The normal platelet count is between 140 and 400 × 109l−1. There is, however, some reserve and haemostasis is normal with a platelet count of above 80 × 109l−1, assuming normal platelet function. If the platelet count falls below this value, the bleeding time progressively prolongs but spontaneous haemorrhage, in particular intracerebral haemorrhage, does not occur until the platelet count falls below 20 × 109l−1. Platelet numbers can be decreased by three mechanisms: decreased production in the bone marrow, increased peripheral destruction, immune consumption and splenic pooling in gross splenomegaly with hypersplenism. In addition, adverse effects of drugs should always be considered as a possible cause in any case of thrombocytopenia.2

Decreased Platelet Production

Decreased platelet production can be due to any condition that causes infiltration and replacement or aplasia of the bone marrow, for example, aplastic anaemia, leukaemia, lymphoma, carcinoma and myelodysplasia or deficiency of vitamin B12 and folate in megaloblastic anaemia.

Increased Peripheral Destruction

In childhood, immune thrombocytopenic purpura (ITP) is usually an acute self-limiting condition, frequently precipitated by a viral infection, which spontaneously remits. In adults, ITP often has an insidious onset without an obvious precipitant cause and runs a chronic course over many months and years, occasionally being extremely refractory to treatment. ITP is due to the production of an autoantibody against platelets, usually directed against the platelet membrane-specific glycoproteins. The binding of the antibody to the platelet surface antigen results in the uptake of the platelet–antibody complex by the reticuloendothelial system and premature destruction of the platelet. Destruction occurs primarily in the spleen and also in the liver and bone marrow and platelet survival is decreased from the normal 7–10 days to only a few hours. Diagnosis is based on the finding of true thrombocytopenia, together with a normal bone marrow showing normal or increased numbers of megakaryocytes, the progenitor cells of platelets and an absence of an alternative cause of excessive peripheral platelet destruction. A low platelet count from an automated blood cell analyser should always be repeated and the blood film should be examined to exclude artefactual thrombocytopenia due either to the sample having clotted or to platelet clumping caused by the anticoagulant. The clotting screen should be normal. ITP in adults, unlike in childhood, seldom remits spontaneously. The initial treatment is with prednisolone, 1 mg kg−1 daily or intravenous immunoglobulin 0.4 g kg−1 daily for 5 days. The condition is usually steroid responsive but frequently steroid dependent, and attempts to withdraw the steroids result in recurrence of thrombocytopenia. Often, the platelet count will stabilize at an acceptable level of above 50 × 109l−1 on no steroids or only a minimal dose, and in the absence of symptoms this is often well tolerated for many years. If there is no response to steroids or an unacceptably high dose is required to maintain a satisfactory platelet count, alternative therapies include intravenous immunoglobulin, 400 mg kg−1 per day for 3–5 days, which usually raises the platelet count for around 3 weeks and sometimes results in a sustained remission and splenectomy, which, although it does not prevent autoantibody production, does prevent premature platelet destruction by the spleen. A splenectomy is successful in achieving complete remission in about 50–75% of cases progressing as far as surgery. Splenectomy should not, however, be undertaken lightly as it is not without hazard, particularly in the thrombocytopenic patient. In addition to the operative risks, there is the risk of subsequent overwhelming postsplenectomy sepsis: preoperative pneumococcal Haemophilus influenzae, a meningococcal vaccination and postoperative penicillin prophylaxis should therefore be given. For those in whom a splenectomy is contraindicated or fails, immunosuppressive therapy with azathioprine or cyclophosphamide is sometimes effective. Danazol, vitamin C, interferon and ciclosporin have all been tried with varying efficacy, as has extracorporeal absorption of the antibody with a protein A column. New thrombopoietin agonists are becoming available which may have a role in the management of severe symptomatic or refractory ITP. In difficult and refractory cases, none of these therapies is frequently or consistently successful.3

Increased Pooling of Platelets

Under normal circumstances, 25% of the peripheral platelet pool is sequestered within the spleen at any one time. With increasing and massive splenomegaly, this can increase to more than 90%, resulting in a peripheral platelet count falling even to 50 × 109l−1. Bleeding, however, is rare as the platelets appear to be mobilized during haemostatic challenge and the platelet mass is usually normal.4

Thrombocytopenia Due to Drugs

Drugs can cause thrombocytopenia by direct bone marrow suppression, for example, cytotoxic drugs, alcohol and chloramphenicol or by inducing an immune response—those most commonly being implicated are aspirin, paracetamol, antibiotics, anticonvulsants, diuretics and other miscellaneous drugs such as tolbutamide, quinine and quinidine. Heparin causes a characteristic syndrome of heparin-induced thrombocytopenia (HIT), which, unlike other drug-induced causes of thrombocytopenia, is associated not only with decreased platelet survival and thrombocytopenia but also with platelet activation and hence arterial and venous thrombosis.

Consequently, this condition is associated with severe morbidity, due to severe venous or arterial thrombosis and a mortality of around 30%. It is more common with unfractionated heparin than with low molecular weight heparin, but can occur with either. Patients receiving heparin for both prophylactic and therapeutic indications should have their platelet counts regularly monitored to anticipate this serious complication. Treatment of suspected HIT involves immediate withdrawal of heparin and commencement of an alternative method of anticoagulation, such as hirudin or heparan but not warfarin.5

Functional Platelet Defects