they are not first‐choice agents for patients with malignancy‐associated thrombosis, but this may change when current trials of these drugs in malignancy are published. At present, they are known to cause increased bleeding, especially in luminal malignancies of the gastrointestinal and urinary tracts.
Warfarin, likewise, is a drug with a narrow therapeutic range, complicated pharmacokinetics, multiple drug interactions, and significant haemorrhagic consequences if given in overdose. Warfarin also requires careful monitoring. There are well‐established guidelines for treating venous thrombosis: an international normalized ratio (INR) of 2–3 for uncomplicated thrombosis and 3–4 for recurrent and complicated thrombosis or in patients with the presence of artificial prosthetic heart valves or similar.
Liver disease is a common cause of an acquired coagulation disorder. In addition to being the site of synthesis of the majority of coagulation proteins, the liver is also extremely important in the clearance of activated clotting factors. In addition, liver disease is often also associated with dysfibrinogenaemia due to increased deposition of sialic acid residues on fibrinogen resulting in charge repulsion and failure to polymerize, and hypofibrinogenaemia due to failure of synthesis. Furthermore, liver disease often causes portal hypertension and hypersplenism with consequent thrombocytopenia due to splenic pooling of platelets. The coagulation defect in liver disease first manifests as a prolongation of the PT and initially is due to decreased production of the active forms of the vitamin K‐dependent clotting proteins, factors II, VII, IX and X. Consequently, vitamin K may be of some use in correcting the coagulation defect in early liver disease. Vitamin K takes a minimum of 6 hours to work, and its effect is maximal at 24 hours. In more advanced liver disease, there is a decreased production of all clotting factors and fibrinogen, except for factor VIII, and vitamin K is usually not effective.10 Disseminated intravascular coagulation is caused by a wide variety of triggering factors and mechanisms and is discussed elsewhere.
Thrombotic thrombocytopenic purpura presents as a classic pentad of fever, thrombocytopenia, neurological and renal involvement, and microangiopathic haemolytic anaemia with red cell fragmentation. It has recently become clear that most thrombotic thrombocytopenic purpura (TTP) cases are due to an autoimmune deficiency of ADAMST13, an enzyme present in the plasma that cleaves high‐molecular‐weight von Willebrand factor multimers. These ultra‐high von Willebrand factor multimers are released from endothelial cells and are usually processed by ADAMST13. If ADAMST13 is deficient, the ultra‐high von Willebrand factor multimers can cause spontaneous aggregation of platelets to the endothelial cells, causing microvascular thrombosis and hence the symptoms of TTP. High‐volume plasma exchange removes the antibody and the ultra‐high‐molecular‐weight multimers, while replacement with plasma results in the patient receiving active enzyme and normal von Willebrand factor multimers. The autoimmune component can be treated either with prednisolone or, more recently, infusions of rituximab. However, the coagulation tests usually remain normal or only very mildly deranged, in contradistinction to the case in disseminated intravascular coagulation, where thrombocytopenia is accompanied by profound disturbances of coagulation. The treatment is with aggressive, large‐volume plasma exchange and plasma transfusion and will involve liaison with haematologists and renal physicians.11
Acquired factor VIII inhibitors are rare, but their incidence is increasing as the population ages. They can occur spontaneously or in association with an underlying autoimmune or lymphoproliferative disorder. Their management involves both treating the active bleeding episode and subsequent efforts to remove or neutralize the antibody. The latter usually involves immunosuppression, although occasionally acquired inhibitors will resolve spontaneously. Treatment of bleeding episodes may require high doses of factor VIII and the use of activated prothrombin complex concentrates or recombinant factor VIIa. Data from the United Kingdom Haemophilia Centre Doctors Organisation has recently shown that the mortality from acquired haemophilia is surprisingly low and that in the elderly patient group, sepsis – an effect of immunosuppression – actually causes more death than bleeding.
Paraproteinaemias can affect coagulation either by non‐specific inhibition of fibrin polymerization by the paraprotein – which can occur in myeloma, Waldenstrom’s macroglobulinaemia, and other lymphoproliferative disorders – or by the paraprotein having specific activity against one or more of the proteins of the coagulation cascade. This is a relatively rare phenomenon, but activity against factor VIII, giving acquired haemophilia, and von Willebrand factor, giving acquired von Willebrand’s disease, is recognized.12
Vascular disorders
In these disorders (Table 24.4), coagulation tests and platelet number and function are normal. The defect lies in the vascular endothelium and supporting tissues.13 Senile purpura is relatively common and occurs on the extensor surfaces of the forearms and hands in particular. It is due to decreased amounts of collagen supporting the small blood vessels, which rupture with minor trauma or apparently spontaneously. The process is considerably accelerated by long‐term treatment with corticosteroids. There is no specific treatment and, other than being cosmetically disturbing, it does not constitute a significant haemorrhagic diathesis. Hereditary haemorrhagic telangiectasia is an autosomally dominantly inherited disease with multiple telangiectasia of the lips, conjunctiva, and oral cavity associated with telangiectasia throughout the gastrointestinal tract and also with pulmonary arteriovenous malformations. The condition tends to become progressively more severe with age and frequently presents in later life, usually as chronic iron deficiency anaemia. Troublesome gastrointestinal bleeding can usually be managed by iron supplementation but may require a chronic transfusion regimen. The fibrinolytic inhibitor tranexamic acid and oestrogens have been used with some success. Owing to the widespread nature of the lesions, surgery is not usually a feasible treatment option.14
Table 24.4 Haemorrhagic vascular defects.
| Senile purpura |
| Steroid purpura |
| Hereditary haemorrhagic telangiectasia |
| Gastrointestinal angiodysplasia |
| Ehlers–Danlos syndrome |
| Henoch–Schönlein purpura |
Scurvy (vitamin C deficiency) is associated with purpura and widespread bleeding, particularly from mucosal surfaces and subperiostally. It is due to both abnormal collagen synthesis and a defect in platelet function but is rare in the Western world, except in association with malnutrition and alcoholism. Amyloidosis may be primary or complicate paraproteinaemias, collagen vascular disorders, and chronic infection. The deposition of amyloid protein in the blood vessels leads to fragility, and consequently purpura is common. Cases of a specific coagulation defect due to absorption of the coagulation factor X by the amyloid protein have occasionally been reported. Ehlers–Danlos syndrome, especially type IV with a deficiency of type III collagen, results in structural weakness of major blood vessels with a tendency to rupture and consequent severe haemorrhage. Henoch–Schönlein purpura is rare in the elderly, being primarily a condition of childhood. It is an anaphylactoid purpura with cutaneous petechia and urticaria, associated with joint swelling, abdominal colic, and melena. Despite the purpura, which is usually a manifestation of severe thrombocytopenia, the platelet count remains normal in this condition. Precipitating drugs should be withdrawn; steroids give relief from the joint and abdominal symptoms.
Thrombotic disorders
Although arterial thrombosis is a major cause of morbidity and mortality, its prevention is not possible at present; likewise, its pathophysiology is not well characterized. Smoking, hyperlipidaemia, and a raised fibrinogen concentration are associated
