Discussion
This 17-year-old Caucasian male’s challenging presentation of DVT and saddle PE occurred in the setting of trauma, immobilization, obesity, and double-heterozygosity for FVL/PT-G20210A with concurrent APS. Given the persistence of his APS in the setting of double-heterozygosity for FVL/PT-G20210A, despite resolution of his previous provoking trauma and immobilization, he will be continued on therapeutic anticoagulation with enoxaparin for least 6 months.
The risks of VTE associated with either FVL or PT-G20210A mutations have been described in a multitude of studies. However, the risk in patients with double-heterozygosity for FVL/PT-G20210A has been more difficult to understand due to lack of power in many studies given the rarity of both polymorphisms together.6 In the meta-analysis by Simone et al, the risk of initial VTE in patients with double-heterozygosity for FVL/PT-G20210A was increased when compared to patients without either mutation or with PT-G20210A heterozygosity alone.7 There is conflicting evidence on VTE recurrence risk in patients with double-heterozygosity for FVL/PT-G20210A. An investigation in the Netherlands reported no increase in risk of VTE recurrence for patients with double-heterozygosity relative to patients without known FVL or PT-G20210A in a population in the Netherlands.1 However, the relative risk of VTE recurrence was reported as high as 3.7 for patients with double heterozygosity compared to patients with a single FVL mutation in a population in Italy.8 It has also been demonstrated that patients with double-heterozygosity for FVL/PT-G20210A may present with the first episode of VTE at a significantly younger age than patients with VTE associated with no genetic risk factors or single gene defects alone (34.7 vs 40.6 years, P<0.01). Despite some differing reports of recurrence risk, there is data to support the use of lifelong anticoagulation for patients with double-heterozygosity alone.
Our patient has the additional risk factor of APS, which with concurrent double heterozygosity of FVL/PT-G20210A has been described in at least one case of catastrophic antiphospholipid syndrome as a contributor to disease. For APS alone, there is conflicting evidence for the use of aspirin for primary prevention of arterial and venous thromboembolism, although The European Alliance of Associations for Rheumatology (EULAR) has recommended primary prevention for even asymptomatic patients with APS and a high-risk profile (presence of persistent LA or any combination of two or more of LA/aCL antibody/aβ2GPI antibody) with low-dose aspirin since 2019.4,10 There is limited evidence for secondary prevention of venous thromboembolism in patients with APS, as would apply to our patient, but warfarin monotherapy is typically utilized with a target international normalized ratio of 2.0-3.0. In the event of recurrent venous thrombosis in a patient with APS while on warfarin, EULAR recommends consideration of warfarin combined with low-dose aspirin or extended therapeutic enoxaparin.4,10. Family discussion regarding the benefits and risks of indefinite anticoagulation with warfarin after 6 months is ongoing for the patient in this case.
Much of the literature examining risk of VTE with genetic mutations specifically exclude individuals with inciting factors, such as trauma, which was an important provoking factor for this patient. This case also highlights the importance of evaluation for thrombophilia in patients in select circumstances with extensive thrombus burden, even in the setting of known risk factors such as trauma and obesity, as the results may have lifelong clinical implications.
Legend: FIGURE 1 Patient’s chest computed tomography at initial diagnosis of saddle PE with thrombus extending into the left and right pulmonary arteries.
Conflict of Interest: The authors declare that there is no conflict of interest.Acknowledgements: We are grateful to Dr. Pamela Camacho for her clinical care of this patient.References
1. Lijfering WM, Middeldorp S, Veeger NJ, et al. Risk of recurrent venous thrombosis in homozygous carriers and double heterozygous carriers of factor V Leiden and prothrombin G20210A. Circulation . 2010;121(15):1706-1712. doi:10.1161/CIRCULATIONAHA.109.906347
2. Effectiveness of Factor V Leiden and Prothrombin Mutation Testing in Patients Presenting With a First Unprovoked Venous Thromboembolic Episode: A Systematic Review and Economic Analysis . Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; March 2015.
3. Negrini S, Pappalardo F, Murdaca G, Indiveri F, Puppo F. The antiphospholipid syndrome: from pathophysiology to treatment. Clin Exp Med . 2017;17(3):257-267. doi:10.1007/s10238-016-0430-5
4. Islabão AG, Trindade VC, da Mota LMH, Andrade DCO, Silva CA. Managing Antiphospholipid Syndrome in Children and Adolescents: Current and Future Prospects. Paediatr Drugs . 2022;24(1):13-27. doi:10.1007/s40272-021-00484-w
5. Cohen H, Efthymiou M, Isenberg DA. Use of direct oral anticoagulants in antiphospholipid syndrome. J Thromb Haemost . 2018;16(6):1028-1039. doi:10.1111/jth.14017
6. Emmerich J, Rosendaal FR, Cattaneo M, et al. Combined effect of factor V Leiden and prothrombin 20210A on the risk of venous thromboembolism–pooled analysis of 8 case-control studies including 2310 cases and 3204 controls. Study Group for Pooled-Analysis in Venous Thromboembolism [published correction appears in Thromb Haemost 2001 Dec;86(6):1598]. Thromb Haemost . 2001;86(3):809-816.
7. Simone B, De Stefano V, Leoncini E, et al. Risk of venous thromboembolism associated with single and combined effects of Factor V Leiden, Prothrombin 20210A and Methylenetethraydrofolate reductase C677T: a meta-analysis involving over 11,000 cases and 21,000 controls. Eur J Epidemiol . 2013;28(8):621-647. doi:10.1007/s10654-013-9825-8
8. De Stefano V, Martinelli I, Mannucci PM, et al. The risk of recurrent deep venous thrombosis among heterozygous carriers of both factor V Leiden and the G20210A prothrombin mutation. N Engl J Med . 1999;341(11):801-806. doi:10.1056/NEJM199909093411104
9. McRae HL, Yang AH, Kruzer K, Scott GA, Refaai MA. A rare case of catastrophic antiphospholipid syndrome triggered by estrogen-containing oral contraceptives in a patient with double heterozygous factor V Leiden and prothrombin G20210A mutations. Am J Hematol . 2022;97(2):239-242. doi:10.1002/ajh.26138
10. Sammaritano LR. Antiphospholipid syndrome. Best Pract Res Clin Rheumatol . 2020;34(1):101463. doi:10.1016/j.berh.2019.101463