beta thalassaemia
What type of anaemia does sickle cell cause?
normocytic (low Hb, normal MCV, increased reticulocytes)
What causes an isolated rise in Hb?
polycythaemia vera
What does IgA deficiency put you at increased risk of with transfusions?
anaphylactic reaction
