Wednesday, 4 April 2012

Neutropenia and Thrombocytopenia

White cells/platelets

*The lower limit of the normal neutrophil count in 2.5 x109 except in black people and the middle east where 1.5 x 109 is normal
*When numbers fall below 0.5 x109 the patient is likely to have recurrent infections, when the count falls to below 0.2 x 109 the risk is very serious
*Neutropenia may be selective of part of a general cytopenia

Causes of Neutropenia

Congenital

  • Kostmann’s syndrome  autosomal recessive disease presenting in the first year of life with life-threatening infections. Mostly caused by mutations in neutrophil elastase

  • Acquired
  • Drug induced  effect is either by direct toxicity of immune “mediated damage
  • Anti-inflammatory drugs (phenylbutazone)
  • Antibacterial drugs (chloramphenicol, co-trimoxazole, sulfasalazine, imipenin
  • Anticonvulsants (phenytoin, carbamazepine)
  • Antithyroids (carbimazole)
  • Hypoglycaemics (tolbutamide)
  • Pheneothiazines (chlorpromazine)
  • Psychotropics and antidepressants (clozapine, mianserin, imipramine)
  • Miscellaneous (gold, penicillamine, mepacrine, frusemide, deferiprone)
  • Benign“ racial or familial
  • Cyclical “ rare syndrome with a 3-4 week periodicity, severe but temporary neutropenia results. Monocytes tend to rise as neutrophils fall
  • Immune
    • Autoimmune
    • SLE
    • Felty’s syndrome
    • Hypersensitivity and anaphylaxis
  • Large granular lymphocytic leukaemia
  • Infections
    • Viral e.g. hepatitis, influenza, HIV
    • Fulminant infections “ military TB, typhoid
  • Part of general pancytopenia
    • BM failure
    • Splenomegaly

Clinical features

  • Particularly associated with infection of the mouth and the throat
  • Ulceration can occur in the mouth, skin and the anus
  • Septicaemia can occur
  • Commensals such as Staph epidermidis and gram-negative organisms of the bowel can become pathogens

Management of neutropenic sepsis

  • Initial examination with FBC, liver and renal function, cultures of blood (peripheral and central if appropriate). CXR if appropriate. Check for pain at sites commonly infected. Don’t perform a rectal examination
  • Empirical antibiotic therapy should be administered promptly to all neutropenic patients at the onset of fever
  • Initial antibiotic therapy “ gentamycin and tazocin
  • Include vancomycin in initial empirical therapy if;
    • You suspect line-related infection
    • There is known colonisation with MRSA
    • There is positive results of blood culture for gram-positive bacteria before final identification and susceptibility testing
    • Patient is very ill with evidence of hypotension or other evidence of cardiovascular impairment
    • There is severe mucositis
  • Give antibiotic treatment for three days to determine efficacy of the initial regime. If the patient becomes afebrile, modify antibiotic therapy for specific organism and continue use of broadspectrum antibiotics for 7 days (can change to oral)
  • If the patient is still febrile for >3days
  • Reassess patient, if this doesn’t yield a cause, there are a number of options;
    • Continue treatment with the initial antibiotic if the patient is not acutely ill and you expect the neutrophil numbers to recover
    • Change or add antibiotics if the patient is ill
    • Add an anti-fungal, generally amphotericin B to the regime
  • Don’t give G-CSF as, although it reduces the period of neutropenia, it does not decrease the period of fever or infection related mortality rates

Thrombocytopenia

  • Abnormal bleeding associated with thrombocytopenia and abnormal platelet function is characterised by spontaneous skin purpura and mucosal haemorrhage and prolonged bleeding after trauma

Causes of Thrombocytopenia

  • Failure of platelet production “ most common cause and generally part of BM failure
    • Selective megakaryocyte depression
    • Rare congenital defects e.g. mutation in the c-MPL thrombopoietin receptor
    • Drugs, chemicals and viral infections
  • Part of general bone marrow failure
    • Cytotoxic drugs
    • Radiotherapy
    • Aplastic anaemia
    • Leukaemia
    • Myelodysplastic syndromes
    • Myelofibrosis
    • Marrow infiltration (e.g. caricinoma, lymphoma)
    • Multiple myeloma
    • Megalobastic anaemia
    • HIV infection
  • Increased consumption of platelets
    • Immune
      • Autoimmune
        • Idiopathic
        • Associated with SLE, CLL, lymphoma
      • Infections – HIV, malaria
      • Drug-induced e.g heparin and quinine
      • Post transfusional purpura – due to antibodies in the recipient developing against platelet antigen Ia (HPA-1a) on transfused platelets
      • Feto-maternal alloimmune thrombocytopenia
    • DIC
    • Thrombotic thrombocytic purpura
  • Abnormal distribution of platelets
    • Splenomegaly
  • Dilutional loss
    • Massive transfusion of stored blood to bleeding patients
  • Autoimmune (idiopathic) thrombocytopenic purpura may be divided into acute and chronic forms

Chronic iodiopathic thrombocytopenic purpura

  • Most common cause of thrombocytopenia without anaemia or neutropenia
  • Highest incidence in women aged 15-50
  • It is usually idiopathic but may be associated with;
  • SLE
  • HIV
  • CLL
  • Hodgkin’s disease
  • Autoimmune haemolytic anaemia

Pathogenesis

  • Platelet autoantibodies (most commonly directed against the glycoprotein IIb-IIIa or Ib complex) results in the premature removal of platelets from the circulationby macrophages particularly in the spleen
  • Normal life span of a platelet is 7-10 days but in ITP it is reduced to a few hours

Clinical features

  • Insidious onset with pretechial haemorrhages, easy bruising and in women menorrhagia
  • Mucosal bleeding can occur but generally intracranial haemorrhage is rare
  • Chronic ITP is generally relapsing and remitting
  • Splenomegaly not generally a sign
Diagnosis
  • Platelet count is generally 10-50 x 109/L
  • Blood film shows reduced numbers of platelets and those that are there are big
  • BM shows normal or increased numbers of megakaryocytes
  • Platelet autoantibodies may be detectable

Treatment

  • In general a platelet count above 50 x 109/L doesn’t require treatment
  • Corticosteroids “ prednisolone
  • Splenectomy
  • High dose IV Ig “ able to produce a rapid rise in platelet count. Particularly useful for patients with life-threatening haemorrhage, in steroid refractory ITP, during pregnancy or prior to surgery
  • Immunosuppressive drugs “ e.g. mycophenolate, ciclosporin
  • Monoclonal antibodies – rituximab (anti-CD20)
  • Platelet transfusions
  • SCT

Acute idiopathic thrombocytopenic purpura

  • Most common in children
  • Can occur following vaccination or infection such as chicken pox of EBV
  • Generally resolves but can become chronic is 5-10% of cases

Disorders of platelet function

  • These are suspected with the patient has normal platelet numbers but still show skin and mucosal haemorrhage and prolonged bleeding time

Hereditary disorders

  • Thrombasthenia “ autosomal recessive disorder leading to failure of primary platelet aggregation because of a deficiency of membrane GPIIb
  • Bernard-Soulier syndrome “ deficiency in GPIb resulting in defective binding to VWF and decreased adherence to exposed subendothelial connective tissue

Acquired disorders

  • Antiplatelet drugs e.g. aspirin
  • Hyperglobulinaemia “ associated with multiple myeloma and Waldenstrom’s disease may cause interference with platelet adherence, release and aggregation
  • Myeloproliferative and myelodysplastic disorders
  • Uraemia â€“ is associated with various abnormalities of platelet function

Investigations

  • Blood count
  • Blood film
  • BM examination to determine whether or not there is a failure in platelet production
  • Screening tests for DIC can be done as well as tests for an underlying disease e.g. HIV, SLE
  • Bleeding time can be investigated or a platelet function test (PFA-100) can be done
  • If von Willebrand disease is suspected , assay of VWF and coagulation factor VIII are required

Aplastic Anaemia

  • Defined as pancytopenia resulting from aplasia of the bone marrow
  • Can be divided into primary and secondary
  • Primary
    • Congenital (Fanconi and non-Fanconi types)
    • Idiopathic acquired – autoimmune CTL
  • Secondary
    • Ionising radiation
    • Chemicals – benzene, organophosphates, DTT, organochlorines, recreational drugs (ecstasy)
    • Drugs
      • Those that cause BM suppression “ cyclophosphamide, anthracyclines, nitroureas
      • Those that occasionally or rarely cause BM suppression “ chlormaphenicol, sulphonamides, gold, anti-inflammatories, antithyroid
    • Viruses “ EBV

Pathogenesis

  • Substantial reduction in the numbers of haematopoietic pluripotent stem cells
  • Due to a fault in the stem cell or an immune reaction that makes them unable to divide and differentiate

Congenital

  • Fanconi type has an autosomal recessive pattern of inheritance
  • It is associated with growth retardation and congenital defects of the skeleton (microcephaly, abscent radii or thumbs), mental retardation, defects of the skin and renal system
  • Defects are involved in DNA repair
  • Cells show increased spontaneous chromosomal breakage “ diagnostic test involved elevated breakage after incubation of peripheral blood lymphocytes with a DNA cross-linking agent
  • Non-Fanconi types include dyskeratosis congenital (sex-linked) associated with mutation in dyskerin or TERC (telomerase reverse transcriptase RNA template) which are both involved in the maintenance of telomere length

Clinical features

  • Peak incidence of onset is 30 with a slight male predominance
  • May be insidious or acute
  • Symptoms and signs result from anaemia, neutropenia and thrombocytopenia
  • Infections, particularly of the mouth and throat are common
  • Generalised infections can be life threatening
  • Bruising
  • Bleeding gums
  • Epistaxes
  • menorrhagia

Life Threatening Thrombocytopenia in Sarcoidosis



Sarcoidosis Presenting as Chronic Thrombocytopenia




Read more: http://myclinicalnotes.com/haematology/white-cellsplatelets#ixzz1r3Dx2lZu

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