Changes of von Willebrand Factor during Pregnancy in Women with and without von Willebrand Disease

Abstract

Delivery in von Willebrand disease (VWD) represents a significant hemostatic challenge because of the variable pattern of changes observed during pregnancy of von Willebrand factor (VWF) and factor VIII (FVIII), the protein carried by VWF. Since a wide heterogeneity of phenotypes and of the underlying pathophysiological mechanisms is associated with this disorder, a prompt and careful evaluation of pregnant women with VWD is requested in order to plan the most appropriate treatment at time of parturition. VWF and FVIII increase significantly during pregnancy in normal women, already within the first trimester, reaching levels by far >100 U/dL by the time of parturition. Women with VWD, levels at baseline of VWF and FVIII >30 U/dL have us a high likelihood to achieve normal levels at the end of pregnancy; thus specific anti-hemorrhagic prophylaxis is seldom required. Women with basal level <20 U/dL usually have a poor increase since most of these women carry mutations associated with increased VWF clearance or are compound heterozygous for different VWF mutations; that prevent the achievement of satisfactory hemostatic levels. While women with mutations associated with increased clearance show a full, albeit transitory correction of their hemostatic deficiency after desmopressin administration, compound heterozygous need replacement therapy because they do not respond well to this agent. Patients with abnormal VWF:RCo/VWF:Ag ratio at baseline (e.g. <0.6), typically associated with type 2 VWD, maintain the abnormality throughout pregnancy and VWF:RCo usually does not attain safe levels ≥50 U/dL. These women require replacement therapy with VWF-FVIII concentrates. Delayed post-partum bleeding may occur when replacement therapy is not continued for some days. Tranexamic acid may be useful at discharge to avoid excessive lochia.

Figure 1. Modifications of FVIII and von Willebrand factor levels during normal pregnancy and in women with the more frequent types of von Willebrand disease

From left to right: while during normal pregnancy an equivalent increase of all moieties occurs, several typical and different changes are observed in VWD. Patients with type 1 and increased VWF clearance do not show any significant improvement of their severely reduced baseline levels, while typical type 1 shows a progressive increase achieving normalization by the end of pregnancy and maintaining the normal 1:1 ratio between FVIII and VWF. In type 2A usually VWF:RCo remains markedly low compared to the increase of VWF:Ag and, by far more significant, of FVIII. In type 2M, the abnormal VWF:Ag/VWF:RCo remains unchanged because of small increase of VWF:RCo throughout. In homozygous type 2N, FVIII is normalized by the end of pregnancy, but its level remains significantly reduced compared to the largely increased VWF, which however maintain its reduced ability to bind FVIII.