When Haemopoiesis Goes Wrong... In Other Ways Flashcards
What are myeloproliferative disorders?
- Now classified by WHO as Myeloproliferative neoplasms (MPN)
- Essential Thrombocythaemia
- Polycythaemia Vera
- Myelofibrosis
- Chronic Myeloid Leukaemia
All of these disorders involve dysregulation at the multipotent haematopoietic stem cell
What are the clinical features of myeloprolifertaive disorders?
- Overproduction of one or several blood elements with dominance of a transformed clone.
- Hypercellular marrow / marrow fibrosis - extra deposition of fibrosis in bone marrow
- Cytogenetic abnormalities.
- MOst have thrombotic and/or haemorrhagic diatheses.
- All have extramedullary haemopoiesis (liver/spleen).
- All have potential to transform to acute leukaemia.
- Overlapping clinical features.
What mutation is common in myeloprolifrative disorders?
Many patients have a specific point mutation in one copy of the Janus kinase 2 gene (JAK2)
- a cytoplasmic tyrosine kinase on chromosome 9, which causes increased proliferation and survival of haematopoietic precursors We now have specific drugs targeting the aberrant protein
What is polycythaemia Vera?
• Diagnostic criteria = High haematocrit (>0.52 in men, >0.48 in
women) OR raised red cell mass
• JAK2 V617F mutation is present in approximately 95% PRV patients
• No reactive cause found
• Some patients also have high platelets & neutrophils
• Median age 60 yrs
• Male=Female
What are the clinical features of PV?
Clinical features: • Significant cause of arterial thrombosis • Venous thrombosis • Haemorrhage into skin or GI tract • Pruritis • Splenic discomfort , splenomegaly • Gout • In some transformation to myelofibrosis or acute leukaemia Capillaries burst
How is PV managed?
- Venesection to maintain the Hct to <0.45 - remove blood
- Aspirin 75 mg unless contraindicated - to reduce risk of thrombosis
- Manage CVS risk factors
- Sometimes drugs to reduce the overproduction of cells should be considered
What needs to be considered if high Hb or haematocrit is noted?
Need to consider why
Is this polycythaemia vera or… Is there another explanation?
What else could cause an excess of red cells to be formed?
What is polycythaemia?
• Polycythaemia= an increase in circulating red cell
concentration typified by a persistently raised haematocrit (Hct).
This increase can be;
Relative = normal red cell mass with decreased plasma volume or
Absolute = increased red cell mass
- primary - polycythemia vera - abnormality originates in bone marrow
- Secondary –driven by erythropoietin EPO production - either a physiological response to hypoxia or abnormal production
Check if on diuretics - these can dehydrate
If it is absolute, need to work out if primary or secondary
What are the classes of secondary polycythemia?
Physiologically appropriate EOP production - in response to tissue hypoxia
Pathological EPO production
Other causes of EPO in blood
What are the causes or each of the classes of secondary polycythemia?
Central Hypoxia – Chronic lung disease R to L shunts Training at altitude CO poisoning - red cell mass increases
Renal Hypoxia – Renal artery stenosis Polycystic disease
Hepatocellular carcinoma Renal cell cancer Cerebellar haemangioblastoma Uterine tumours Phaeochromocytoma ..all produce ectopic EPO
Some people give thesmseves erythropoietin so that RBC mass increases so their athletic/cycling performance increases
What is essential thrombocythaemia?
Excess platelets - overproduction of megakaryocytes (large and excess) - leads to thrombotic events
What is the management of essential thrombocythaemia?
• Any cardiovascular risk factors should be aggressively managed
• Aspirin
• High risk patients:
• >60 years, platelet count >1500 or disease-related thrombosis/haemorrhage
• return the platelet count into the normal range with drug such as hydroxycarbomide
- difficult to selectively remove platelets
What should be done if a high platelet count is noted?
Ensure it is persistent rather than transient before investigating for ET
First look for and exclude reactive causes
• Infection
• Inflammation (Inflammatory bowel disease, Rh arthritis)
• Other tissue injury (e.g. surgery, trauma, burns)
• Haemorrhage
• Cancer
• Redistribution of platelets - Post-splenectomy and hyposplenism
What is myelofibrosis?
Heavily fibrotic marrow, little space for haemopoiesis
Blood film shows red cells looking like tear drops
• clonal haemopoietic stem cell proliferation
• May be end result of PV or ET, or
• Primary disease (PMF)
• PMF starts with proliferative phase when all counts may be
high
• Then in all cases progressive pancytopeniadue to bone
marrow fibrosis and hypersplenism
Describe the bone marrow liver and spleeen I myelofibrosis
Increasing stages of collagen and then fibrotic tissue - fewer areas of normal production of blood cells
clinically myelofibrosis quite rare
spleen grows liver starts to grow - they take over with extramedullary haematopoiesis - splenomegaly and hepatomegaly
What are the clinical features of myelofibrosis?
Patients with advanced disease experience severe
constitutional symptoms – fatigue, sweats
• The consequences of massive splenomegaly - big heard spleen - discomfort and swelling of the abdomen
• pain, early satiety (stomach cant expand so get full quickly), splenic infarction
• Progressive marrow failure requiring transfusions of blood products
• Transformation to leukaemia
• Early death
What is CML?
Overproduction of all stages of myeloid cells - promyelocytes, etc etc etc, neutrophils
Very high white count
Pain in the bone marrow - ribs, back, pelvis etc,
bc viscous blood can get stuck - leads to visual disturbance and tiredness as it is not circulating well
• Usually presents with very high WCC, this may be incidental
finding
• Patients may present with symptomatic splenomegaly,
hyperviscosity (sticky blood) or bone pain
• Disease of adults, v rare in children
• Blood film and marrow will show excess of all myeloid series from blast through to fully mature neutrophils
What causes CML?
The Philadelphia chromosome - chromosome 22 with bcr - abl from 9 attached
BCR-abl gene switches on a receptor tyrosise kinase - bcr-abl protein which has an ATP binding site - which drives proliferation of leukaemia cells
What is imatinib?
Tyrosine kinase inhibitor
Imatinib competitively binds to binding site on bcr-abl protein - substrate cannot enter kinase site - tumour cell cannot proliferate
What is pancytopenia
Reduction in white cells, red cells and platelets
Recused production or
Increased removal:
What are ways in which there can be an increased removal or blood cells
- immune destruction (rare to cause pancytopenia)
- splenic pooling (in splenomegaly)
- haemophagocytosis = chewing up of cells in marrow (v v rare)
Why might there be a reduced production of blood cells?
B12/folate deficiency
Bone marrow infiltration by malignancy (blood cancers of other cancers) - if there isn’t solace to make normal blood counts bc infiltrated
Marrow fibrosis
Radiation - precursors die
Drugs – chemotherapy, antibiotics, anticonvulsants, psychotropic drugs, DMARDs
Viruses – EBV, viral hepatitis ,HIV, CMV - can stop bone marrow working temporarily
Idiopathic aplastic anaemia
Congenital bone marrow failure eg Fanconi’s anaemia, dyskeratosis congenital – present in childhood
What is aplastic anaemia?
Pancytopenia with a hypocellular bone marrow in the absence of an abnormal infiltrate and with no increase in reticulin (fibrosis)
Difficult to treat
have to be very fit to be treated
driven by t lymphocytes
problem with thymus gland
heavy immunosupression
Refractory neutropenia infection, fungal infection
Mortality is high as cure is difficult – immune treatments and bone marrow transplantation Deaths often due to neutropenic infection or bleeding
What are the roles of platelets in haemostasis
Key role in Haemostasis to facilitate clot formation, initially via a platelet ‘plug’: Adhesion to damaged endothelial wall and to vWF Activation – change in shape from disc and release of granules Aggregation – clumping together of more platelets to form the plug
