Risk Factors for Clinical Manifestations in Patients with Factor V Leiden and Prothrombin Gene Mutations.
Authors: De Sancho Maria Teresa , Berlus Nickisha , Rand Jacob H. 
Published: April 2020

Abstract
Factor V Leiden (FVL) and prothrombin G20210A gene mutations are the most prevalent hereditary thrombophilias (HT). Carriers of these HT are at greater risk for developing thromboembolic events (TEE) and/or pregnancy complications (PC) compared to non-carriers, but not all carriers develop clinical manifestations. We retrospectively analyzed the risk factors (RF) for clinical manifestations of all subjects who tested positive for FVL and/or PG20210A gene mutations in our hematology clinic between January 2000 and July 2006. Symptomatic carriers (cases) and asymptomatic carriers (controls) were compared. Cases were defined as having had a TEE (venous and/or arterial) or a PC (pregnancy loss (PL), preeclampsia, abruption placenta and intrauterine growth restriction). Data analyzed included secondary RF for thrombosis, use of female hormones (FH), family history of thrombosis (FHT), and the presence of other thrombophilias. During the study period, 197 subjects were fully evaluable; 9 were excluded due to insufficient data. The clinical characteristics are shown in Table 1. Of the 85 venous thromboses (VT), 59 (69%) had DVT and/or PE, 10 (12%) had superficial thrombophlebitis, 9 (11%) intra-abdominal thrombosis, 2 (2%) cerebral VT, 2 (2%) had retinal VT and 3 (4%) had &gt; 1 site of VT. Of the 25 arterial thromboses (AT), 11 (44%) were CVA, 7 (28%) had TIA, 6 (24%) had other AT, and 1 (4%) had an MI. Of the 52 cases with PL, 27 (52%) were early recurrent 1st trimester PL, 8 (15%) were 2nd or 3rd trimester PL, 4 (8%) had infertility and 13 (25%) had both PL and infertility. Of the 5 PC, 3 were abruption placenta, 1 preeclampsia and 1 had &gt; 1 PC. The most common RF was the presence of &gt; 1 secondary RF (Table 2). There was no significant difference between cases and controls regarding the use of FH, FHT, and presence of other thrombophilias. Fertility medications were used by 12 (10%) of cases vs. 1 (2%) of controls. Antiphospholipid (aPL) antibody-positivity was the most prevalent concurrent thrombophilic factor and occurred in 18 of cases (12%) vs. 2 (4%) of controls. Cases and controls were similar regarding gender, age, family history of thrombosis, and presence of other thrombophilias. In summary, fertility medications and aPL antibodies appear to be significant risk factors for clinical manifestations in cases. Larger multicenter studies are warranted to identify additional RF in carriers of these HT.
Clinical Characteristics Cases (n=145) Controls (n=52) *85 heterozygous, 6 homozygous, **29 heterozygous, 2 homozygous, ***37 heterozygous, 2 homozygous, ****100% heterozygous Mean Age, yr [+/−SD] 44+/−13 42+/−13 Gender, female 115 (79%) 42 (81%) FVL 91 (63%)* 31 (60%)** PG20210A 39 (27%)*** 18 (35%)**** FVL + PG20210A 15 (10%) 3 (6%) VT 85 (59%) --- AT 25 (17%) --- PC and infertility (female carriers, n=115) 57 (50%) --- Risk Factors Cases (n=145) Controls (n=52) p value Includes obesity, postoperative period, pregnancy, puerperium, long airplane flight, smoking, hypertension, hypercholesterolemia, and immobilization; **oral contraceptives, hormone replacement therapy, selective estrogen receptor modulators, progesterone OC, fertility medications Secondary RF* 74 (51%) 15 (29%) 0.265 NS Use of female hormones**, n=115 59 (51%) 21 (50%) 0.478 NS Family history of thrombosis 73 (50%) 34 (65%) 0.252 NS Other thrombophilias 60 (41%) 21 (40%) 0.232 NS