Introduction

Individuals diagnosed with inherited bleeding disorders in the UK are registered centrally by the United Kingdom Haemophilia Centre Doctors’ Organisation (UKHCDO) and are provided with a card indicating their diagnosis and the contact details of their local haemophilia centre where further information is available about their precise diagnosis and appropriate haemostatic support. Their advice should be sought as soon as possible about the usual haemostatic strategy and products for the patient concerned.

The most frequently occurring inherited bleeding disorders include von Willebrand disease, haemophilia A, haemophilia B and disorders of platelet function as well as the much less frequently occurring rare disorders of other coagulation factors and hereditary thrombocytopenias.

von Willebrand disease

This is the most frequently occurring bleeding disorder in Western Europe being detected in 1% of the population when routine screening is undertaken although only a fraction of these are symptomatic. Its inheritance is autosomal and usually dominant, occurring equally in males and females.

It is characterized by a quantitative and/or qualitative defect of von Willebrand factor and is classified into three types:

• Type 1 (85% cases) is associated with a mild to moderate deficiency of normally functioning von Willebrand factor.
  
• Type 2 is characterized by a functional defect of von Willebrand factor and is further subdivided into four types:
  
  
  
  • Type 2A (10%) individuals have significant reduction of von Willebrand activity caused by an absence of high-molecular-weight von Willebrand multimers.
    
  • Type 2 B (5%) is characterized by increased avidity for platelets so individuals may present with thrombocytopenia.
    
  • Type 2 M (rare) individuals exhibit decreased platelet binding to the vascular sub-endothelium with normal amounts of high-molecular-weight von Willebrand multimers.
    
  • Type 2 N (rare) is associated with selectively impaired binding of factor VIII.
  
  
• Type 3 (rare) is associated with a severe deficiency (<1%) of von Willebrand factor.

von Willebrand factor is produced in platelets and by the vascular endothelium. This is required for both normal platelet–platelet interaction and platelet binding to the vascular sub-endothelium as well as binding to factor VIII to prevent the proteolysis of this important coagulation factor in the circulation. It is an acute-phase reactant, which is increased in inflammation.

The majority of people with the disorder (type 1) have a quantitative defect of functionally normal von Willebrand factor (normal range of 50–150%). Haemostatic support is, therefore, directed at increasing the amount of available von Willebrand factor either by boosting native values using DDAVP (a synthetic vasopressin) or supplementation with intermediate purity plasma-derived factor VIII concentrate rich in von Willebrand factor (e.g. Haemate P, Wilate). There is as yet no recombinant products available to replenish von Willebrand factor. Those with type 2 and type 3 von Willebrand disease will usually require the latter to restore normal von Willebrand function.

The dose of DDAVP is 0.3 µg/kg to a total not in excess of 30 µg administered intravenously in 100 mL normal saline over 30 min. It may also be given intranasally 150 µg in each nostril. Common side effects which may make it less suited to use in critical care include flushing, hypertension and hyponatraemia. The low sodium is as a consequence of retention of free water necessitating fluid restriction to 1500 mL in the 24 h following administration of DDAVP in order to avoid severe headache. On second and subsequent dosing in a short period of time (<7 days), DDAVP is associated with a degree of tachyphylaxis. Supplementary treatment with concentrate may, therefore, be required when normal levels of von Willebrand activity must be maintained for a period of days, especially in the post-operative setting after major surgeries. In the event of bleeding, the antifibrinolytic agent tranexamic acid may be a useful addition although this must be carefully considered in the presence of a consumptive coagulopathy.

Monitoring of von Willebrand factor replacement is different based on different indications. In most cases, a factor VIII and ristocetin cofactor levels of 100 U/dL if not at least 50 U/dL (in minor cases) will be required to prevent bleeding. Specialized laboratories should be performing these tests since quality checks are crucial in obtaining accurate and reliable results.