L10: When haemopoiesis goes wrong... in other ways

Question 1

What else can go wrong with haemopoiesis?

Answer 1

Overproduction of cells

Underproduction of cells

Question 2

What are myeloproliferative neoplasms?

Answer 2

Group of disease in bone marrow
Excess cells are produced
Genetic mutation in precursor cells of myeloid lineage

Question 3

What are the 4 main types of myeloproliferative neoplasms?

Answer 3

1- Polycythaemia vera–> Excess erythrocytes
2- Essential thrombocythaemia–> ↑megakaryocytes–> platelets
3- Primary myelofibrosis–> initial proliferative phase–> replacement of haemopoietic tissue with CT
4- Chronic myeloid leukaemia –> essential granulocytes

Question 4

What causes myeloproliferative disorders? Can they be treated?

Answer 4

Point mutation in one copy of Janus Kinase 2 gene (JAK2) on Chr9
Increased proliferation and survival of haematopoietic precursors
Specific drugs to target the abberant proteins

Question 5

What happens in polycythaemia vera?

Answer 5

Too many erythrocytes produced
Diagnosis criteria –> haematocrit* >0.52 in men and >0.48 in women or raised red cell mass
95% cases caused by mutation in gene coding for JAK2

*ratio of RBC to total volume of blood

Question 6

What are the clinical features of polythaemia vera?

Answer 6

Thromboisis (venous and arterial)--> blood thicker
Haemorrhage (skin or GI)
Headache and dizziness 
Plethora (large amount of body fluids)
Burning pain (hands and feet)
Pruritus (itching of skin)
Splenic discomfort
Gout
Arthritis 
Transform to myelofibrosis or acute leukaemia

Question 7

How is it polycythaemia vera treated?

Answer 7

Venesection –> remove some RBC–> Hct<0.45
Aspirin 75mg–> antiplatelet effect
Manage CVS risk factors
Sometimes drugs to reduce overproduction

Question 8

What could be the reasons for raised RBC?

Answer 8

Relative–> normal RC mass with ↓ plasma volume
Absolute–> ↑ RC mass
–> Primary –> polycythaemia vera
–> Secondary –> Erythropoietin EPO production
–> Physiologically appropriate
–> Physiologically inappropiate (pathological)

Question 9

What would be an physiological appropriate reason for increased EPO?

Answer 9

Hypoxia

• Central–> Chronic lung disease, R to L shunt, Training at altitude, CO poisoning
• Renal –> local hypoxia, renal artery stenosis, polycystic disease

Question 10

What are the pathological reasons (inappropriate reasons) for EPO?

Answer 10

Hepatocellular carcinoma
Renal cell cancer
Uterine tumours
Phaeochromocytoma (endocrine tumour) 
All --> abnormal production of EPO

Question 11

What is essential thrombocythaemia?

Answer 11

Increased platelet production
–> excess platelets in blood
–> megakaryocytes in bone marrow
>50% mutation in JAK2, also can be thrombopoietin receptor

Question 12

What are the most common symptoms of thrombocythaemia?

Answer 12

Numbness in extremities 
Thrombosis (most often arterial)
Disturbances in hearing and vision
Headaches
Burning pain in hands or feet

Question 13

How is essential thrombocythaemia treated?

Answer 13

CVS risk factors managed
Aspirin–> reduce clotting
High risk patients–> >60yrs, platelet count >1500 or disease related thrombosis/haemorrhage
–> Hydroxycarbomide–> returns platelet count to normal

Question 14

What could be other (secondary) causes of thrombocythaemia?

Answer 14

Infection
Inflammation
Other tissue injury
Haemorrhage
Cancer
Redistribution of platelets–> post splenectomy and hyposplenism
–> ensure it is persistant rather than transient before treating

Question 15

What is myelofibrosis?

Answer 15

Proliferation of mutated haemopoietic stem cells result in reactive marrow fibrosis
Replaced with scar tissue (collagen deposition)
Starts proliferative ends as pancytopenia (low blood cell count)
RBC look like tear drops

Question 16

What are the consequences of myelofibrosis?

Answer 16

Little space for haemopoiesis

Massive splenomegaly and hepatomegaly –> extramedullary haematopoiesis

Question 17

What are the symptoms of myelofibrosis?

Answer 17

Splenomegaly (hepatosplenomaegaly)
Bruising
Fatigue --> other anaemia symptoms 
Weight loss 
Fever
Increased sweating 
Portal hypertension

Question 18

What are the treatment options for myelofibrosis?

Answer 18

Largely supportive –> median survival time -5yrs
Blood transfusion
Splenectomy
Ruxolitinib–> JAK2 inhibitor

Question 19

What is chronic myeloid leukaemia?

Answer 19

Acute–> rapidly causes bone marrow failure–> ↑ immature blasts overwhelm the ability to produce mature ones

Chronic–> often found by chance, usually high WBC count
–> unregulated growth of myeloid cells–> accumulation of mature granulocytes in the blood
Disease of adults

Question 20

What chromosomal translocation is CML associated with?

Answer 20

Philidelphia chromosome
Translocation between chromosome 9 and 22
BCR-abl fusion –> tyrosine kinase activity –> proliferation, differentiation and inhibition of apoptosis

Question 21

How does the Philidephia translocation cause proliferation? How does the treatment work to stop this?

Answer 21

The tyrosin kinase binds substrate–> phosphorylates it activating it
Imatinib (drug)–> competitively binds to tyrosine kinase –> substrate cannot enter–> tumour cannot develop

Question 22

What is pancytopenia?

Answer 22

Reduction in RBC, WBC and platelets

Question 23

What could cause pancytopenia?

Answer 23

Decreased production of cells –> common
Increased removal –> immune destruction, splenic pooling (splenomegaly), haemophagocytosis (chewing up of RBC in bone marrow)

Question 24

What causes reduced cell production in pancytopenia?

Answer 24

1. B12/folate deficiency
2. Bone marrow infiltration by other cells
3. Marrow fibrosis
4. Radiation to bone marrow
5. Drugs–> chemotherapy, antibiotics, anticonvulsants, psychotropic drugs
6. Virus –> Ebstein Barr virus (glandular fever), viral hepititis, HIV, CMV
7. Idiopathic aplastic anaemias- Unknown cause
8. Congential bone marrow failure

Question 25

What are aplastic anaemias?

Answer 25

Pancytopenia caused by hypocellular bone marrow

Absence of abnormal infiltrate and with no increase in reticulin (fibrosis)

Question 26

What are platelets required for?

Answer 26

Haemostasis–> facilitate clot formation - platelet plug
Adhesion to damaged endothelial cells and to von Willebrand factor
Activation changes shape from disc–> release granules
Aggregation–> Clumping together of platelet form plug

Question 27

What are the types of platelet disorders?

Answer 27

Quantitative–> low (thrombocytopenia)

Qualitative–> often normal number but don’t function

Question 28

What is thrombocytopenia? What are the different categories?

Answer 28

Low platelet levels
Inherited or aquired
Inherited –> rare
Bernard Souiler syndrome, Glanzmann’s thrombasthenia

Acquired--> more common
--> decreased platelet production
--> increase platelet consumption 
--> Increased platelet destruction
Aspirin, NASIDS, clopidogrel (drugs can cause it)
Uraemia 
Hypergammaglobulinaemia
Myeloproliferative disorders

Question 29

What are the symptoms of thrombocytopenia?

Answer 29

Not symptomatic until platelet <30
Easy bruising
Petechiae, purpura (small red/purple spots on skin)
Mucosal bleeding
Severe bleeding after trauma
Intercranial haemorrhage

Question 30

What is immune throbocytopenia purpura? How is it treated?

Answer 30

Most common
Autoantibodies against glycoprotein on platelets–> IIb/IIIa and GPIB/IX
Can be secondary to autoimmune disease
Treated–> immunosupression (corticosteroids, intravenous immunoglobin first line), splenectomy, throbopoietin receptor agonists
Platelet transfusions do not work–> get destroyed by antibodies too