APC-resistance as a possible predictor of recurrent thrombosis in women with Factor V Leiden

Cover Page


Cite item

Full Text

Abstract

Hypothesis/aims of study. The current analysis was undertaken to elucidate the role of Factor Va resistance to proteolytic cleavage by activated protein C in FVL(1691)GA female carriers in the development of acute and recurrent thromboses.

Study design, materials and methods. A prospective clinical cohort study of 1100 women of reproductive age was conducted, with the course and outcomes of 2,707 pregnancies analyzed. Two cohorts were specified: the main group consisted of 500 patients with FV(1691)GA genotype, and the control group consisted of 600 patients with FVL(1691)GG genotype.

Results. FVL(1691)GA genotype was significantly associated with the development of venous thromboembolic complications (VTEC) compared to FVL(1691)GG genotype (OR 9.3; p < 0.0001). Episodes of recurrent thrombosis during and outside of pregnancy were registered only in FVL(1691)GA patients (OR 5.7, p = 0.2). In all cases, at the time of the thrombotic event and during the period before the episode of acute or recurrent thrombosis, an APC resistance normalized ratio (NR) value was ≤ 0.49, with no episodes of VTEC registered with an APC resistance NR value ≥ 0.5.

Conclusion. Venous thromboses occur under the condition of expressed APC resistance with underlying FVL(1691)GA carriage. The APC resistance index can serve as an objective biochemical marker to determine the feasibility of thromboprophylaxis within the framework of personalized medicine.

About the authors

Maria G. Nikolayeva

Altay State Medical University

Author for correspondence.
Email: nikolmg@yandex.ru

MD, PhD, Assistant Professor. The Department of Obstetrics and Gynecology (with a course of additional professional education), Medical Faculty

Russian Federation, Barnaul

Andrey P. Momot

National Medical Research Center of Hematology

Email: xyzan@yandex.ru

MD, PhD, DSci (Medicine), Professor, the Head of the Altay Branch Office

Russian Federation, Barnaul

Marina S. Zaynulina

Academician I.P. Pavlov First Saint Petersburg State Medical University

Email: zainulina@yandex.ru

MD, PhD, DSci (Medicine), Professor. The Department of Obstetrics, Gynecology, and Reproductive Sciences

Russian Federation, Saint Petersburg

Ksenia A. Momot

Regional Clinical Hospital

Email: mslove88@mail.ru

MD

Russian Federation, Barnaul

Natalia N. Yasafova

Regional Clinical Hospital

Email: jasafova@mail.ru

MD

Russian Federation, Barnaul

References

  1. Савельев В.С., Кириенко А.И., Богачев В.Ю., и др. Хроническая венозная недостаточность нижних конечностей как общемедицинская проблема // Consilium-Medicum. - 2004. - Т. 6. - № 6. - С. 433-435. [Savel’ev VS, Kirienko AI, Bogachev VY, et al. Khronicheskaya venoznaya nedostatochnost’ nizhnikh konechnostey kak obshchemeditsinskaya problema. Consilium Medicum. 2004;6(6):433-435. (In Russ.)]
  2. Бокерия Л.А., Затевахин И.И., Кириенко А.И., и др. Российские клинические рекомендации по диагностике, лечению и профилактике венозных тромбоэмболических осложнений (ВТЭО) // Флебология. - 2015. - Т. 9. - № 4-2. - С. 1-52. [Bokeriya LA, Zatevakhin II, Kirienko AI, et al. Rossiyskie klinicheskie rekomendatsii po diagnostike, lecheniyu i profilaktike venoznykh tromboembolicheskikh oslozhneniy (VTEO). Flebologiia. 2015;9(4-2):1-52. (In Russ.)]
  3. Heit JA. Venous thromboembolism: disease burden, outcomes and risk factors. J Thromb Haemost. 2005;3(8):1611-1617. doi: 10.1111/j.1538-7836.2005.01415.x.
  4. Hylek EM, Evans-Molina C, Shea C, et al. Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation. Circulation. 2007;115(21):2689-2696. doi: 10.1161/CIRCULATIONAHA.106.653048.
  5. Кириенко А.И., Андрияшкин В.В., Золотухин И.А., и др. Результаты системной профилактики венозных тромбоэмболических осложнений в масштабах Российской Федерации // Флебология. - 2014. - Т. 8. - № 3. - С. 4-10. [Kirienko AI, Andriyashkin VV, Zolotukhin IA, et al. The results of systemic prophylaxis of venous thromboembolism in the Russian Federation. Flebologiia. 2014;8(3):4-10. (In Russ.)]
  6. Beyth RJ, Cohen AM, Landefeld CS. Long-term outcomes of deep-vein thrombosis. Arch Intern Med. 1995;155(10):1031-1037. doi: 10.1001/archinte.1995.00430100053006.
  7. McKean SC, Deitelzweig SB, Sasahara A, et al. Assessing the risk of venous thromboembolism and identifying barriers to thromboprophylaxis in the hospitalized patient. J Hosp Med. 2009;4(8 Suppl):S1-7. doi: 10.1002/jhm.587.
  8. Kahn SR, Shrier I, Julian JA, et al. Determinants and time course of the postthrombotic syndrome after acute deep venous thrombosis. Ann Intern Med. 2008;149(10):698-707. doi: 10.7326/0003-4819-149-10-200811180-00004.
  9. Sultan AA, West J, Tata LJ, et al. Risk of first venous thromboembolism in and around pregnancy: a population-based cohort study. Br J Haematol. 2012;156(3):366-373. doi: 10.1111/j.1365-2141.2011.08956.x.
  10. Jackson E, Curtis KM, Gaffield ME. Risk of venous thromboembolism during the postpartum period: a systematic review. Obstet Gynecol. 2011;117(3):691-703. doi: 10.1097/AOG.0b013e31820ce2db.
  11. Акиньшина С.В., Макацария А.Д., Бицадзе В.О., Андреева М.Д. Клиника, диагностика и профилактика венозных тромбоэмболических осложнений во время беременности // Акушерство, гинекология и репродукция. - 2014. - Т. 8. - № 4. - С. 27-36. [Akin’shina SV, Makatsariya AD, Bitsadze VO, Andreeva MD. Clinical picture, diagnosis and prevention of venous thromboembolic complications during pregnancy. Akusherstvo, ginekologiya i reproduktsiya. 2014;8(4):27-36. (In Russ.)]
  12. Pabinger I, Grafenhofer H, Kyrle PA, et al. Temporary increase in the risk for recurrence during pregnancy in women with a history of venous thromboembolism. Blood. 2002;100(3):1060-1062. doi: 10.1182/blood-2002-01-0149.
  13. Kane EV, Calderwood C, Dobbie R, et al. A population-based study of venous thrombosis in pregnancy in Scotland 1980-2005. Eur J Obstet Gynecol Reprod Biol. 2013;169(2):223-229. doi: 10.1016/j.ejogrb.2013.03.024.
  14. Liu S, Rouleau J, Joseph KS, et al. Epidemiology of pregnancy-associated venous thromboembolism: a population-based study in Canada. J Obstet Gynaecol Can. 2009;31(7):611-620. doi: 10.1016/S1701-2163(16)34240-2.
  15. De Stefano V, Martinelli I, Rossi E, et al. The risk of recurrent venous thromboembolism in pregnancy and puerperium without antithrombotic prophylaxis. Br J Haematol. 2006;135(3):386-391. doi: 10.1111/j.1365-2141.2006.06317.x.
  16. Письмо Министерства здравоохранения Российской Федерации № 15-4/10/2-3792 от 27 мая 2014 г. «Профилактика венозных тромбоэмболических осложнений в акушерстве и гинекологии. Клинические рекомендации (протокол лечения)». [Letter of the Ministry of Health of the Russian Federation No. 15-4/10/2-3792 of 27 May 2014. “Profilaktika venoznykh tromboembolicheskikh oslozhneniy v akusherstve i ginekologii. Klinicheskie rekomendatsii (protokol lecheniya)ˮ. (In Russ.)]
  17. James AH. Venous thromboembolism in pregnancy. Arterioscler Thromb Vasc Biol. 2009;29(3):326-331. doi: 10.1161/ATVBAHA.109.184127.
  18. Bates SM, Greer IA, Middeldorp S, et al. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis. 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e691S-e736S. doi: 10.1378/chest.11-2300.
  19. Момот А.П. Проблема тромбофилии в клинической практике // Российский журнал детской гематологии и онкологии. - 2015. - Т. 2. - № 1. - С. 36-48. [Momot AP. The problem of thrombophilia in clinical practice. Rossiyskiy zhurnal detskoy gematologii i onkologii. 2015;2(1):36-48. (In Russ.)]. doi: 10.17650/2311-1267-2015-1-36-48.
  20. Lockwood CJ, Krikun G, Rahman M, et al. The role of decidualization in regulating endometrial hemostasis during the menstrual cycle, gestation, and in pathological states. Semin Thromb Hemost. 2007;33(1):111-117. doi: 10.1055/s-2006-958469.
  21. Margaglione M, Grandone E. Population genetics of venous thromboembolism. A narrative review. Thromb Haemost. 2011;105(2):221-231. doi: 10.1160/TH10-08-0510.
  22. Nicolaides AN, Fareed J, Kakkar AK, et al. Prevention and treatment of venous thromboembolism - International Consensus Statement. Int Angiol. 2013;32(2):111-260.
  23. Rcog.org.uk [Internet]. The Royal College of Obstetricians and Gynaecologists Green-top Guideline No. 37a. April 2015. Reducing the Risk of Venous Thromboembolism during Pregnancy and the Puerperium [cited 2018 Nov 19]. Available from: https://www.rcog.org.uk/globalassets/documents/guidelines/gtg-37a.pdf.
  24. Dahlback B, Carlsson M, Svensson PJ. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C. Proc Natl Acad Sci U S A. 1993;90(3):1004-1008. doi: 10.1073/pnas.90.3.1004.
  25. Meinardi JR, Middeldorp S, de Kam PJ, et al. The incidence of recurrent venous thromboembolism in carriers of factor V Leiden is related to concomitant thrombophilic disorders. Br J Haematol. 2002;116(3):625-631. doi: 10.1046/j.0007-1048.2001.03303.x.
  26. Макацария А.Д., Бицадзе В.О., Хизроева Д.Х., и др. Тромбопрофилактика у беременных с тромбофилией и тромбозами в анамнезе // Бюллетень Сибирского отделения Российской академии медицинских наук. - 2013. - Т. 33. - № 6. - С. 99-109. [Makatsariya AD, Bitsadze VO, Khizroeva DK, et al. Thromboprophylaxis in pregnant women with thrombophilia and thrombosis in past medical history. Bull Sib Otd Ross Akad Med Nauk. 2013;33(6):99-109. (In Russ.)]
  27. Venousdisease.com [Internet]. Caprini JA. Thrombotic Risk Assessment: A Hybrid Approach [cited 19.11.2018]. Available from: http://www.venousdisease.com/Publications/JACaprini-HybridApproach3-10-05.pdf.
  28. Савельев В.С., Кириенко А.И., Золотухин И.А., Андрияшкин В.В. Профилактика послеоперационных венозных тромбоэмболических осложнений в российских стационарах (предварительные результаты проекта «Территория безопасности») // Флебология. - 2010. - Т. 4. - № 3. - С. 3-8. [Savel’ev VS, Kirienko AI, Zolotukhin IA, Andriyashkin VV. Prevention of postoperative venous thromboembolism in the Russian Federation’s hospitals (preliminary results of the Safety zone Project). Flebologiia. 2010;4(3):3-8. (In Russ.)]
  29. Кириенко А.И., Андрияшкин В.В., Золотухин И.А., и др. Соблюдение клинических рекомендаций как условие предотвращения госпитальных тромбоэмболических осложнений // Флебология. - 2016. - Т. 10. - № 1. - С. 4-7. [Kirienko AI, Andriyashkin VV, Zolotukhin IA, et al. The Compliance with the Clinical Practice Guidelines as a Condition for the Prevention of Hospital-Associated Venous Thromboembolism. Flebologiia. 2016;10(1):4-7. (In Russ.)]
  30. Zhu T, Martinez I, Emmerich J. Venous thromboembolism: risk factors for recurrence. Arterioscler Thromb Vasc Biol. 2009;29(3):298-310. doi: 10.1161/ATVBAHA.108.182428.
  31. Weitz JI. Unanswered questions in venous thromboembolism. Thromb Res. 2009;123 Suppl 4:S2-S10. doi: 10.1016/S0049-3848(09)70135-5.
  32. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e419S-e496S. doi: 10.1378/chest.11-2301.
  33. Воробьева Н.М., Добровольский А.Б., Титаева Е.В., и др. Практические аспекты продления терапии эноксипарином до одного месяца в амбулаторных условиях у больных венозными тромбоэмболическими осложнениями // Атеротромбоз. - 2014. - № 1. - С. 33-43. [Vorob’eva NM, Dobrovol’skiy AB, Titaeva EV, et al. Prakticheskie aspekty prodleniya terapii enoksiparinom do odnogo mesyatsa v ambulatornykh usloviyakh u bol’nykh venoznymi tromboembolicheskimi oslozhneniyami. Aterotromboz. 2014;(1):33-43. (In Russ.)]
  34. Iorio A, Kearon C, Filippucci E, et al. Risk of recurrence after a first episode of symptomatic venous thromboembolism provoked by a transient risk factor: a systematic review. Arch Intern Med. 2010;170(19):1710-1716. doi: 10.1001/archinternmed.2010.367.
  35. James AH, Tapson VF, Goldhaber SZ. Thrombosis during pregnancy and the postpartum period. Am J Obstet Gynecol. 2005;193(1):216-219. doi: 10.1016/j.ajog.2004.11.037.
  36. Blanco-Molina A, Trujillo-Santos J, Criado J, et al. Venous thromboembolism during pregnancy or postpartum: findings from the RIETE Registry. Thromb Haemost. 2007;97(2):186-190. doi: 10.1160/TH06-11-0650.
  37. Verhovsek M, Douketis JD, Yi Q, et al. Systematic review: D-dimer to predict recurrent disease after stopping anticoagulant therapy for unprovoked venous thromboembolism. Ann Intern Med. 2008;149(7):481-490, W494. doi: 10.7326/0003-4819-149-7-200810070-00008.
  38. Cosmi B, Legnani C, Cini M, et al. D-dimer levels in combination with residual venous obstruction and the risk of recurrence after anticoagulation withdrawal for a first idiopathic deep vein thrombosis. Thromb Haemost. 2005;94(5):969-974. doi: 10.1160/TH05-02-0095.
  39. Siragusa S, Malato A, Anastasio R, et al. Residual vein thrombosis to establish duration of anticoagulation after a first episode of deep vein thrombosis: the Duration of Anticoagulation based on Compression UltraSonography (DACUS) study. Blood. 2008;112(3):511-515. doi: 10.1182/blood-2008-01-131656.
  40. Schulman S. Current strategies in prophylaxis and treatment of venous thromboembolism. Ann Med. 2008;40(5):352-359. doi: 10.1080/07853890802010717.
  41. Marchiori A, Mosena L, Prins MH, Prandoni P. The risk of recurrent venous thromboembolism among heterozygous carriers of factor V Leiden or prothrombin G20210A mutation. A systematic review of prospective studies. Haematologica. 2007;92(8):1107-1114. doi: 10.3324/haematol.10234.

Supplementary files

Supplementary Files
Action
1. JATS XML
Download
2. Fig. 1. Thrombotic event rate in patients with thrombophilic FVL(1961)GA genotype depending on the personal thrombotic history

Download (40KB)
Indexing metadata
3. Fig. 2. APC resistance values in control points preceding venous rethrombosis in patients with thrombophilic FVL(1961)GA genotype: the median is a marker; the “box” is an interquartile range between 25th and 75th percentiles; the “whiskers” represent the values corresponding to 2.5th and 97.5th percentiles, free elements indicate outliers

Download (83KB)
Indexing metadata

Copyright (c) 2018 Nikolayeva M.G., Momot A.P., Zaynulina M.S., Momot K.A., Yasafova N.N.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies