Given such risk, afected women are treated during pregnancy with heparin regardless of whether they have had a prior thrombosis. When anticoagulation is necessarily withheld, such as during surgery or delivery, Paidas and colleagues (2016) found that treatment with recombinant human antithrombin protected against VTE development. Sharpe and associates (201a1) described successful use of antithrombin concentrate infusions plus therapeutic anticoagulation in a pregnant woman with antithrombin deficiency who developed a thrombosis during the third trimester despite therapeutic LMWH.
When thrombin is bound to thrombomodulin on endothelial cells of small vessels, its procoagulant activities are neutralized. his binding also activates protein C, a natural anticoagulant that in the presence of protein S controls thrombin generation, in part, by inactivating factors Va and VIlla (see Fig. 52-1). Protein C activity increases modestly but significantly throughout the first half of pregnancy, and some have speculated that this augmentation may play a role in maintaining early pregnancy through both anticoagulant and inflammatory regulatory pathways (Said, 2010b).
More than 160 diferent autosomal dominant mutations for the protein C gene have been described (Louis-Jacques, 2016). he prevalence of protein C deiciency is 2 to 3 per 1000, but many of these individuals do not have a thrombosis history because the phenotypic expression is highly variable (Anderson, 2011). hese prevalence estimates correspond with functional activity threshold values of 50 to 60 percent, which are used by most laboratories and which are associated with a six-to 12-fold higher risk for VTE (Lockwood, 2012).
his circulating aticoagulant is activated by protein C, which enhances the capacity of protein S to inactivate factors Va and VIlla (see Fig. 52-1). Protein S deiciency may be caused by more than 130 diferent mutations, with an aggregate prevalence of approximately 0.3 to 1.3 per 1000 individuals (LouisJacques, 2016). Protein S deiciency may be measured by antigenically determined free, functional, and total S levels. ll three decline substantively during normal gestation (Appendix, p. 1256). Thus, the diagnosis in pregnant women-as well as in those taking certain oral contraceptives-is diicult (Archer, 1999). If screening during pregnancy is necessary, threshold values for free protein S antigen levels in the second and third trimesters have been identiied at <30 percent and <24 percent, respectively. Among those with a positive family history, the VTE risk in pregnancy is 6 to 7 percent (American College of Obstetricians and Gynecologists, 2017c).
Conard and coworkers (1990) described thrombosis in five of 29 pregnant women with protein S deiciency. hey, as well as Burneo and colleagues (2002), reported maternal cerebral vein thrombosis. Neonatal homozygous protein C or S deiciency is usually associated with a fatal clinical phenotype known as purpurafulminans (Shanbhag, 2015).
his is the most prevalent of the known thrombophilia syndromes and is characterized by resistance of plasma to the anticoagulant efects of activated protein C. here are several mutations that create this resistance, but the most common is the factor V Leiden mutation, which was named after the city in which it was described. his missense mutation in the factor V gene results from a substitution of glutamine for arginine at position 506 in the factor V polypeptide. As a result of this mutation, activated factor V is neutralized approximately tenfold more slowly by activated protein C (see Fig. 52-1). his leads to enhanced thrombin generation (MacCallum, 2014).