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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.

Figure 24.1 Coagulation cascade.

Von Willebrand’s disease is extremely common and has an incidence of up to 1% in the general population. It is autosomally dominantly inherited and, therefore, occurs in males and females equally. The majority of cases are mild; the condition is significantly underdiagnosed, and in milder cases, bleeding occurs only with significant haemostatic challenges. Consequently, mild von Willebrand’s disease can present and be diagnosed at any age. Von Willebrand’s disease is due to a decreased concentration of the protein von Willebrand factor, which is important in mediating platelet adhesion to the subendothelium; von Willebrand factor also circulates non‐covalently bound to coagulation factor VIII and so protects factor VIII from premature proteolytic degradation. Therefore, in von Willebrand’s disease, diminished levels of the von Willebrand factor result in both a mild platelet defect and a mild defect of the coagulation cascade consequent upon the diminished amounts of factor VIII. Unlike in haemophilia, the skin bleeding time is increased, and bleeding tends to be primarily mucocutaneous, with epistaxis, gum bleeding, gastrointestinal bleeding, and menorrhagia. Diagnosis and classification require the determination of factor VIII concentration, the von Willebrand factor antigen, and the von Willebrand factor activity using the ristocetin cofactor activity or collagen‐binding activity and analysis of the von Willebrand factor multimer distribution. Mild type I cases can usually be treated with desmopressin (DDAVP) prior to significant haemostatic challenge, whereas the rarer, more severe forms of von Willebrand’s disease usually require treatment with clotting factor concentrates, which should contain both factor VIII and the von Willebrand factor.⁷ DDAVP is contraindicated in patients with ischaemic heart disease and uncontrolled hypertension.

Figure 24.2 The natural anticoagulant pathway directly inhibits and negatively regulates the formation of thrombin by the coagulation cascade.

Table 24.3 Causes of acquired coagulation defects.

Heparin: unfractionated or low molecular weight

Warfarin

DOAC: Dabigatran, Rivaroxaban, Apixaban, Edoxaban

Liver disease

Specific coagulation factor inhibitors

Disseminated intravascular coagulation

Paraproteins: myeloma, MGUS, amyloid