Von Willebrand’s disease (vWD) is a heterogeneous group of mainly autosomal dominant disorders in which there is reduced or abnormal circulating von Willebrand factor (vWF); it is the most common inherited bleeding disorder.
Von Willebrand factor has two functions. Firstly, it combines with factor VIII in vivo to produce a procoagulant complex (VIIIc) that protects factor VIII from premature destruction. Hence, factor VIII activity may be reduced in vWD. Secondly, vWF assists platelet adhesion to exposed sub-endothelium of damaged capillaries and is excreted by endothelium and activated platelets. Deficiency of vWF therefore affects platelet adherence and the clotting cascade itself. It ranges from a mild disease of little significance, seen in up to 1% of the population, to a very severe form in which vWF is absent.
Haemophilia A and B (factor VIII and IX deficiency respectively) are X-linked disorders and classically do not affect the female population. As many as a third of female carriers, however, will have sub-threshold factor levels.
Problems and special considerations
Von Willebrand’s disease
This is classified into three main variants:
• Type I (80-90% of cases). vWF is normal but present in diminished quantities.
In pregnancy, vWF increases and may even return to normal, although this may not be the case in patients with severe disease. Following delivery, VIIIc levels can fall dramatically (though this change maybe delayed until late in the puerperium), and there is an increased incidence of postpartum haemorrhage. Levels of VIIIc can be increased by the administration of desmopressin (DDAVP) intravenously.
• Type II (9-15% of cases). There is an abnormal vWF; hence additional release of abnormal vWF following administration of DDAVP does not generally improve the coagulopathy. Clotting does not improve in pregnancy. Several subtypes have been described, including IIA, IIB, IIM, and IIN. In the IIB subtype, abnormal vWF clumps inactivated platelets and causes thrombocytopenia. In this variant, DDAVP exacerbates the coagulopathy because increased amounts of abnormal vWF worsen the thrombocytopenia. In IIN (Normandy), there is an isolated decrease in factor VIII concentration because of decreased affinity of the abnormal vWF for factor VIII, which results in increased factor VIII consumption. Thus it can be confused with haemophilia A.
• Type III (autosomal recessive; < 1% of cases). vWF is undetectable and VIIIc concentration is very low. The bleeding abnormality is severe and does not respond to DDAVP.
No consensus exists regarding the safe levels of VIIIc and vWF for using neuraxial techniques, and the literature consists only of case reports and series.
Haemophilia
Levels of factor VIII may normalise by the end of pregnancy; however, factor IX does not increase and will require supplementation. Half of all fetuses will be affected, and therefore fetal blood sampling and forceps or ventouse deliveries should be avoided unless chorionic villous sampling or amniocentesis has shown the fetus to be unaffected. After delivery, factor VIII level can fall abruptly, resulting in secondary haemorrhage.
Management options
Close liaison with haematologists is necessary throughout pregnancy. A management plan, including treatment for significant haemorrhage, is essential. An epidural is rarely contraindicated in type I vWD, but specialist interpretation of laboratory tests (particularly VIIIc concentration) is required. Because of the sometimes precipitous drop in vWF and VIIIc following delivery, removal of the epidural catheter postpartum may be more of a problem; it is advisable either to remove epidural catheters immediately or to wait until the bleeding diathesis can be assessed.
The usual dose of DDAVP is 20 mg (0.3 mg/kg) in 50 ml of saline given over 30 minutes. DDAVP also stimulates fibrinolysis, so tranexamic acid is often given simultaneously. DDAVP can cause fluid retention and therefore hyponatraemia.
Patients with type I disease may deliver vaginally. Patients with type II or III disease frequently have an elective caesarean section, with correction of their coagulopathy. In this situation, regional anaesthesia has been used if clotting is corrected. Where DDAVP is contraindicated, fresh frozen plasma, cryoprecipitate or infusions of vWF and factor VIII may be given.
In haemophilia, close monitoring of factor VIII or IX levels as appropriate is required. The aim is to bring peripartum factor VIII or IX levels to > 50 IU/dL, which may be achieved by the administration of factor concentrates. DDAVP may be used in some patients with haemophilia A carrier status. Regional analgesia/anaesthesia is generally contraindicated unless haematological advice suggests a fully corrected coagulation profile and the possible risks are outweighed by the benefits particular to the case concerned.
Factor VIII levels rapidly decline in the postpartum period. Supplementation is therefore required in these women and in those with low vWF or factor IX for 3-5 days after delivery, in order to reduce the risk of secondary postpartum haemorrhage.
Key points
• Von Willebrand’s disease is a heterogeneous condition that ranges in severity.
• The commonest form of von Willebrand’s disease is usually improved by pregnancy.
• Coagulation may rapidly deteriorate after delivery in both von Willebrand’s disease and haemophilia.
• In haemophilia, the fetus should be assumed to be affected.
• Specialist advice is necessary before, during and after delivery.
Further reading
Chi C, Kadir RA. Inherited bleeding disorders in pregnancy. Best Pract Res Clin Obstet Gynaecol 2012; 26: 103-17.
Katz D, Beilin Y. Disorders of coagulation in pregnancy. Br J Anaesth 2015; 115: ii75-88.
Pavord S, Rayment R, Madan B, et al.; Royal College of Obstetricians and Gynaecologists.
Management of inherited bleeding disorders in pregnancy. Green-top Guideline 71. BJOG 2017; 124: e193-263.
Peyvandi F, Garagiola I, Young G. The past and future of haemophilia: diagnosis, treatments, and its complications. Lancet 2016; 388: 187-97.