Wrong Haemopoiesis

Question 1

What else can go wrong with haemopoiesis?

Answer 1

Over production caused by myeloproliferative disorders or as a physiological reaction.

Question 2

What are myeloproliferative disorders?

Answer 2

Essential thrombocytopenia

Polycythemia vera

Myelofibrosis

Chronic Myeloid leukaemia

Question 3

What are the clinical features of myeloproliferative disorders?

Answer 3

Over production of one or several blood elements with dominance of a transformed clone

Hypercellualar marrow / Marrow fibrosis

Cytogenetic abnormalities Thrombotic and / or haemorrhaging diatheses

Extramedullary haemopoiesis (liver / spleen)

Potential to transform to acute leukaemia

Overlapping clinical features.

Question 4

Genetic mutation?

Answer 4

Point mutation in one copy of the Janus kinase 2 gene (JAK2) -a cytoplasmic tyrosine kinase on chromosome 9 which causes increased proliferation and survival of haematopoietic precursors. We now have specific drug targeting the aberrant protein

Question 5

Polycythaemia Vera?

Answer 5

Too many red cells

Diagnostic criteria = High haematocrit or raised red celll mass

JAK2 mutation is present in approx 95% PRV patients

No reactive cause found

Same patients also have high platelets and neutrophils

Median age 60yrs.

Males=Females

Question 6

Clinical features of PV?

Answer 6

Significant cause of arterial thrombosis

Venous thrombosis

Haemorrhage into the skin / GI tract

Pruritis - itching especially when wet

Splenic discomfort

Gout

In some transformations to myelofibrosis or acute leukaemia

Question 7

PV management?

Answer 7

Venesection to maintain the Hct to <0.45

Aspiring 75mg unless contraindicated

Manage CVS risk factors

Some drugs to reduce the overproduction of cells should be considered.

Question 8

Polycythemia?

Answer 8

An increase in circulation red blood cell concentration typified by a persistently raised haematocrit.

Relative = Diatuetic (causes dehydration), clinical dehydration. -normal red cell mass with decreased plasma volume.

Absolute = Primary or Secondary - increased red cell mass

Primary = Polycythaemia Vera

Secondary = Driven by erythropoietin (EPO) production. -

Physiological appropriate in response to tissue hypoxia -

Physiologically inappropriate -Or due to an abnormal high affinity Hb

Question 9

Physiologically appropriate?

Answer 9

Central Hypoxia

• Chronic lung disease
• R to L shuts
• Training at altitude
• CO poisoning

Renal hypoxia

• Renal artery stenosis
• Polycystic disease

Question 10

Pathological EPO production?

Answer 10

Hepatocellular carcinoma

Renal cell cancer

Uterine tumours

Phaeochromocytoma

…all produce ectopic EPO

Question 11

Other causes of EPO in blood?

Answer 11

Doping

Question 12

Management for Throbocythaemia?

Answer 12

CVS risk factors should be aggressively managed

Aspirin

High risk patients (over 60, platelet >1500 or disease related thrombosis / haemorrhage) : Give hydroxycarbomide to retun platelet to normal range.

Question 13

Reactive causes of essential thrombocythaemia?

Answer 13

Infection

Inflammation (Imflammatory bowel disease, RA)

Other tissue injury (surgery, trauma, burns)

Haemorrhage

Cancer

Redistribution of platelets

Question 14

Myelofibrosis

Answer 14

Bone eventually ossifies.

Little space for haematopoiesis so blood count go down

Look like tear drops red cells in fibrotic bone marrow.

Massive splenomegaly and hepatomegaly die to extramedullary haematopoiesis

Question 15

Clinical features of myelofibrosis?

Answer 15

Patients with advanced disease experience severe constitutional symptoms - fatigue, sweats

The consequences of massive splenomegaly -Pain, Early satiety (full quickly), splenic infarction

Progressive marrow failure requiring transfusions of blood products.

Transformation to leukaemia - Early death

Question 16

Chronic myeloid leukaemia?

Answer 16

Usually presents with very high WCC, this may be an incidental finding.

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

Disease of adults v rare in children.

Can get visual disturbance, confusion , tiredness or breathlessness as blood vessels will get clogged up.

Due to philadelphia chromosome (exchange between 9 and 22)

Question 17

Treatment of CML

Answer 17

Philadelphia chromosome - switch of material between 9 and 22.

Fusion of Abel part of 9 and BCR portion of 22.

This turns on tyrosine kinase which leads to proliferation.

Design drug (Imatinib) that competitively binds so that the substrate cannot bind to kinase site.

This means that tumour cells cannot proliferate.

Median survival has gone form 5 years to 20 years with this drug.

Also no longer need bone marrow transplants in the first 6 months.

Question 18

Pancytopenia?

Answer 18

Reduction in white cells red cells and platelets

It is caused by reduced production or increased removal.

Increased removal is less likely as the cause.

Question 19

Increase removal?

Answer 19

Immune destruction - rare to cause pancytopenia

Splenic pooling - Hypersplenism in massive splenomegaly

Haemophagocytosis + chewing up of the cells in the bone marrow (vv rare)

Question 20

Reduced production?

Answer 20

B12 / Folate deficiency

Bone marrow infiltration by malignancy (blood cancers of other cancers)

Marrow fibrosis

Radiation

Drugs - chemotherapy, antibiotics, anticonvulsants, psychotropic drugs, DMARDs

Viruses - EBV, viral hepatitis, HIV, CMV

Idiopathic aplastic anaemia

Congenital bone marrow failure

Question 21

Idiopathic aplastic anaemia

Answer 21

It is pancytopenia with a hypocellular bone marrow in the absence of an abnormal infiltrate and with no increase in reticulum (fibrosis)

High death as treatment difficult Screen for viruses and abnormal stuff…

Death is often due to neutropenic infection or bleeding

Question 22

Platelets?

Answer 22

Key role in Hemostasis to facilitate clot formation initially via a platelet ‘plug’.

Adhesion: to damaged endothelial wall and to vWF (Vin Willebrand Factor)

Activation: change in shape form disk and release granules

Aggregation: clumping together of more platelets to form the plug

Question 23

Platelets disorders?

Answer 23

Quantative - low (thrombocytopenia

Qualitative - Often normal number but defective function

Question 24

Thrombocytopenia?

Answer 24

Inherited or Acquired

-Firstly think of drugs!

Decreased platelet production?

Increased platelet consumption?

Increased platelet destruction?

Question 25

Consequences of severe thrombocytopenia?

Answer 25

Patients generally not symptomatic intel the platelet count gets below 30

Easy bruising

Petechiae, purpura

Mucosal bleeding

Severe bleeding after trauma

Intracranial haemorrhage

Question 26

Immune destruction?

Answer 26

Immune thrombocytopenia purpura most common cause - autoantibodies against glycoproteins

Can be secondary to autoimmune disease e.g. SLE and lymphoproliferative disorders eg lymphoma, CLL

Treated with immunosuppression (corticosteroids or IV immuniglobulins first line)

Platelet transfusions do not work (as the transfuse platelets get distroyed too)

Question 27

What are some disorders of platelet function?

Answer 27

Hereditary (v rare)

E.g. Bernard Soulier syndrome, Glanzmann’s thrombasthenia

Acquired (common)

Aspirin / NSAIDS / Clopidpgrel

Uraemia (raised Urea)

Hypergammaglobulinaemia e.g. myeloma

Myeloproliferative disorders