Obstet Gynecol Sci.  2024 Sep;67(5):435-448. 10.5468/ogs.22084.

Genetic landscape of thrombophilia in recurrent miscarriages

• Athar A
• Kashyap P
• Khan S
• Sattar RSA
• Khan SA
• Prasad S
• Husain SA
• Parveen F

• KMID: 2559476
• DOI: http://doi.org/10.5468/ogs.22084

Abstract

The etiology of recurrent miscarriage (RM) is extremely heterogeneous, encompassing genetic, immunological, anatomical, endocrine, thrombophilic, infectious, and uterine abnormalities. Thrombophilia is a major contributor to pregnancy complications, potentially harming the fetus and jeopardizing the continuation of pregnancy. Therefore, successful pregnancy outcomes depend on maintaining a delicate balance between coagulation and fibrinolytic factors, crucial for ensuring the adjustment of the basal plate to facilitate adequate placental perfusion. Despite numerous studies shedding light on the role of thrombophilic factors and genetic variations in RM, the exact pathogenesis remains unclear. It is imperative to systematically rule out thrombophilia and other related factors responsible for pregnancy disorders and RMs to guide appropriate and active management strategies. Addressing thrombophilia continues to present challenges in terms of effective treatment. The current review aims to address the heterogeneity of RM as a therapeutic challenge, emphasizing the need for standardized diagnostic tests and welldesigned multicenter research trials to gather robust, evidence-based data on thrombophilic causes of RM and provide effective treatment. The goal is to enhance the understanding of thrombophilic factors and genetic landscapes associated with RM through various approaches, including candidate gene studies, genome-wide association studies, and high-throughput sequencing. Meta-analyses have underscored the significance of genetic aberrations in RM, highlighting the necessity for identifying critical mutations implicated in the etiopathogenesis of miscarriages to pave the way for implementation of targeted clinical therapies.

Keyword

Recurrent miscarriages; Genetics; Thrombophilia; Pregnancy complications; Coagulation disorders

Figure

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  Fig. 1 Pathway showing various pro- and anticoagulatory factors required for coagulation. The prothrombin-convertase complex (factor Va+factor Xa) causes coagulation by converting prothrombin into thrombin. Thrombin is inactivated by antithrombin III, and the thrombomodulin-thrombin complex initiates the activation of protein C. Activated protein C, along with protein S, inactivates factors Va and VIIIa, which work as a feedback control system by inhibiting the prothrombin convertase. Thrombin further converts fibrinogen into fibrin, and this is stabili zed by the action of factors XIII and XII through the crosslinking of fibrin monomers, leading to clot formation. ACE, angiotensin converting enzyme; TM, thrombomodulin; APC, activated protein C; PAI-1, plasminogen activator inhibitor-1.

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  Fig. 2 Thrombotic factors associated with RM along with their genes. THBD, hrombomodulin; ERCR, endothelial cell receptor C; SER-PINC1, serpin family C member 1 (antithrombin III); MTR/MS, methionine synthase; F13A1, coagulation factor XIII A chain; MTHFR, methylenetetrahydrofolate reductase; PAI-1, plasminogen activator inhibitor-1, ACE, angiotensin-converting enzyme; MTRR, methionine synthase reductase; RM, recurrent miscarriage.

Reference

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