Absence of the Factor V Leiden mutation and genetic risk for CTEPH
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2 Absence of the Factor V Leiden mutation and genetic risk for CTEPH Mark W. Dodson, MD, PhD Assistant Professor, Pulmonary/Critical Care Intermountain Medical Center Murray, Utah
3 A paradox in our current understanding of genetic risk for CTEPH Unprovoked PE is a major risk factor for CTEPH. 1 Patients with unprovoked PE are twice as likely to carry the Factor V Leiden mutation. 2 But the frequency of the Factor V Leiden mutation is no different in patients with CTEPH than in the general population. 3,4,5 1. Klok, et al. J Thromb Haemost, Couturaud, et al. Blood, Lang, et al. Thromb Haemost, Wolf, et al. Eur Resp J, Suntharalingam, et al. Eur Resp J, 2008.
4 A paradox in our current understanding of genetic risk for CTEPH Unprovoked VTE is associated: increased risk of recurrent VTE 1 increased occurrence of VTE in family members 2 Thus, unprovoked VTE is a marker of increased genetic risk for VTE. Does the high frequency of unprovoked VTE in patients with CTEPH reflect increased genetic risk for VTE that is not explained by the Factor V Leiden mutation? 1. Kearon, et al. Chest, Couturaud, et al. Blood, 2014.
5 Methods Two cohorts: 1. Patients with CTEPH 2. Patients with VTE (PE or proximal LE DVT) without signs or symptoms of CTEPH who are matched to the CTEPH cohort on: Age at first diagnosed VTE event Proportion with unprovoked VTE Simultaneously compare the frequency of Factor V Leiden positivity and family history of VTE.
6 Family history as a marker of genetic risk for VTE Known inherited thrombophilias are estimated to explain only a small percentage (~5%) of the genetic risk for VTE. 1 Relative risk of VTE in person with VTE in one first degree family member is ~2.5 2,3,4. Relative risk increases if: VTE in family member is unprovoked. 5 Younger age at time of VTE in family member. 4,5 Multiple affected first degree family members. 3,4,5 1. Morange, et al. Thromb Haemost, Noboa et al. Thromb Res, Bezemer et al. Arch Int Med, Zoller et al. Circulation, Couturand et al. Blood, 2014.
7 Baseline characteristics of CTEPH cohort CTEPH cohort (n=56) Mean age at diagnosis with CTEPH (years SD) Prior history of acute VTE (%) 80.4% Status post PTE surgery (%) 64.3% Mean WHO functional class at diagnosis ( SD) Mean 6WD at diagnosis (meters SD) Hemodynamics at diagnosis: - mean mpap (mmhg SD) - mean PAOP (mmhg SD) - mean CO (L/min SD) - mean PVR (Wood units SD)
8 VTE history in the CTEPH and VTE cohorts CTEPH cohort (n=56) VTE cohort (n=93) Mean age at first VTE dx (years SD) History of unprovoked VTE (%) 82.2% 80.6% Female (%) 46.4% 44.1% Caucasian (%) 92.9% 94.6% History of acute PE (%) 71.4% 65.6% History of acute proximal LE DVT (%) 53.6% 75.3% Recurrent VTE (%) 32.1% 47.3%
9 Frequencies of the Factor V Leiden mutation and family history of VTE CTEPH cohort (n=56) VTE cohort (n=93) p-value Factor V Leiden positive 10.7% 24.7% First degree family member with VTE 51.8% 40.9% first degree family members with VTE 28.6% 10.8% Factor V Leiden negative AND 2 first degree family members with VTE 25.0% 5.4%
10 Frequency of inherited thrombophilias in CTEPH patients with strong family histories of VTE
11 Frequency of inherited thrombophilias in CTEPH patients with strong family histories of VTE
12 Frequency of inherited thrombophilias in CTEPH patients with strong family histories of VTE Factor V Leiden: 2/16 (12.5%)
13 Frequency of inherited thrombophilias in CTEPH patients with strong family histories of VTE Factor V Leiden: 2/16 Prothrombin G20210A: 1/16
14 Frequency of inherited thrombophilias in CTEPH patients with strong family histories of VTE Factor V Leiden: 2/16 Prothrombin G20210A: 1/16
15 Frequency of inherited thrombophilias in CTEPH patients with strong family histories of VTE Factor V Leiden: 2/16 Prothrombin G20210A: 1/16 Protein S deficiency: 1/11
16 Frequency of inherited thrombophilias in CTEPH patients with strong family histories of VTE Factor V Leiden: 2/16 Prothrombin G20210A: 1/16 Protein S deficiency: 1/11 Protein C deficiency: 0/11
17 Frequency of inherited thrombophilias in CTEPH patients with strong family histories of VTE Factor V Leiden: 2/16 Prothrombin G20210A: 1/16 Protein S deficiency: 1/11 Protein C deficiency: 0/11 Anti-thrombin 3 deficiency: 0/11
18 Frequency of inherited thrombophilias in CTEPH patients with strong family histories of VTE Factor V Leiden: 2/16 Prothrombin G20210A: 1/16 Protein S deficiency: 1/11 Protein C deficiency: 0/11 Anti-thrombin 3 deficiency: 0/11 75% (12/16) of CTEPH patients with a strong family history of VTE do not carry one of the common inherited thrombophilias.
19 Conclusions As compared to a matched cohort with uncomplicated VTE, CTEPH patients are significantly less likely to carry the Factor V Leiden mutation significantly more likely to have a strong family history of VTE The Factor V Leiden mutation is associated with decreased risk for CTEPH. The combination of Factor V Leiden negativity and a strong family history of VTE may indicate patients at high risk for CTEPH.
20 Conclusions We propose that: The high frequency of unprovoked PE in CTEPH patients is due to genetic risk factors for VTE. Genetic risk factors for VTE in CTEPH patients: are distinct from common inherited thrombophilias that predispose to acute PE. may specifically predispose to chronic/nonresolving VTE events.
21 Familial CTEPH Pedigree 1 Pedigree 2 Pedigree 3 Key: male female deceased DVT PE DVT/PE CTEPH Familial CTEPH identified in 3/56 (5.4%) pedigrees. Desmarais and Elliott. Chest, 2016.
22 Acknowledgments Greg Elliott, MD Lynn Brown, MD, PhD Kirk Knowlton, MD Scott Stevens, MD Scott Woller, MD Julianna Desmarais, MD Lisa Cannon-Albright, PhD Hunter Best, PhD Kelli Sumner, BS Jadyn Sander, BS Funding source: Intermountain Research and Medical Foundation
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