Asides from anaemia, how else can haemopoeisis go wrong?
Overproduction of cells - caused by Myeloproliferative disorders or as a physiological reaction (Myeloproliferative neoplasms)
What are myeloproliferative neoplasms?
Myeloproliferative neoplasms (MPNs) are a group of diseases of the bone marrow in which excess cells are produced.
- They arise from genetic mutations in the precursors of the myeloid lineage in the bone marrow
What are the 4 major types of MPN?
- Polycythaemia vera
- Essential thrombocythaemia
- Primary myelofibrosis
- Chronic myeloid leukaemia
What do all these disorders have in common?
All of these disorders involve dysregulation at the multipotent haematopoietic stem cell
What are the clinical features of myeloproliferative disorders?
- Overproduction of one or several blood elements with dominance of a transformed clone
- Hypercellular marrow / marrow fibrosis
- Cytogenetic abnormalities
- Thrombotic and/or haemorrhagic diatheses
- Extramedullary haemopoiesis (liver/spleen)
- Potential to transform to acute leukaemia
- Overlapping clinical features
What is the most common cause of MPN?
- Mutation of the gene coding for Janus Kinase 2 (JAK2)
JAK2 is a cytoplasmic tyrosine kinase which normally stimulates erythropoeisis in response to the hormone erythropoietin
- Multipotent stem cells harbouring the JAK2 mutation survive longer and proliferate continuously
What is polycytheamia vera?
- Diagnostic criteria = High haematocrit (>0.52 in men, >0.48 in women) OR raised red cell mass
- JAK2 mutation is almost always present
- No reactive cause found
- Some patients also have high platelets & neutrophils
- Median age 60 yrs
What is Polycythaemia?
Disease state in which the volume percent of erythrocytes in the blood (the haematocrit) exceeds 52% (males) or 48% (females).
What are some of the clinical features of polycythemia vera?
- Significant cause of arterial thrombosis
Venous thrombosis Haemorrhage into skin or GI tract
Splenic discomfort , splenomegaly
- In some transformation to myelofibrosis or acute leukaemia
How is Polycythemia vera managed?
Venesection to maintain the Hct to <0.45
Aspirin 75 mg
- Manage CVS risk factors
- Sometimes drugs to reduce the overproduction of cells should be considered
Define the two types of polycythemia
Relative = normal red cell mass with ↓ plasma volume
Absolute = ↑ red cell mass:
Define primary and secondary polycythemia
Primary – polycythaemia vera
Secondary – driven by erythropoietin EPO production
What are the causes of the secondary for each of the classes of secondary polycythaemia
- Physiologically appropriate EPO production
- Pathological EPO production
- Other causes of EPO in blood
Give an example of pathological appropriate overproduction of EPO
Production of ectopic EPO by:
- Hepatocellular carcinoma
- Renal cell cancer
- Cerebellar haemangioblastoma
- Uterine tumours
Give an example of physiologically appropriate overproduction of EPO
Central Hypoxia – Chronic lung disease R to L shunts; Training at altitude CO poisoning
Renal Hypoxia – Renal artery stenosis; Polycystic disease
How is polycythaemia classified?
What is Thrombocytosis?
Increase in the platelet count compared to the normal range of a person of the same gender and age
How does thrombocythapenia arise?
- Common reaction to infection and inflammation
- From a myeloproliferative neoplasm - essential thrombocythaemia
What is essential thrombocythaemia?
Thrombocytosis which arises from myeloproliferative neoplasm
What happens in essential thrombocythaemia?
Chronic blood cancer characterised by overproduction of platelets by megakaryocytes in the bone marrow
Identify the causes of essential thrombocythaeamia
- Half - by JAK2 mutations
- Mutations in the thrombopoietin receptor can also result in the disease
Identify some common symptoms of essential thrombocythaemia
Numbness in the extremities
Thrombosis (most often arterial e.g. stroke or peripheral gangrene)
Disturbances in hearing and vision (related to microvascular complications)
Burning pain in the hands or feet (Erythromelalgia
Identify the treatment of essential thrombocythaemia
- Low risk patients: aspirin
- High risk patients: also given hydroxycarbamide
What other reactive causes must we identify and look for when assessing high platelet counts
Inflammation (Inflammatory bowel disease, Rh arthritis)
- Other tissue injury (e.g. surgery, trauma, burns)
Redistribution of platelets - Post-splenectomy and hyposplenism
What is myelofibrosis?
A myeloproliferative neoplasm where the proliferation of mutated hematopoietic stem cells results in reactive bone marrow fibrosis eventually leading to the replacement of marrow with scar tissue (collagen deposition)
What does myelofibrosis cause?
- Heavily fibrotic marrow; little space for haemopoiesis
Extramedullary haemopoeisis - because of massive splenomegaly +/- hepatomegaly
- Results in progressive pancytopenia due to bone marrow fibrosis and hypersplenism
How do blood films appear for myelofibrosis
Blood film shows red cells looking like tear drops
Identify some complications myelofibrosis
- Patients with advanced disease experience severe constitutional symptoms – fatigue, sweats
- Consequences of massive splenomegaly: pain, early satiety, splenic infarction
Progressive marrow failure requiring transfusions of blood products
- Transformation to leukaemia
- Early death
What are some treatments of myelofibrosis?
- Largely supportive
- Sometimes splenectomy
- Recent drug: ruxolitinib, an inhibitor of JAK2- significantly reduce spleen volume and improve symptoms
What is chronic myeloid leukaemia?
Unregulated growth of myeloid cells in the bone marrow
- Leading to the accumulation of mature granulocytes (mainly neutrophils) as well as myelocytes in blood
What is thought to be the cause of chronic myeloid leukaemia?
- Chromosomal translocation called the Philadelphia chromosome - a reciprocal translocation between chromosomes 9 and 22
- Results in an oncoprotein (BCR-ABL) with tyrosine kinase activity
Switches on a receptor tyrosine kinase which drives proliferation
Identify two further characteristics of chronic myeloid leukaemia
- Patients may present with symptomatic splenomegaly, hyperviscosity (sticky blood) or bone pain
- Disease of adults
What is pancytopenia?
Reduction in white cells, red cells and platelets
How has the mechanism of chronic myeloid leukaemia lead to drug development for its treatment
Drug development ot inhibit the ATP-binding site on the tyrosine kinase i.e. targeted cancer therapy
Identify the causes of pancytopenia?
- Reduced production
- Immune destruction (rare)
- Splenic pooling/ Hypersplenism in Massive splenomegaly
- Haemophagocytosis - Chewing up of the cells in the bone marrow (very rare)
How does pancytopenia caused by reduced production arise?
Bone marrow infiltration by malignancy (blood cancers of other cancers)
Drugs – chemotherapy, antibiotics, anticonvulsants, psychotropic drugs, DMARD
Viruses – EBV, viral hepatitis ,HIV, CMV
- Idiopathic aplastic anaemia
Congenital bone marrow failure eg Fanconi’s anaemia, dyskeratosis congenital – present in childhood
What is aplastic anaemia?
- Disease resulting in damage to bone marrow and hematopoietic stem cells leading to pancytopenia (a deficiency of all three blood cell types: RBCs, WBCs and platelets
- “Aplastic” - inability of the stem cells to generate mature blood cells
Pancytopenia with a hypocellular bone marrow in the absence of an abnormal infiltrate and with no increase in reticulin (fibrosis)
Identify possible treatments for aplastic anaemia
- Immune treatments
- Bone marrow transplantation
Identify the role of platelets
Key role in Haemostasis to facilitate clot formation, initially via a platelet ‘plug’:
Describe the adhesion, activation and aggregation of platelets
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
What are the two different sorts of platelet disorders
Quantitative – low (thrombocytopenia)
Qualitative – often normal number but defective function
In what two ways can thrombocytopenia arise ?
- Inherited (rare)
What are the three broad ways in which thrombocytopenia arises?
- Decreased production
- Increased destruction
- Increased consumption
Based on the three broad methods, identify some ways in which thrombocytopenia arises
What are the consequences of thrombocytopenia
- Patients can be assymptomatic until the platelet count < 30
- Easy bruising
- Petechiae, purpura
- Severe bleeding after trauma
- Intracranial haemorrhage
What is Immune thrombocytopenic purpura (ITP)
- Autoimmune disease characterised by isolated thrombocytopenia
- Caused by autoantibodies against Glycoprotein(GP) IIb/IIIa and GPIb/IX
- Can be secondary to autoimmune disease eg SLE and lymphoproliferative disorders eg lymphoma, CLL
How is Immune thrombocytopenic purpura (ITP) treated?