Risk Factors, Clinical Manifestations, Treatment Duration and Outcomes in Carriers of Severe Inherited Thrombophilias

Background

Severe Inherited thrombophilia comprisses deficiencies of natural anticoagulants (antithrombin (AT), protein C (PC), and protein S (PS), and homozygosity for factor V Leiden (FVL) or prothrombin gene mutation (PGM) or double heterozygosity or other combined thrombophilia.

Carriers of AT, PC and PS have a high risk of thrombosis starting at a young age, usually several members of the same family are affected and thrombosis may occur at unusual locations. Conversely homozygotes for either FVL, PGM or double heterozygotes may not have a family history of thrombosis and the first thrombotic event may present later on life. It is also unclear what is the duration and type of anticoagulation and long-term outcomes of these carriers. The purpose of this study was to compare risk factors, clinical manifestations, type and duration of anticoagulation and clinical outcomes between carriers of anticoagulant deficiencies and those with gain of function mutations (homozygosity or double heterozygosity for FVL and PGM).

Methods

Retrospective evaluation of electronic medical records of patients with severe inherited thrombophilia referred to the Center for Blood Disorders at Weill Cornell Medicine-New York Presbyterian Hospital between January 2009 and June 2019. Severe deficiencies of AT, PC and PS were defined and (AT ≤ 60%, PC ≤ 50% and PS ≤ 40% (2). Patients without confirmatory laboratory results for the anticoagulant deficiencies were excluded from the study. We collected demographic data, risk factors for thrombosis, family history, type of thrombotic events, pregnancy complications in females, type and duration of anticoagulant and outcomes. Statistical analysis was performed using descriptive statistics and chi-square test was applied for comparison of variables between anticoagulant deficiency carriers and gain of function mutation carriers.

Results

Of a total of 107 patients identified,17 were excluded due to absence of confirmatory results. A total of 90 patients were analyzed; 70 (78%) females; mean age and range 44 (22- 82). There were 34 (38%)patients with anticoagulant deficiencies (10 AT, 6 PC and 18 PS) and 56 (62%) homozygotes for FVL, PGM or double heterozygote. Of those, 23 (39%) homozygote for FVL with one also heterozygote for the PGM, 2 (3.6%) homozygote PGM and 31(55.4%) double heterozygote. Overall risk factors for thrombosis were similar in both groups. There were no identified thrombosis risk factors in 12 and 19 patients in the anticoagulant deficiency and gain of function mutation respectively. The most common type of clinical presentation in both groups was deep vein thrombosis and pulmonary embolism. A positive family history of either thrombosis of thrombophilia in a first degree family member was equal in both groups. Likewise age less than 40 at first thrombotic event was similar. The most frequent anticoagulant prescribed in the patients with anticoagulant deficiency was a direct oral anticoagulant in 26.%% and vitamin K antagonists 22.3% in the ones with gain of function mutation. More patients with anticoagulant deficiencies remain on anticoagulation for more than 1 year than the ones with a gain of function mutation (88.5% vs 64%) and had more recurrent thrombotic events (20.6% vs.5.4%). Within the 70 female patients, 5 (7%) had first trimester pregnancy loss and 14 (20%) had multiple pregnancy losses.

Conclusions:

Our results suggest that patients with severe inherited antithrombin, protein C and S deficiencies have worse outcomes despite longer duration of anticoagulation than patients homozygote or double heterozygote for gain of function mutations.