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Absence of the Factor V Leiden Mutation and Genetic Risk for Chronic Thromboembolic Pulmonary Hypertension
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A6332 - Absence of the Factor V Leiden Mutation and Genetic Risk for Chronic Thromboembolic Pulmonary Hypertension
Author Block: M. W. Dodson1, K. L. Sumner2, J. Sanders2, L. M. Brown1, H. Best2, L. Cannon-Albright3, G. Elliott4; 1Intermountain Medical Center, Murray, UT, United States, 2ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT, United States, 3University of Utah, Salt Lake City, UT, United States, 4Intermountain Med Center, Murray, UT, United States.
Rationale: Chronic thromboembolic pulmonary hypertension (CTEPH) is the most serious consequence of unresolved venous thromboembolism (VTE). Little is known about how genetic factors influence risk for CTEPH, although common inherited thrombophilias including the Factor V Leiden mutation (FVL) occur with the same frequency in patients with CTEPH as in the general population. This is surprising given that pulmonary embolism (PE) not associated with an environmental risk factor for VTE (i.e. unprovoked PE) is a major risk factor for CTEPH, and relative to provoked PE, unprovoked PE is significantly more likely to be associated with FVL. This study aims to address this apparent paradox. Methods: We systematically analyzed family history of VTE and FVL status in all available CTEPH patients at our institution (n=60) and in a cohort of patients with uncomplicated VTE (n=110) matched to the CTEPH cohort for age at VTE diagnosis and presence/absence of an environmental risk factor for VTE. Results: FVL was less frequent in CTEPH patients than in matched controls (CTEPH: 10.0% vs VTE: 23.6%, p=0.04). However, CTEPH patients were just as likely as controls to have at least one first degree relative with VTE (CTEPH: 46.7% vs VTE: 41.8%, p=0.54), and were significantly more likely to have two or more first degree relatives with VTE (CTEPH: 26.7% vs VTE: 10.9%, p=0.008). We also report the first systematic analysis of the frequency of familial CTEPH, which we identified in 5.0% of patients in our CTEPH cohort. Conclusions: In comparison to matched VTE controls, CTEPH patients in our cohort are significantly less likely to carry FVL but significantly more likely to have a strong family history of VTE. Thus, the presence of FVL is associated with a reduced risk of CTEPH. This suggests the presence of distinct and as-yet unidentified genetic variants in CTEPH patients that contribute to VTE risk, and may specifically predispose to non-resolving VTE events. We also report a surprisingly high frequency of familial CTEPH in our cohort, further suggesting a genetic predisposition to the disease.
Author Block: M. W. Dodson1, K. L. Sumner2, J. Sanders2, L. M. Brown1, H. Best2, L. Cannon-Albright3, G. Elliott4; 1Intermountain Medical Center, Murray, UT, United States, 2ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT, United States, 3University of Utah, Salt Lake City, UT, United States, 4Intermountain Med Center, Murray, UT, United States.
Rationale: Chronic thromboembolic pulmonary hypertension (CTEPH) is the most serious consequence of unresolved venous thromboembolism (VTE). Little is known about how genetic factors influence risk for CTEPH, although common inherited thrombophilias including the Factor V Leiden mutation (FVL) occur with the same frequency in patients with CTEPH as in the general population. This is surprising given that pulmonary embolism (PE) not associated with an environmental risk factor for VTE (i.e. unprovoked PE) is a major risk factor for CTEPH, and relative to provoked PE, unprovoked PE is significantly more likely to be associated with FVL. This study aims to address this apparent paradox. Methods: We systematically analyzed family history of VTE and FVL status in all available CTEPH patients at our institution (n=60) and in a cohort of patients with uncomplicated VTE (n=110) matched to the CTEPH cohort for age at VTE diagnosis and presence/absence of an environmental risk factor for VTE. Results: FVL was less frequent in CTEPH patients than in matched controls (CTEPH: 10.0% vs VTE: 23.6%, p=0.04). However, CTEPH patients were just as likely as controls to have at least one first degree relative with VTE (CTEPH: 46.7% vs VTE: 41.8%, p=0.54), and were significantly more likely to have two or more first degree relatives with VTE (CTEPH: 26.7% vs VTE: 10.9%, p=0.008). We also report the first systematic analysis of the frequency of familial CTEPH, which we identified in 5.0% of patients in our CTEPH cohort. Conclusions: In comparison to matched VTE controls, CTEPH patients in our cohort are significantly less likely to carry FVL but significantly more likely to have a strong family history of VTE. Thus, the presence of FVL is associated with a reduced risk of CTEPH. This suggests the presence of distinct and as-yet unidentified genetic variants in CTEPH patients that contribute to VTE risk, and may specifically predispose to non-resolving VTE events. We also report a surprisingly high frequency of familial CTEPH in our cohort, further suggesting a genetic predisposition to the disease.
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