Familial thrombophilia--the scientific rationale for thrombophylaxis in recurrent pregnancy loss?

Abstract

Johnny S.Younis1,4, Gonen Ohel2, pregnancy, had a 90% chance of fetal loss (Rai et al., 1995a). However, APS has been found in no more than 5–10% of all Benjamin Brenner3 and Moshe Ben-Ami1 patients with recurrent pregnancy loss. Moreover, as many as 1Unit of Reproductive Medicine, Department of Obstetrics 50% of cases with repeat fetal loss are invariably unexplained and Gynecology, Poriya Hospital, Tiberias, 2Department of with no obvious discernible causes (ACOG, 1995; Bulleti Obstetrics and Gynecology, Bnai-Zion Hospital, Haifa, and et al., 1996; Christiansen, 1996). 3Thrombosis and Homeostasis Unit, Rambam Hospital, Haifa, Israel Until recently, primary hypercoagulable states or inherited thrombotic disorders, were responsible for less than 10% 4To whom correspondence should be addressed of cases presenting with documented episodes of different thrombotic phenomena. These inherited thrombotic disorders, This debate was previously published on Webtrack, March termed today ‘familial thrombophilia’, are the result of specific 18, 1997 defects in the genes for plasma coagulation proteins involved in heparin-antithrombin III and protein C anticoagulant pathways. Deficiencies of antithrombin III, protein C and protein S are As many as 5% of all couples attempting to conceive have rare familial disorders that are usually inherited as autosomal two successive pregnancy losses, and 1% have three or more dominant disorders (Bauer, 1995). The homozygous variety of consecutive losses. Uncertainties regarding the aetiology and these disorders is often fatal in the neonatal period. Heterozygcontroversies surrounding management of repeat fetal demise ous patients have an age related risk for thrombosis and it is are two reasons that keep this issue a particularly frustrating estimated that up to 70% of them will develop a thrombotic challenge for physicians and patients. There is a general event by age 50 (Bauer, 1995). agreement today in regard to genetic, endocrine, uterine and Lately, the situation has changed dramatically with the autoimmune factors being associated with repeat fetal loss. discovery of a novel genetic defect associated with thrombotic However, there is still considerable disagreement in regard to disorders. In 1993, Dahlback et al. (1993) reported a new other potential conditions associated with consecutive losses, mechanism for familial thrombophilia characterized by an such as infectious, alloimmune, environmental, psychological inherited resistance to activated protein C (APC). Subsequent and other factors (Berry et al., 1995). studies revealed that APC-resistance is almost always caused For several decades now clinicians have presumed that a by a single point mutation of G to A at nucleotide 1691 in significant proportion of women suffering from repeat pregthe factor V gene, which destroys one of the APC-cleavage nancy loss have a homeostatic disturbance in the placental sites by the substitution of glutamine for arginine at amino bed, but neither actual evidence nor methodical documentation acid 506 in factor V (Arg 506 Gln) (Bertina et al., 1994). This have been presented. The assumption is that microthrombi of new mutation of factor V has been termed factor V Leiden the placental bed vessels could lead to multiple placental and it is inherited as an autosomal dominant. Moreover, it has infarctions that adversely affect the feto–maternal circulatory been revealed that this point mutation increases the risk for system leading eventually to fetal death. Several empirical thrombosis by 5–10-fold in heterozygous and by 50–100-fold antithrombotic treatments, such as aspirin, dipyridamole and in homozygous patients. Most importantly, several studies heparin have been advocated in the past but without any have shown that factor V Leiden is a very common finding in scientific validation or medical proof of efficacy. patients with venous thrombosis and that this derangement is The introduction of the antiphospholipid syndrome (APS), a widespread mutation with an estimated prevalence of 2–7% in the early 1980s, as an aetiological cause for recurrent in different populations (Bauer, 1995). pregnancy loss, has substantiated the ‘thrombosis theory’ of With the discovery of this new genetic risk factor for repeat fetal loss. A necrotizing decidual vasculopathy has been thrombosis, a major step forward has been made in understandfound in the placentas of women with APS presenting with ing the clustering of thrombophilia in selected families and/or fetal death, providing strong evidence for a thrombotic basis young patients. Especially the fact that, in contrast to other of fetal loss (Silver and Branch, 1994). Although the pathoknown rare hereditary thrombophilias, APC resistance is a physiology of APS-associated thrombosis is still not well very common disorder which is responsible almost for 50% characterized, antithrombotic treatments employing aspirin of cases with familial thrombophilia (Bertina et al., 1995). and/or heparin have proved to be effectual in these women. This new finding has led some groups of investigators to explore whether a relationship could be found between this Moreover, APS patients who declined treatment in their next