S5 Haemopoiesis Gone Wrong Flashcards
What can overproduction of cells be caused by?
- myeloproliferative disorders
* physiological reactions
What are 4 examples of myeloproliferative disorders?
- essential thrombocythaemia
- polycythaemia vera
- myelofibrosis
- chronic myeloid leukaemia
What mutation can cause myeloproliferative disorders?
Specific point mutation in one copy of the Janus kinase 2 gene (JAK2) - codes for a cytoplasmic tyrosine kinase which causes increased proliferation and survival of haemopoietic precursors
What is Polycythaemia Vera?
High haematocrit or raised cell mass
(Some also have high platelet and neutrophil count)
JAK2 mutation is present in 95% of patients
Equal in men (haematocrit >0.52) and women (haematocrit >0.48), median age 60yrs
What are the clinical features of Polycythaemia Vera?
- significant cause of arterial thrombosis
- venous thrombosis
- haemorrhage into skin/GI tract
- pruritis (blood in peripheries is thicker)
- splenic discomfort, splenomegaly
- gout
- can go onto myelofibrosis or acute leukaemia
How do you manage Polycythaemia Vera?
- venesection to maintain the haematocrit below 0.45
- aspirin (75mg)
- manage the CVS risk factor
- sometimes consider drugs to reduce overproduction of cells
What is polycythaemia?
An increase in circulating red cell concentration typified by a persistently raised haematocrit
What can cause red cell concentration to increase?
- relative - normal red cell mass, but a reduced plasma volume
- absolute - increase in red cell mass - primary or secondary?
What are primary and secondary increases in red cell mass (absolute) - Polycythaemia?
Primary - Polycythaemia Vera
Secondary - driven by erythropoietin (EPO) production (in response to hypoxia or due to an abnormally high affinity for Hb)
What is essential thrombocythaemia?
High platelet count (excess platelets in blood)
(Also large and excess megakaryocytes in bone marrow)
Can lead to thrombosis
How do you manage essential thrombocythaemia?
- manage CVS risk
- aspirin
- give hydroxycarbomide to high risk patients to return platelet count to normal
What classes as a high risk patient with essential thrombocythaemia?
- over 60 yrs
- have a platelet count of over 1500
- have disease related thrombosis/haemorrhage
If there is a high platelet count, what should you do before assume into essential thrombocythaemia?
Look for and excuse any reaction causes e.g.
- infection
- inflammation
- haemorrhage
- cancer
- redistribution of platelets after a splenectomy or in hyposplenism
Is it persistent rather than transient?
What does myelofibrosis cause?
Causes massive splenomegaly with/without hepatomegaly due to extramedullary haemopoiesis
What is myelofibrosis?
Fibrosis in bone marrow tissue so there is little space for haemopoiesis
What do RBCs look like on a blood film for myelofibrosis?
Tear drop shaped as they’re squeezed out of the bone marrow
How can myelofibrosis occur?
- as an end result of Polycythaemia Vera or essential thrombocythaemia
- as a primary disease
What are the clinical features of myelofibrosis?
- if patient has advanced disease have severe symptoms - fatigue an sweats
- due to splenomegaly experience pain, early satiety (fill up quickly as speed is reducing stomach size) and splenic infarction
- can transform into leukaemia
- early death
How do you manage chronic marrow failure?
Blood transfusions
What does a patient with chronic myeloid leukaemia present with? Who is it more common in?
Presents with high WCC, symptomatic splenomegaly, hyperviscosity and bone pain
Disease in adults (rare in children)
What can you see on the blood film (and marrow) for someone with chronic myeloid leukaemia?
Excess of all myeloid series from blast through to fully mature neutrophils
What drug can be used to treat chronic myeloid leukaemia? What used to be used as treatment?
Imatinib - inhibits BCR-abl fusion from phosphorylating the substrate which switches on a receptor tyrosine kinase that drives proliferation
Previously standard treatment was bone marrow transplant (not very good treatment)
What is pancytopenia?
Reduction in white blood cells, red blood cells and platelets
How can pancytopenia arise?
- reduced production
* increased removal
How can pancytopenia arise from reduced production?
- B12/folate deficiency
- bone marrow infiltration by malignancy
- marrow fibrosis
- radiation
- drugs
- viruses
- idiopathic aplastic anaemia
- congenital bone marrow failure
How can pancytopenia arise from increased removal?
- immune destruction (rare)
- splenic pooling (leads to hypersplenism and splenomegaly)
- haemophagocytosis (very rare)
What is aplastic anaemia?
Pancytopenia with a hypocellular bone marrow - not caused by an abnormal infiltrate or an increase in reticulin (fibrosis)
Autoimmune disease - bone marrow fails to produce RBC, WBC and platelets
Is aplastic anaemia hard or easy to cure?
Hard (immune treatments and bone marrow transplant) but still a high mortality rate (deaths due to neutropenic infection or bleeding)
What are the 3 stages in platelet action?
- Adhesion - to damage endothelial wall (and do vWF - activated clotting)
- Activation - change in shape from disc, release of granules
- Aggregation - clumping together of more platelets to form a ‘plug’
What are the two types of platelet disorders?
- quantitative - low number of platelets
* qualitative - normal number but defective function (thrombocythaemia)
How can you get thrombocytopenia?
- acquired (common) - decreased platelet production, increased platelet consumption, increased platelet destruction
- inherited (rare syndromes)
How can platelet production be decreased?
- B12 or folate deficiency
- acute leukaemia or aplastic anaemia
- liver failure (reduced production of thrombopoietin)
- sepsis
- cytotoxic chemotherapy
How can platelet consumption be increased?
- massive haemorrhage
- disseminated intravascualar coagulation (DIT) in sepsis
- thrombotic thrombocytopenic purpura (clotting in small blood vessels)
How can platelet destruction be increased?
- autoimmune thrombocytopenic purpura (blood doesn’t clot normally)
- drug induced e.g. heparin
- hypersplenism - increased destruction and splenic pooling of platelets
What are the consequences of severe thrombocytopenia?
- generally asymptomatic until platelet count is below 30
- easy bruising
- petechiae and purpura
- mucosal bleeding
- severe bleeding after trauma
- intracranial haemorrhage
Why doesn’t a platelet transfusion work with immune thrombocytopenic purpura?
Transfused platelets are destroyed by spleen as well
What can cause disorders of platelet function?
- hereditary (rare)
- acquired (common) - aspirin, NSAIDS, clopidogrel (decrease) uraemia (blood in urine)(decrease), myeloma, myeloproliferative disorders (increase)
