5a - When Haemopoiesis goes wrong

Question 1

Asides from anaemia, how else can haemopoeisis go wrong?

Answer 1

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

Question 2

What are myeloproliferative neoplasms?

Answer 2

• 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

Question 3

What are the 4 major types of MPN?

Answer 3

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

Question 4

What do all these disorders have in common?

Answer 4

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

Question 5

What are the clinical features of myeloproliferative disorders?

Answer 5

• 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

Question 6

What is the most common cause of MPN?

Answer 6

• 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

Question 7

What is polycytheamia vera?

Answer 7

• 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

Question 8

What is Polycythaemia?

Answer 8

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

Question 9

What are some of the clinical features of polycythemia vera?

Answer 9

• 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

Question 10

How is Polycythemia vera managed?

Answer 10

• 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

Question 11

Define the two types of polycythemia

Answer 11

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

Question 12

Define primary and secondary polycythemia

Answer 12

• Primary – polycythaemia vera
• Secondary – driven by erythropoietin EPO production

Question 13

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

Answer 13

• Physiologically appropriate EPO production
• Pathological EPO production
• Other causes of EPO in blood

Question 14

Give an example of pathological appropriate overproduction of EPO

Answer 14

Production of ectopic EPO by:

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

Question 15

Give an example of physiologically appropriate overproduction of EPO

Answer 15

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

Question 16

How is polycythaemia classified?

Answer 16

Question 17

What is Thrombocytosis?

Answer 17

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

Question 18

How does thrombocythapenia arise?

Answer 18

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

Question 19

What is essential thrombocythaemia?

Answer 19

Thrombocytosis which arises from myeloproliferative neoplasm

Question 20

What happens in essential thrombocythaemia?

Answer 20

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

Question 21

Identify the causes of essential thrombocythaeamia

Answer 21

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

Question 22

Identify some common symptoms of essential thrombocythaemia

Answer 22

• 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

Question 23

Identify the treatment of essential thrombocythaemia

Answer 23

• Low risk patients: aspirin
• High risk patients: also given hydroxycarbamide

Question 24

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

Answer 24

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

Question 25

What is myelofibrosis?

Answer 25

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)

Question 26

What does myelofibrosis cause?

Answer 26

* 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**

Question 27

How do blood films appear for myelofibrosis

Answer 27

Blood film shows red cells looking like **tear drops**

Question 28

Identify some complications **myelofibrosis**

Answer 28

* 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

Question 29

What are some _treatments_ of **myelofibrosis**?

Answer 29

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

Question 30

What is chronic myeloid leukaemia?

Answer 30

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

Question 31

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

Answer 31

* Chromosomal translocation called the **Philadelphia chromosome** - a **reciprocal translocation** between chromosomes **9** and **22** * Results in an **oncoprotei**n (BCR-ABL) with **tyrosine kinase** activity * **Switches on a** receptor tyrosine kinase which drives **proliferation**

Question 32

Identify _two_ further characteristics of chronic myeloid leukaemia

Answer 32

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

Question 33

What is pancytopenia?

Answer 33

**Reduction** in white cells, red cells and platelets

Question 34

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

Answer 34

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

Question 35

Identify the causes of pancytopenia?

Answer 35

* **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)_

Question 36

How does pancytopenia caused by reduced production arise?

Answer 36

* **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

Question 37

What is aplastic anaemia?

Answer 37

* 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)**

Question 38

Identify possible treatments for aplastic anaemia

Answer 38

* Immune treatments * Bone marrow transplantation

Question 39

Identify the role of platelets

Answer 39

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

Question 40

Describe the adhesion, activation and aggregation of platelets

Answer 40

* **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

Question 41

What are the two different sorts of platelet disorders

Answer 41

* **Quantitative** – low (thrombocytopenia) * **Qualitative** – often normal number but defective function

Question 42

In what _two_ ways can **thrombocytopenia** arise ?

Answer 42

1. Acquired 2. Inherited (rare)

Question 43

What are the three broad ways in which thrombocytopenia arises?

Answer 43

1. Decreased production 2. Increased destruction 3. Increased consumption

Question 44

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

Answer 44

Question 45

What are the consequences of thrombocytopenia

Answer 45

* Patients can be **assymptomatic** until the platelet count \< 30 * Easy **bruising** * Petechiae, **purpura** * **Mucosal** bleeding * Severe **bleeding** after **trauma** * Intracranial **haemorrhage**

Question 46

What is Immune thrombocytopenic purpura (ITP)

Answer 46

* 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

Question 47

How is Immune thrombocytopenic purpura (ITP) treated?

Answer 47

* Immunosuppression (corticosteroids or Intravenous immunoglobulin first line) * _Platelet transfusions do not work_ (as the transfuse platelets get destroyed too)