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MEH > 5a - When Haemopoiesis goes wrong > Flashcards

5a - When Haemopoiesis goes wrong Flashcards

1
Q

Asides from anaemia, how else can haemopoeisis go wrong?

A

Overproduction of cells - caused by Myeloproliferative disorders or as a physiological reaction (Myeloproliferative neoplasms)

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2
Q

What are myeloproliferative neoplasms?

A
  • 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
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3
Q

What are the 4 major types of MPN?

A
  1. Polycythaemia vera
  2. Essential thrombocythaemia
  3. Primary myelofibrosis
  4. Chronic myeloid leukaemia
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4
Q

What do all these disorders have in common?

A

All of these disorders involve dysregulation at the multipotent haematopoietic stem cell

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5
Q

What are the clinical features of myeloproliferative disorders?

A
  • 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
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6
Q

What is the most common cause of MPN?

A
  • 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
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7
Q

What is polycytheamia vera?

A
  • 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
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8
Q

What is Polycythaemia?

A

Disease state in which the volume percent of erythrocytes in the blood (the haematocrit) exceeds 52% (males) or 48% (females).

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9
Q

What are some of the clinical features of polycythemia vera?

A
  • 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
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10
Q

How is Polycythemia vera managed?

A
  • 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
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11
Q

Define the two types of polycythemia

A
  1. Relative = normal red cell mass with ↓ plasma volume
  2. Absolute = ↑ red cell mass:
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12
Q

Define primary and secondary polycythemia

A
  • Primary – polycythaemia vera
  • Secondary – driven by erythropoietin EPO production
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13
Q

What are the causes of the secondary for each of the classes of secondary polycythaemia

A
  • Physiologically appropriate EPO production
  • Pathological EPO production
  • Other causes of EPO in blood
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14
Q

Give an example of pathological appropriate overproduction of EPO

A

Production of ectopic EPO by:

  • Hepatocellular carcinoma
  • Renal cell cancer
  • Cerebellar haemangioblastoma
  • Uterine tumours
  • Phaeochromocytoma
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15
Q

Give an example of physiologically appropriate overproduction of EPO

A
  1. Central Hypoxia – Chronic lung disease R to L shunts; Training at altitude CO poisoning
  2. Renal Hypoxia – Renal artery stenosis; Polycystic disease
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16
Q

How is polycythaemia classified?

A
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17
Q

What is Thrombocytosis?

A

Increase in the platelet count compared to the normal range of a person of the same gender and age

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18
Q

How does thrombocythapenia arise?

A
  • Common reaction to infection and inflammation
  • From a myeloproliferative neoplasm - essential thrombocythaemia
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19
Q

What is essential thrombocythaemia?

A

Thrombocytosis which arises from myeloproliferative neoplasm

20
Q

What happens in essential thrombocythaemia?

A

Chronic blood cancer characterised by overproduction of platelets by megakaryocytes in the bone marrow

21
Q

Identify the causes of essential thrombocythaeamia

A
  • Half - by JAK2 mutations
  • Mutations in the thrombopoietin receptor can also result in the disease
22
Q

Identify some common symptoms of essential thrombocythaemia

A
  • 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
23
Q

Identify the treatment of essential thrombocythaemia

A
  • Low risk patients: aspirin
  • High risk patients: also given hydroxycarbamide
24
Q

What other reactive causes must we identify and look for when assessing high platelet counts

A
  • Infection
  • Inflammation (Inflammatory bowel disease, Rh arthritis)
  • Other tissue injury (e.g. surgery, trauma, burns)
  • Haemorrhage
  • Cancer
  • Redistribution of platelets - Post-splenectomy and hyposplenism
25
Q

What is myelofibrosis?

A

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)

26
Q

What does myelofibrosis cause?

A
  • 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
27
Q

How do blood films appear for myelofibrosis

A

Blood film shows red cells looking like tear drops

28
Q

Identify some complications myelofibrosis

A
  • 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
29
Q

What are some treatments of myelofibrosis?

A
  • Largely supportive
  • Hydroxycarbamide
  • Folic acid
  • Allopurinol
  • Blood transfusions
  • Sometimes splenectomy
  • Recent drug: ruxolitinib, an inhibitor of JAK2- significantly reduce spleen volume and improve symptoms
30
Q

What is chronic myeloid leukaemia?

A
  • Unregulated growth of myeloid cells in the bone marrow
  • Leading to the accumulation of mature granulocytes (mainly neutrophils) as well as myelocytes in blood
31
Q

What is thought to be the cause of chronic myeloid leukaemia?

A
  • 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
32
Q

Identify two further characteristics of chronic myeloid leukaemia

A
  1. Patients may present with symptomatic splenomegaly, hyperviscosity (sticky blood) or bone pain
  2. Disease of adults
33
Q

What is pancytopenia?

A

Reduction in white cells, red cells and platelets

34
Q

How has the mechanism of chronic myeloid leukaemia lead to drug development for its treatment

A

Drug development ot inhibit the ATP-binding site on the tyrosine kinase i.e. targeted cancer therapy

35
Q

Identify the causes of pancytopenia?

A
  • 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)
36
Q

How does pancytopenia caused by reduced production arise?

A
  • 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
37
Q

What is aplastic anaemia?

A
  • 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)
38
Q

Identify possible treatments for aplastic anaemia

A
  • Immune treatments
  • Bone marrow transplantation
39
Q

Identify the role of platelets

A

Key role in Haemostasis to facilitate clot formation, initially via a platelet ‘plug’:

40
Q

Describe the adhesion, activation and aggregation of platelets

A
  • 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
41
Q

What are the two different sorts of platelet disorders

A
  • Quantitative – low (thrombocytopenia)
  • Qualitative – often normal number but defective function
42
Q

In what two ways can thrombocytopenia arise ?

A
  1. Acquired
  2. Inherited (rare)
43
Q

What are the three broad ways in which thrombocytopenia arises?

A
  1. Decreased production
  2. Increased destruction
  3. Increased consumption
44
Q

Based on the three broad methods, identify some ways in which thrombocytopenia arises

A
45
Q

What are the consequences of thrombocytopenia

A
  • Patients can be assymptomatic until the platelet count < 30
  • Easy bruising
  • Petechiae, purpura
  • Mucosal bleeding
  • Severe bleeding after trauma
  • Intracranial haemorrhage
46
Q

What is Immune thrombocytopenic purpura (ITP)

A
  • 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
47
Q

How is Immune thrombocytopenic purpura (ITP) treated?

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

MEH (6 decks)

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