My Clinical Notes

• Describes a group of conditions arising from marrow stem cells and charcterised by clonal proliferation of one or more haematopoetic components in the bone marrow  and in many cases the liver and the spleen
• Three disorders are included in this classification;
  • Polycythaemia rubra vera (PRV)
  • Essential thrombocythaemia (ET)
  • Myelofibrosis
• There is a common aetiology with a mutation in the cytoplasmic tyrosine kinase, JAK-2 occuring in almost all patients with PRV and half of the patients with ET and myelofibrosis
• The mutation occurs in a highly conserved region of the pseudokinase gene which is believed to be important in negative regulation of JAK-2 signalling
• JAK-2 is involved in the signal transduction of various growth factor e.g. IL-3, EPO. GM-CSF
• CML used to be classed as a myeloproliferative disorder but is now recognized as a separate entity

 

Polycythaemia

 

• Also called erythrocytosis is defined as an increase in Hb concentration above the normal limit for a person’s age and sex
• It can be divided into ABSOLUTE polycythaemia where there is an increased red cell mass and RELATIVE polycythaemia where the red cell mass is normal but the plasma volume is reduced
• Absolute polycythaemia can be divided into primary and secondary
• Causes
  • Primary
    • Polycythaemia rubra vera
    • Familial polycythaemia
  • Secondary
    • Appropriately increased EPO i.e.;
      • High altitude
      • Chronic lung disease
      • Cyanotic heart disease
      • Increased affinity haemoglobin
      • Heavy cigarette smoking
    • Inappropriate EPO increase;
      • Renal disease e.g. carcinoma, cysts, transplants
      • Uterine leiomyoma
      • Hepatocellular carcinoma
      • Cerebellar haemangioblastoma

 

• Causes of relative polycythaemia
  • Fluid depletion – dehydration and plasma loss (e.g. burns)
  • Cigarette smoking
  • Stress (associated with smoking, alcohol, hypertension, obesity and diuretic therapy)

 

Polycythaemia rubra vera

 

• Seen in older patients with an equal sex incidence
• Clinical features are a result of hyperviscosity, hypervolaemia or hypermetabolism
  • Headaches, dyspnoea, blurred vision, night sweats and purities
  • Plethoric appearance – ruddy cyanosis and retinal venous engorgement
  • Splenomegaly
  • Haemorrhage (GI, uterine, cerebral) or venous/arterial thrombosis
  • Hypertension
  • Gout
  • Peptic ulceration

 

Haematological findings include;

• Increased HB, haematocrit and red cell count
• Raised WCC
• Raised neutrophil alkaline phosphatase
• Raised platelet count
• BM hyperplasia of erythroid, granulocytic and megakaryocytic cell
• Decreased serum EPO
• Increased plasma urate
• Increased total blood vol and viscosity
• PCR for JAK2 mutation

 

Treatment

• Aimed at achieving a normal blood count, a haematocrit of 0.45 and a platelet count below 400 x109
• Venesection – doesn’t control platelet count
• Cytotoxic myelosuppression e.g. hydroxyurea
• Phosphorus-32 therapy – usually reserved for older people with severe disease. Patients may go on to develop leukaemia
• Interferon – given subcut
• Asprin – reduces thrombotic complications without an increased risk of major haemorrhage

 

Course and prognosis

• Generally prognosis is good with a median survival of 10-16 years
• Main clinical problems are thrombosis and haemorrhage
• 30% of patients progress to myelofibrosis
• 5% progress to AML

 

Essential thrombocythaemia

 

• Here there is a sustained increase in platelet count, because of megakeryocyte proliferation and production of platelet
• The central diagnostic feature is a platelet count of >400

 

Causes of a raised platelet count;

• Reactive (need to be excluded before there is a diagnosis of ET)
  • Haemorrhage, trauma, post operatively
  • Chronic iron deficiency
  • Malignancy
  • Chronic infections
  • CT diseases (e.g. RA)
  • Post splenectomy
• Endogenous
  • Essential thrombocytopenia
  • Some cases of PRV, myelofibrosis and CML

 

Clinical and lab findings

• Dominant clinical features are thrombosis and haemorrhage
• A characteristic symptom is erythromelalgia, a burning sensation felt in the hands or feet that is promptly relieved by asprin
• Some patients have a splenomegaly, the others may have splenic atrophy because of infarction
• Abnormal large platelets and megakaryocyte fragments may be seen on the blood film
• BM is similar to PRV but there may be an excess of abnormal megakaryocytes
• Cytogenics for the BCR-ABL fusion protein should be done to exclude CML
• Platelet function tests are abnormal with a failure of aggregation

 

Treatment

• Hydroxyurea and interferon
• In those with high risk of complications, keep the platelet count below 600
• Asprin is used to reduce the thrombotic risk and in young patients with low risk it may be the drug of choice

 

Course

• Often the disease is stationary for 10-20 years
• Disease may transform to myelofibrosis although the risk of transformation to AML is low (<5%)

 

Myelofibrosis

 

• Predominant feature is a progressive generalized reactive fibrosis of the bone marrow in association with the development of haematopoeisis in the spleen and liver (called myeloid metaplasia)
• Clinically this results in anaemia and massive hepatosplenomegaly
• In some patients there is osterosclerosis
• The fibrosis of the bone marrow is secondary to hyperplasia of abnormal megakaryocytes with fibroblasts being stimulated by PDGF and other cytokines released by the platelets and megakaryocytes
• 1/3 of patients have a previous history of PRV

 

Clinical features

• Insidious onset in elderly people with anaemia
• Symptoms resulting from splenomegaly – abdo discomfort, indigestion, pain
• Hypermetabolic symptoms – loss of weight, anorexia, fever, night sweats
• Bleeding problems
• Bone pain
• Gout

 

Lab findings

• Anaemia
• White cell and platelet counts are generally high at the time of presentation. Later leucopenia and thrombocytopenia can develop
• In the peripheral blood film there are characteristic ‘tear-drop’ poikilocytes
• BM is usually unobtainable by aspiration and trephine biopsy shows a fibrotic hypercellular marrow. Increased megkaryocytes and frequently seen
• Neutrophul alkaline phosphatase is generally increased
• High serum urate and LDH – reflecting increased turnover of haematopoietic cells
• Transformation to AML occurs in 10-20% of patients

 

Treatment

• Usually palliative and aims to reduce the anaemia and splenomegaly
• Blood transfusions and folic acid
• Hydroxyurea
• Splenectomy
• Allopurinol to prevent gout and urate nephropathy
• Allogeneic stem cell transplants may be curative in young patients
• Median survival is 3.5 years
• Cause of death includes, heart failure, infection and leukaemic transformation
• A worse prognosis is associated with an Hb <10, WCC <4 or >30 and the presence of abnormal chromosomes

This entry was posted on Tuesday, January 29th, 2008 at 3:01 pm and is filed under Haematology. You can follow any responses to this entry through the RSS 2.0 feed. You can leave a response, or trackback from your own site.