vaccination should be given, and postoperative penicillin prophylaxis should be considered, although compliance can be poor and the prevalence of resistant organisms is increasing. For those in whom a splenectomy is contraindicated or fails, the last resort is immunosuppressive therapy with azathioprine or cyclophosphamide, which 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. 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 × 109/l. However, bleeding 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 a variety of mechanisms, including direct bone marrow suppression – for example, cytotoxic drugs, alcohol, and chloramphenicol – or by inducing an immune response. Those most commonly 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 that cause bleeding, is associated not only with decreased platelet survival and thrombocytopenia due to immune destruction 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 mortality of around 30% if not recognized and treated. It is more common with unfractionated heparin than with low‐molecular‐weight heparin but can occur with either. Patients receiving heparin for both therapeutic indications, particularly cardiac patients treated with UFH, 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 argatroban by IV infusion for acute HIT or fondaparinux given by daily subcutaneous injection for subsequent treatment or prophylaxis. Warfarin can make acute HIT more severe and should be withdrawn or reversed with vitamin K, and an alternative anticoagulant started.5
Functional platelet defects
By far the most frequent platelet functional defects (Table 24.2) are those acquired following treatment with aspirin or clopidogrel medication. Aspirin works by irreversibly acetylating the platelet enzyme prostaglandin synthase and thereby decreases platelet reactivity and aggregation for the platelet’s entire lifespan. Aspirin also prolongs the skin bleeding time. In recent years, aspirin has become established in treating acute arterial thrombotic events, such as unstable angina and myocardial infarction, and in the secondary prophylaxis of myocardial infarction and transient ischaemic attack and stroke. There is a trend toward decreasing the dose of aspirin, which not only decreases gastrointestinal toxicity but also results in the platelet being irreversibly acetylated by aspirin in the portal circulation; with low total dose, aspirin is then deacetylated within the liver, resulting in no systemic bioavailability of aspirin and thus in no inhibition of the beneficial effects of endothelial cell prostacyclin production. Clopidogrel is another orally active antiplatelet agent that acts by irreversible inhibition of the platelet ADP receptor. Prasugrel and Ticagrelor work by inhibiting irreversibly the same target. Other drugs that affect platelet function include non‐steroidal anti‐inflammatory drugs (NSAIDs), high doses of penicillin and cephalosporins, and some antidepressants and anaesthetics. Abnormal platelet function can occur in any of the myeloproliferative disorders – primary proliferative polycythaemia, essential thrombocythaemia, chronic myeloid leukaemia, and myelofibrosis – leading to both bleeding and thrombosis. Bleeding is paradoxically more common with raised platelet counts, especially when greater than 1000 × 109/l.
Table 24.2 Causes of acquired platelet functional defects other than due to drugs, especially aspirin or clopidogrel.
| Myeloproliferative syndromes |
| Myelodysplasia |
| Uraemia |
| Cardiopulmonary bypass |
Similarly, in myelodysplastic syndromes, in addition to frequent thrombocytopenia, abnormal platelet function is common, and bleeding can cause severe morbidity requiring platelet transfusion; bleeding and infection are the most common causes of death. Abnormalities of platelet function leading to a prolonged bleeding time frequently occur in uraemia. This improves with dialysis and can be specifically treated, if necessary, with desmopressin (DDAVP). Due primarily to proteolytic degradation of platelet surface glycoproteins by plasma, an acquired platelet function defect occurs during extracorporeal circulation in cardiopulmonary bypass. It can be ameliorated by using the fibrinolytic inhibitor aprotinin but may also require platelet transfusion. Congenital functional platelet defects are extremely rare, with an incidence of less than one per million of the population. Deficiency of the platelet‐specific glycoprotein Ib, which allows interaction with the von Willebrand factor, occurs in Bernard–Soulier syndrome; and deficiency of the platelet surface glycoprotein IIb/IIIa occurs in Glanzmann’s thrombasthenia. Deficiency of platelet alpha and dense granules, which are usually released upon platelet aggregation and are involved in the recruitment of large numbers of platelets into the platelet plug, are deficient in storage pool disease.6
Hereditary coagulation defects
Severe deficiency (<0.01 IU/ml) of factor VIII (haemophilia A) or factor IX (haemophilia B) will have been diagnosed at a young age, and management of these conditions is highly specialized and age‐independent. Spontaneous bleeding into muscles and joints is frequent and is managed by infusions of appropriate clotting factor concentrates (Figure 24.1). In addition, many older patients have severe complications of advanced haemophiliac arthropathy and often hepatic impairment due to chronic infection with hepatitis viruses, especially hepatitis C virus but also chronic hepatitis B. Both types of hepatitis can now be successfully treated. Haemophilia A and B both have gender‐linked inheritance and occur in males. Mild (>0.05 IU/ml) and moderate (0.01–0.05 IU/ml) cases may have escaped diagnosis until a later age and will not present until they have a severe haemostatic challenge such as surgery, which can occur at any age. These patients will have a long APTT, and specific factor assays will reveal the diagnosis. Patients with mild haemophilia A can usually be managed with desmopressin, a long‐acting synthetic analogue of vasopressin, the antidiuretic hormone, rather than with clotting factor concentrates, with the attendant cost savings and reduced risk of viral transmission. Female carriers of haemophilia A and B usually have around half the normal levels of the respective clotting factor, although, owing to the randomness of the lyonization effect (random inactivation of one X chromosome in all female cells), up to 30% of carriers have factor VIII or factor IX levels sufficiently low to require treatment at times of surgery. Conversely, many carriers have entirely normal levels of factor VIII and factor IX; therefore, carrier status cannot be determined accurately simply by measuring the appropriate factor levels but instead requires genetic analysis.