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 |
Acquired coagulation defects
Probably the most commonly acquired coagulation defect (Table 24.3) in the elderly is iatrogenic because of the use of the anticoagulants such as unfractionated heparin or low‐molecular‐weight heparin, warfarin, or direct‐acting oral anticoagulants (DOACs). Heparin is given parenterally and acts by potentiating the action of antithrombin to inhibit thrombin. It is a difficult drug to use, with a narrow therapeutic range, complicated pharmacokinetics, and significant interpatient variation in dose requirements. Insufficient heparin will result in thrombosis or extension of previously existing thrombosis, while excess treatment rapidly precipitates haemorrhage, which is potentially life‐threatening. Heparin infusion should be monitored by use of the APTT; the therapeutic range is a ratio of between 1.5 and 2.8 The introduction of low‐molecular‐weight heparins (LMWHs) for both prophylaxis and treatment of venous thrombosis has the significant advantages of a longer half‐life, increased bioavailability, and more predictable pharmacokinetics; consequently, they can be given by once‐daily subcutaneous injection without the need for monitoring, even in the doses required for treatment. Since low‐molecular‐weight heparin has a greater effect on factor Xa than on thrombin (IIa), it cannot be monitored with the APTT but instead requires an antifactor Xa assay. However, in overdosage, even low‐molecular‐weight heparin will prolong the APTT, and bleeding under these circumstances may require neutralization of the heparin with protamine sulfate.9 LMWH use has been shown to have a survival advantage in patients with malignancy and thrombosis and is the anticoagulant of choice in this group.
DOAC use has increased very rapidly in recent years. These drugs are equivalent to warfarin at an INR of 2‐3 but can be given orally and do not require monitoring. They can be used at a treatment dose and a reduced thromboprophylactic dose. They have been used at full dose to treat atrial fibrillation and acute deep vein thrombosis (DVT) and pulmonary embolism (PE), which can now frequently be managed without hospital admission. They have been used at lower doses for extended out‐of‐hospital thromboprophylaxis in high‐risk orthopaedic surgery, such as hip and knee replacement, and secondary prophylaxis in patients with venous thromboembolism. They can also be used in reduced doses in patients with impaired renal function, low body weight, advanced age, or increased risk of bleeding. This flexibility of reduced dosage, not possible with warfarin, and the freedom from blood tests has led to their widespread use.
DOACs are only the equivalent of an INR of 2‐3 and so should not be used in preference to warfarin in those with a higher target range, such as metal mechanical heart valves, recurrent thrombosis with anticoagulation failure, and some patients with antiphospholipid syndrome. At present, 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