5a - When Haemopoiesis goes wrong Flashcards Preview

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Flashcards in 5a - When Haemopoiesis goes wrong Deck (47):

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? 

  1. Polycythaemia vera
  2. Essential thrombocythaemia
  3. Primary myelofibrosis
  4. 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
  • Pruritis
  • Splenic discomfort , splenomegaly
  • Gout
  • 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

  1. Relative = normal red cell mass with ↓ plasma volume 
  2. Absolute = ↑ red cell mass:


Define primary and secondary polycythemia

  • Primarypolycythaemia 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
  • Phaeochromocytoma 


Give an example of physiologically appropriate overproduction of EPO

  1. Central Hypoxia – Chronic lung disease R to L shunts; Training at altitude CO poisoning
  2. 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)
  • Headaches
  • 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

  • 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? 

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 splenomegalypain, 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
  • Hydroxycarbamide
  • Folic acid
  • Allopurinol
  • Blood transfusions
  • 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 

  1. Patients may present with symptomatic splenomegaly, hyperviscosity (sticky blood) or bone pain
  2. 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 

Increased removal  

  • 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? 

  • B12/folate deficiency
  • Bone marrow infiltration by malignancy (blood cancers of other cancers)
  • Marrow fibrosis
  • Radiation
  • 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 ? 

  1. Acquired 
  2. Inherited (rare) 


What are the three broad ways in which thrombocytopenia arises? 

  1. Decreased production
  2. Increased destruction 
  3. 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
  • Mucosal bleeding
  • 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? 

  • Immunosuppression (corticosteroids or Intravenous immunoglobulin first line)
  • Platelet transfusions do not work (as the transfuse platelets get destroyed too)