Ocular Vascular Thrombotic Events: A Diagnostic Window to Familial Thrombophilia (Compound Factor V Leiden and Prothrombin Gene Heterozygosity) and Thrombosis

Abstract

In a 12-member, 3-generation kindred with conjoint inheritance of G1691A factor V Leiden (FVL) and G20210A prothrombin gene (PTG) mutations, identified through a proband with amaurosis fugax and his father with nonarteritic ischemic optic neuropathy (NAION), the authors' hypothesis was that ocular thrombosis was a diagnostic window to familial thrombophilia-thrombosis. The authors used polymerase chain reaction (PCR) measures for thrombophilia (FVL, PTG, C677T-A1298C methylenetetrahydrofolate reductase [MTHFR], platelet glycoprotein PLA1A2) and hypofibrinolysis (plasminogen activator inhibitor-1 4G4G). The 39-year-old white male proband, with amaurosis fugax and transient ischemic attacks (TIA), was found to be a compound heterozygote for FVL and PTG mutations. His symptoms resolved only after coumadin. His 44-year-old brother (deep venous thrombosis [DVT]) and 46-year-old sister (DVT, pulmonary embolus [PE]) were compound FVL-PTG gene heterozygotes. Of 4 asymptomatic children born to these 3 siblings, 2 were FVL heterozygotes and 2 PTG heterozygotes. The proband's 69-year-old father, with NAION and ischemic stroke, had PTG heterozygosity, familial high factor VIII, and compound MTHFR C677T-A1298C mutation with homocysteinemia. The proband's 61-year-old aunt had PTG heterozygosity, recurrent DVT, and mesenteric artery thrombosis. The proband's 67-year-old mother, free of thrombotic events, was a FVL heterozygote, had high factor VIII, and PAI-1 4G4G homozygosity. In this extended kindred, ocular thrombotic events (amaurosis fugax, NAION) were associated with variegated thrombotic events, including TIA, ischemic stroke, DVT, PE, and mesenteric artery thrombosis, and opened a diagnostic window to family screening and treatment for complex thrombophilias, which had previously been undiagnosed.

Ocular artery thrombosis as an initial presentation of a prothrombin G20210A mutation

“…The prothrombin G20210A mutation has been associated with the factor V Leiden R506Q mutation [7], but in our case, the prothrombin G20210A mutation was isolated, i.e., without any other thrombophilia. We found no other case of isolated prothrombin G20210A mutation in CRAO in the literature.…”

Retinopathy in pregnancy in women with type 1 diabetes - a study of associations with arterial wall elasticity and mutation in coagulation genes

“…With this mutation, the anticoagulant protein secreted is inhibited, leading to an increased tendency to form dangerous, abnormal blood clots. Factor V Leiden is the most common hereditary hypercoagulability disorder amongst ethnic Europeans and linked with increased risk of preeclampsia, abortions, intrauterine growth restriction, placental abruption, and thrombosis [12][13][14].…”

“…Thrombin in turn acts as a protease that converts soluble fibrinogen into insoluble strands of fibrin that form part of a clot, as well as catalyzing many other coagulationrelated reactions. Prothrombin mutations increase the risk of ocular thrombosis and abortions [14].…”

“…With this mutation, the anticoagulant protein secreted is inhibited, leading to an increased tendency to form dangerous, abnormal blood clots. Factor V Leiden is the most common hereditary hypercoagulability disorder amongst ethnic Europeans and linked with increased risk of preeclampsia, abortions, intrauterine growth restriction, placental abruption, and thrombosis [12][13][14].Glycoprotein IIb/IIIa (Gp2b3a, also known as integrin αIIbβ3) is a complex found on platelets. It is a receptor for fibrinogen and von Lauszus FF (2017) Retinopathy in pregnancy in women with type 1 diabetes -a study of associations with arterial wall elasticity and mutation in coagulation genes…”

Double-trouble: An unusual case of two simultaneous arterial thromboses in thrombophilia

“…Pulmonary embolism (PE) is usually a major clinical manifestation of venous thromboembolism [2], while in situ thrombosis in the pulmonary artery is rare and is most often related to an underlying thrombophilic condition. Factor V Leiden (FVL), prothrombin gene mutation G20210A (FII G20210), genetic variant C677T of the methylentetrahydrofolate reductase (MTHFR), as well as the polymorphism A2 (PlA2) in platelet glycoprotein IIb/IIIa and antiphospholipid syndrome have recently been discussed as possible causes of recurrent thromboses [3,4]. The C677T variant of MTHFR has recently also been suggested as a risk factor for venous and arterial thrombosis resulting in a thermo-stable, less active enzyme form [5].…”