Inherited thrombophilias and adverse pregnancy outcome: screening and management.

Inherited thrombophilias are a heterogenous group of conditions which have been implicated in a variety of pregnancy complications. Evidence is mounting that implicates these inherited disorders in a range of pregnancy outcomes, including recurrent miscarriage, late fetal loss, preeclampsia, abruptio placentae, and intrauterine growth restriction. The most commonly identified inherited thrombophilias consist of Factor V Leiden and the prothrombin gene mutation G20210A. Rarer inherited thrombophilic conditions include deficiencies of protein S, C and antithrombin. More recently, deficiency of protein Z has been linked to pregnancy complications, including preterm delivery. Clinical manifestations often are associated with the presence of more than one inherited thrombophilia, consistent with their multigenic nature. Some, but not all, studies investigating the use of heparin to prevent adverse pregnancy outcome have demonstrated a benefit. However, an adequate randomized trial is required to definitively determine whether heparin anticoagulation is the best prevention option in patients who harbor one or more inherited thrombophilias and are at risk for adverse pregnancy outcome. This review will summarize the association of thrombophilic conditions and obstetrical complications.

Screening and management of inherited thrombophilias in the setting of adverse pregnancy outcome.

Inherited thrombophilic conditions are associated with adverse pregnancy outcomes, including severe pre-eclampsia, fetal loss, abruptio placentae, and intauterine growth restriction. Although the prevalence of these complications is approximately 8% in the general population, their presence is associated with a significantly increased recurrence risk. Thrombophilic conditions most strongly associated with adverse pregnancy outcome include factor V Leiden, prothrombin gene mutation, and deficiencies of protein S, protein C, and antithrombin. Other thrombophilic conditions, such as protein Z deficiency, also appear to be associated with an increased risk of pregnancy complications. Antenatal administration of heparin to prevent pregnancy complications has shown promise in small studies, but a randomized, placebo-controlled trial is necessary to determine whether heparin administration is beneficial in preventing adverse pregnancy outcome.

Circulating levels of inflammatory cytokines (IL-1 beta and TNF-alpha), resistance to activated protein C, thrombin and fibrin generation in uncomplicated pregnancies.

We studied 33 women during normal uneventful pregnancies and with no history of previous adverse pregnancy events for markers of activated coagulation and thrombin activity including prothrombin fragment 1.2(PF1.2), thrombin- antithrombin (TAT), and soluble fibrin polymer (SFP). In addition, we measured potential thrombin generation through the addition of thromboplastin to patient plasma in the presence of a thrombin-specific chromogenic substrate determined serially over a period of time--Endogenous Thrombin Potential assay (ETP). This assay was performed with plasma treated and untreated with activated protein C (APC). The fibrinolytic system was assessed by measurement of thrombin activatable fibrinolysis inhibitor (TAFI). These findings were correlated with the levels of pro-inflammatory cytokines, interleukine-1 beta and tumor necrosis factor-alpha. Our data supports previous reports that indicate that resistance to activated protein C and coagulation activation markers are commonly increased in the later 2/3rds of pregnancy. There are no differences in thrombin generation potential, as determined by the ETP assay without the addition of APC, in the three trimesters. However, the thrombin reserve (TR), the ETP result without APC divided by the ETP result with the addition of APC, is increased above the reference range in the 2nd and 3rd trimesters. Patients with increased TR and resistance to APC had increased levels of TNF-alpha. Increased proinflammatory cytokines are reportedly associated with changes in the APC system with a decrease in the ability to generate APC. A sub-group of pregnancies with APC resistance had increased levels of TNF-alpha and may be important in the risk for adverse pregnancy outcomes.

Perioperative topical bovine thrombin exposure is not associated with hemodialysis graft thrombosis.

Arteriovenous (AV) graft use as hemodialysis access remains highly prevalent, with a consequent high thrombosis rate. The magnitude of this problem requires that all potentially modifiable risk factors for graft thrombosis be thoroughly investigated. During graft surgery, topical bovine thrombin is often administered, which can lead to the development of antibovine thrombin antibodies and subsequent hemostatic changes. A recent study correlated the presence of plasma antibovine thrombin antibodies with graft thrombosis in hemodialysis patients. We therefore hypothesized that perioperative topical bovine thrombin exposure would lead to the development of antibovine thrombin antibodies and graft thrombosis. We screened 314 hemodialysis patients and identified 73 patients who had 74 grafts placed for whom complete data on perioperative topical bovine thrombin exposure and subsequent graft outcomes was available. Sixty-one of these patients were available for retrospective measurement of antibovine thrombin antibodies, antihuman thrombin antibodies, and the thrombin activation markers thrombin activatible fibrinolysis inhibitor (TAFI) and thrombin precursor protein (TpP). In these grafts, there was no significant association between topical bovine thrombin exposure and primary assisted patency (P = 0.37). The presence of antibovine thrombin antibodies (P = 0.13), antihuman thrombin antibodies (P = 0.10), and increased TAFI (P = 0.18) were associated with trends toward reduced primary assisted patency which did not reach significance. There was a correlation between antibovine thrombin antibodies and antihuman thrombin antibodies (r = 0.30, P < 0.0001) and between TAFI and TpP trade mark (r = 0.30, P < 0.0001), but no significant correlation between topical bovine thrombin exposure and elevated levels of antibovine thrombin antibodies, antihuman thrombin antibodies, TAFI or TpP trade mark. We conclude that perioperative topical bovine thrombin exposure is not associated with subsequent graft thrombosis.