Prothrombin------....Thrombin---....Coagulation Factor V Leiden mutation Factor V resistant to degradation by protein C\\\,, "0''� Inactivates factor Va PROTEINS . /" IIIII Inactivates factor Villa Thrombin binds to thrombomodulin on endothelial cells Protein C deficiencyIIIIII tProtein S deficiency -; ActivatedproteinC ProteinCII Hyperhomocysteinemia (inhibits activation of protein C)
FIGURE 52-1 Inherited thrombophilias and their efect(s) on the coagulation cascade.
aOdds ratio for pregnancy-associated TE compared with gravid noncarriers.
Data from the American College of Obstetricians and Gynecologists, 2017c; Croles, 2017.
2011). Some aspects of the more common inherited thrombophilias are summarized in Table 52-2.
Patients with inherited thrombophilic disorders often have a family history of thrombosis. Inherited thrombophilias are also found in up to half of all patients who present with VTE before the age of 45 years, particularly in those whose event occurred in the absence of well-recognized risk factors. Of greatest significance is a family history of sudden death due to pulmonary embolism or a history of multiple family members requiring long-term anticoagulation therapy because of recurrent thrombosis (Anderson, 2011).
Synthesized in the liver, antithrombin is one of the most important inhibitors of thrombin and inactivates thrombin and factor Xa (heaume, 2016). Notably, the rate of antithrombin interaction with its target is accelerated by heparin (Anderson, 2011). Antithrombin deiciency may result from hundreds of diferent mutations that are almost always autosomal dominant. Type I deficiency results from reduced synthesis of biologically normal antithrombin, and type II deficiency is characterized by normal levels of antithrombin with reduced functional activity (Anderson, 2011). Homozygous antithrombin deficiency is lethal.
Antithrombin deiciency is rare-it afects approximately 1 in 500 to 5000 individuals (Ilonczai, 2015; Rheaume, 2016). It is the most thrombogenic of the heritable coagulopathies. Indeed, antithrombin deiciency is associated with a 25-to 50-fold higher relative risk of VTE in the general population and a sixfold increased risk of thromboembolic complications during pregnancy (Ilonczai, 2015). Those afected have approximatelyaa 50-percent lifetime risk ofVTE (Duhl, 2007).
Sabadell and associates (2010) studied the outcomes of 18 pregnancies complicated by antithrombin deiciency. Twelve of these women were treated with therapeutic doses of lowmolecular-weight heparin (LMWH), and six were not treated because antithrombin deiciency had not yet been diagnosed. Three of the untreated patients sufered a thromboembolic episode compared with none in the treated group. Untreated women also had a 50-percent risk of stillbirth and fetal-growth restriction. By comparison, none of the treated women had a stillbirth, but a fourth developed fetal-growth restriction. Similar results were reported by Ilonczai and colleagues (2015). Garda-Botella and associates (2016) described a mesenteric vein thrombosis in a pregnant woman with antithrombin deiciency. In one review of outcomes in 23 newborns with antithrombin deficiency, there were 11 cases of thrombosis and 10 infant deaths (Seguin, 1994).