L10: When haemopoiesis goes wrong... in other ways Flashcards
What else can go wrong with haemopoiesis?
Overproduction of cells
Underproduction of cells
What are myeloproliferative neoplasms?
Group of disease in bone marrow
Excess cells are produced
Genetic mutation in precursor cells of myeloid lineage
What are the 4 main types of myeloproliferative neoplasms?
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
What causes myeloproliferative disorders? Can they be treated?
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
What happens in polycythaemia vera?
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
What are the clinical features of polythaemia vera?
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
How is it polycythaemia vera treated?
Venesection –> remove some RBC–> Hct<0.45
Aspirin 75mg–> antiplatelet effect
Manage CVS risk factors
Sometimes drugs to reduce overproduction
What could be the reasons for raised RBC?
Relative–> normal RC mass with ↓ plasma volume
Absolute–> ↑ RC mass
–> Primary –> polycythaemia vera
–> Secondary –> Erythropoietin EPO production
–> Physiologically appropriate
–> Physiologically inappropiate (pathological)
What would be an physiological appropriate reason for increased EPO?
Hypoxia
- Central–> Chronic lung disease, R to L shunt, Training at altitude, CO poisoning
- Renal –> local hypoxia, renal artery stenosis, polycystic disease
What are the pathological reasons (inappropriate reasons) for EPO?
Hepatocellular carcinoma Renal cell cancer Uterine tumours Phaeochromocytoma (endocrine tumour) All --> abnormal production of EPO
What is essential thrombocythaemia?
Increased platelet production
–> excess platelets in blood
–> megakaryocytes in bone marrow
>50% mutation in JAK2, also can be thrombopoietin receptor
What are the most common symptoms of thrombocythaemia?
Numbness in extremities Thrombosis (most often arterial) Disturbances in hearing and vision Headaches Burning pain in hands or feet
How is essential thrombocythaemia treated?
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
What could be other (secondary) causes of thrombocythaemia?
Infection
Inflammation
Other tissue injury
Haemorrhage
Cancer
Redistribution of platelets–> post splenectomy and hyposplenism
–> ensure it is persistant rather than transient before treating
What is myelofibrosis?
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
What are the consequences of myelofibrosis?
Little space for haemopoiesis
Massive splenomegaly and hepatomegaly –> extramedullary haematopoiesis
What are the symptoms of myelofibrosis?
Splenomegaly (hepatosplenomaegaly) Bruising Fatigue --> other anaemia symptoms Weight loss Fever Increased sweating Portal hypertension
What are the treatment options for myelofibrosis?
Largely supportive –> median survival time -5yrs
Blood transfusion
Splenectomy
Ruxolitinib–> JAK2 inhibitor
What is chronic myeloid leukaemia?
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
What chromosomal translocation is CML associated with?
Philidelphia chromosome
Translocation between chromosome 9 and 22
BCR-abl fusion –> tyrosine kinase activity –> proliferation, differentiation and inhibition of apoptosis
How does the Philidephia translocation cause proliferation? How does the treatment work to stop this?
The tyrosin kinase binds substrate–> phosphorylates it activating it
Imatinib (drug)–> competitively binds to tyrosine kinase –> substrate cannot enter–> tumour cannot develop
What is pancytopenia?
Reduction in RBC, WBC and platelets
What could cause pancytopenia?
Decreased production of cells –> common
Increased removal –> immune destruction, splenic pooling (splenomegaly), haemophagocytosis (chewing up of RBC in bone marrow)
What causes reduced cell production in pancytopenia?
- B12/folate deficiency
- Bone marrow infiltration by other cells
- Marrow fibrosis
- Radiation to bone marrow
- Drugs–> chemotherapy, antibiotics, anticonvulsants, psychotropic drugs
- Virus –> Ebstein Barr virus (glandular fever), viral hepititis, HIV, CMV
- Idiopathic aplastic anaemias- Unknown cause
- Congential bone marrow failure
What are aplastic anaemias?
Pancytopenia caused by hypocellular bone marrow
Absence of abnormal infiltrate and with no increase in reticulin (fibrosis)
What are platelets required for?
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
What are the types of platelet disorders?
Quantitative–> low (thrombocytopenia)
Qualitative–> often normal number but don’t function
What is thrombocytopenia? What are the different categories?
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
What are the symptoms of thrombocytopenia?
Not symptomatic until platelet <30 Easy bruising Petechiae, purpura (small red/purple spots on skin) Mucosal bleeding Severe bleeding after trauma Intercranial haemorrhage
What is immune throbocytopenia purpura? How is it treated?
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
