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J Reconstr Microsurg 2022; 38(09): 734-741
DOI: 10.1055/s-0042-1749337
Original Article

Genomic Analysis of Thrombophilia Variants in the General Population for the Creation of an Effective Preoperative Screening Tool

Fadi M. Azar 
1   Kirk Kerkorian School of Medicine at University of Nevada, Las Vegas (UNLV), Las Vegas, Nevada
,
John M. Menezes
2   Department of Plastic Surgery, Kirk Kerkorian School of Medicine at University of Nevada, Las Vegas (UNLV), Las Vegas, Nevada
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Abstract

Background The loss of a free flap in reconstructive microsurgery is a devastating complication in both the intraoperative and postoperative setting. Previous research has identified a variety of genetic polymorphisms that induce a hypercoagulable state and predispose patients to clot formation and subsequent free flap loss. We aim to review the risks of performing microsurgery on patients who are genetically predisposed to hypercoagulability, as well as identify options, for preoperative screening of inherited thrombophilia.

Methods A thorough literature review was conducted with an online database. A total of 30 studies were reviewed to identify genetic polymorphisms that cause inherited thrombophilia. Through manual review of the literature, a table was created that included thrombotic risk factors and their associated genetic polymorphisms. If the information was available, prevalence for each thrombotic risk was also reported.

Results Overall, 18 thrombotic risk factors that contribute to hereditary thrombophilia were identified and linked with specific genes and/or genetic polymorphisms. In studies that did not look at particular ethnic groups, 13 unique thrombotic risk factors were identified. In studies that examined specific ethnic groups exclusively, 12 thrombotic risk factors were identified and related to their respective gene or group of genes. Five of the 18 thrombotic risk factors identified were associated with increased risks of both venous and arterial thrombosis. The remainder of the thrombotic risk factors was associated with increased risk of venous thrombosis exclusively.

Conclusion The use of genetic screening tests for hereditary thrombophilia in the preoperative setting can serve as an effective preventative measure against postoperative thrombosis. Further exploration of thrombotic risk factors and their related genetic polymorphisms are important steps in reducing postoperative free flap loss.

Keywords

genetic screening - thrombophilia - postoperative thrombosis


Publication History

Received: 30 November 2021

Accepted: 22 March 2022

Article published online:
17 June 2022

© 2022. Thieme. All rights reserved.

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  • References

  • 1 Pannucci CJ, Bailey SH, Dreszer G. et al. Validation of the Caprini risk assessment model in plastic and reconstructive surgery patients. J Am Coll Surg 2011; 212 (01) 105-112
    CrossrefPubMedGoogle Scholar
  • 2 Wang TY, Serletti JM, Cuker A. et al. Free tissue transfer in the hypercoagulable patient: a review of 58 flaps. Plast Reconstr Surg 2012; 129 (02) 443-453
    CrossrefPubMedGoogle Scholar
  • 3 Heit JA. Thrombophilia: clinical and laboratory assessment and management. In: Consultative Hemostasis and Thrombosis. Philadelphia, PA: Elsevier;; 2013
    Google Scholar
  • 4 Colomina MJ, Méndez E, Sabate A. Altered fibrinolysis during and after surgery. Semin Thromb Hemost 2021; 47 (05) 512-519
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Griffiths NJ. Factors affecting the fibrinolytic response to surgery. Ann R Coll Surg Engl 1979; 61 (01) 12-16
    PubMedGoogle Scholar
  • 6 Pannucci CJ, Fleming KI, Bertolaccini C. et al. Optimal dosing of prophylactic enoxaparin after surgical procedures: results of the double-blind, randomized, controlled fixed or variable enoxaparin (FIVE) trial. Plast Reconstr Surg 2021; 147 (04) 947-958
    CrossrefPubMedGoogle Scholar
  • 7 Davison SP, Kessler CM, Al-Attar A. Microvascular free flap failure caused by unrecognized hypercoagulability. Plast Reconstr Surg 2009; 124 (02) 490-495
    CrossrefPubMedGoogle Scholar
  • 8 Bui DT, Cordeiro PG, Hu QY, Disa JJ, Pusic A, Mehrara BJ. Free flap reexploration: indications, treatment, and outcomes in 1193 free flaps. Plast Reconstr Surg 2007; 119 (07) 2092-2100
    Google Scholar
  • 9 Kotamarti VS, Shiah E, Rezak KM, Patel A, Ricci JA. Does anticoagulation improve flap outcomes in hypercoagulable patients? A systematic review. J Reconstr Microsurg 2020; 36 (03) 204-212
    Article in Thieme ConnectPubMedGoogle Scholar
  • 10 Nelson JA, Chung CU, Bauder AR, Wu LC. Prevention of thrombosis in hypercoagulable patients undergoing microsurgery: a novel anticoagulation protocol. J Plast Reconstr Aesthet Surg 2017; 70 (03) 307-312
    CrossrefPubMedGoogle Scholar
  • 11 Bertolaccini CM, Prazak AMB, Goodwin IA. et al. Prevention of venous thromboembolism in microvascular surgery patients using weight-based unfractionated heparin infusions. J Reconstr Microsurg 2021
    PubMedGoogle Scholar
  • 12 DeFazio MV, Economides JM, Anghel EL, Tefera EA, Evans KK. Lower extremity free tissue transfer in the setting of thrombophilia: analysis of perioperative anticoagulation protocols and predictors of flap failure. J Reconstr Microsurg 2019; 35 (04) 270-286
    Article in Thieme ConnectPubMedGoogle Scholar
  • 13 Reuter KD, Nicksic PJ, Poore SO. Risks of free tissue transfer in the hypocoaguable patient. J Reconstr Microsurg 2020; 36 (03) e5
    Article in Thieme ConnectPubMedGoogle Scholar
  • 14 Petrilli CM, Heidemann L, Mack M, Durance P, Chopra V. Inpatient inherited thrombophilia testing. J Hosp Med 2016; 11 (11) 801-804
    CrossrefPubMedGoogle Scholar
  • 15 Thrombophilia genetic panel. Accessed April 29, 2022 at: https://www.machaondiagnostics.com/panel/thrombophilia-genetic-panel/
    PubMedGoogle Scholar
  • 16 Invitae hereditary thrombophilia panel. Accessed April 29, 2022 at: https://www.invitae.com/en/physician/tests/05251/
    PubMedGoogle Scholar
  • 17 Berse B, Lynch JA, Bowen S, Grosse SD. In reference to: “cost and utility of thrombophilia testing”. J Hosp Med 2017; 12 (09) 783-783
    CrossrefPubMedGoogle Scholar
  • 18 Zavlin D, Chegireddy V, Jubbal KT, Agrawal NA, Spiegel AJ. Management of microsurgical patients using intraoperative unfractionated heparin and thromboelastography. J Reconstr Microsurg 2019; 35 (03) 198-208
    Article in Thieme ConnectPubMedGoogle Scholar
  • 19 Kolbenschlag J, Daigeler A, Lauer S. et al. Can rotational thromboelastometry predict thrombotic complications in reconstructive microsurgery?. Microsurgery 2014; 34 (04) 253-260
    CrossrefPubMedGoogle Scholar
  • 20 Patel H, Srinivasa DR, Volod O, Wang ED, Kim EA. Rotational thromboelastometry derivative fibrinogen-platelet ratio predicts thrombosis in microsurgery. J Reconstr Microsurg 2021; 37 (09) 774-782
    Article in Thieme ConnectPubMedGoogle Scholar
  • 21 McCormack T, Harrisingh MC, Horner D, Bewley S. Guideline Committee. Venous thromboembolism in adults: summary of updated NICE guidance on diagnosis, management, and thrombophilia testing. BMJ 2020; 369: m1565
    CrossrefPubMedGoogle Scholar
  • 22 UMC prices for all services. Accessed April 29, 2022 at: https://www.umcsn.com/patients-visitors/prices-for-all-services
    PubMedGoogle Scholar
  • 23 Souto JC, Almasy L, Borrell M. et al. Genetic susceptibility to thrombosis and its relationship to physiological risk factors: the GAIT study. Genetic Analysis of Idiopathic Thrombophilia. Am J Hum Genet 2000; 67 (06) 1452-1459
    CrossrefPubMedGoogle Scholar
  • 24 Meraz-Ríos MA, Majluf-Cruz A, Santana C. et al. Association of vWA and TPOX polymorphisms with venous thrombosis in Mexican mestizos. BioMed Res Int 2014; 2014: 697689
    PubMedGoogle Scholar
  • 25 Bene NC, Minasian RA, Khan SI, Desjardins HE, Guo L. Ethnic disparities in thrombotic and bleeding diatheses revisited: a systematic review of microsurgical breast reconstruction across the east and west. J Reconstr Microsurg 2022; 38 (01) 84-88
    Article in Thieme ConnectPubMedGoogle Scholar
  • 26 Parisi R, Costanzo S, Di Castelnuovo A, de Gaetano G, Donati MB, Iacoviello L. Different anticoagulant regimens, mortality, and bleeding in hospitalized patients with COVID-19: a systematic review and an updated meta-analysis. Semin Thromb Hemost 2021; 47 (04) 372-391
    Article in Thieme ConnectPubMedGoogle Scholar
  • 27 Henry BM, Cheruiyot I, Benoit JL. et al. Circulating levels of tissue plasminogen activator and plasminogen activator inhibitor-1 are independent predictors of coronavirus disease 2019 severity: a prospective, observational study. Semin Thromb Hemost 2021; 47 (04) 451-455
    Article in Thieme ConnectPubMedGoogle Scholar
  • 28 Favaloro EJ, Henry BM, Lippi G. Increased VWF and decreased ADAMTS-13 in COVID-19: creating a milieu for (micro)thrombosis. Semin Thromb Hemost 2021; 47 (04) 400-418
    Article in Thieme ConnectPubMedGoogle Scholar
  • 29 Chi D, Chen AD, Dorante MI, Lee BT, Sacks JM. Plastic surgery in the time of COVID-19. J Reconstr Microsurg 2021; 37 (02) 124-131
    Article in Thieme ConnectPubMedGoogle Scholar
  • 30 Mandelbaum AD, Thompson CK, Attai DJ. et al. National trends in immediate breast reconstruction: an analysis of implant-based versus autologous reconstruction after mastectomy. Ann Surg Oncol 2020; 27 (12) 4777-4785
    CrossrefPubMedGoogle Scholar
  • 31 Srikanthan K, Viswanathan N, Yuen JC. Free-flap failure in thrombophilia: case report and systematic review of the literature. Ann Plast Surg 2013; 71 (06) 675-681
    CrossrefPubMedGoogle Scholar
  • 32 Chang CS, Chu MW, Nelson JA. et al. Complications and cost analysis of intraoperative arterial complications in head and neck free flap reconstruction. J Reconstr Microsurg 2017; 33 (05) 318-327
    Article in Thieme ConnectPubMedGoogle Scholar
  • 33 Herman C. What makes a screening exam “good”?. Virtual Mentor 2006; 8 (01) 34-37
    PubMedGoogle Scholar
  • 34 Endler G, Mannhalter C. Polymorphisms in coagulation factor genes and their impact on arterial and venous thrombosis. Clin Chim Acta 2003; 330 (1-2): 31-55
    CrossrefPubMedGoogle Scholar
  • 35 Trégouët D-A, Morange P-E. What is currently known about the genetics of venous thromboembolism at the dawn of next generation sequencing technologies. Br J Haematol 2018; 180 (03) 335-345
    CrossrefPubMedGoogle Scholar
  • 36 Federici EH, Al-Mondhiry H. High risk of thrombosis recurrence in patients with homozygous and compound heterozygous factor V R506Q (Factor V Leiden) and prothrombin G20210A. Thromb Res 2019; 182: 75-78
    CrossrefPubMedGoogle Scholar
  • 37 Merriman L, Greaves M. Testing for thrombophilia: an evidence-based approach. Postgrad Med J 2006; 82 (973) 699-704
    CrossrefPubMedGoogle Scholar
  • 38 Colucci G, Tsakiris DA. Thrombophilia screening: universal, selected, or neither?. Clin Appl Thromb Hemost 2017; 23 (08) 893-899
    CrossrefPubMedGoogle Scholar
  • 39 Dzimiri N, Meyer B. World distribution of factor V Leiden. Lancet 1996; 347 (8999): 481-482
    CrossrefPubMedGoogle Scholar
  • 40 Hinds DA, Buil A, Ziemek D. et al; METASTROKE Consortium, INVENT Consortium. Genome-wide association analysis of self-reported events in 6135 individuals and 252 827 controls identifies 8 loci associated with thrombosis. Hum Mol Genet 2016; 25 (09) 1867-1874
    CrossrefPubMedGoogle Scholar
  • 41 Koster T, Blann AD, Briët E, Vandenbroucke JP, Rosendaal FR. Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis. Lancet 1995; 345 (8943): 152-155
    CrossrefPubMedGoogle Scholar
  • 42 Kamphuisen PW, Eikenboom JCJ, Bertina RM. Elevated factor VIII levels and the risk of thrombosis. Arterioscler Thromb Vasc Biol 2001; 21 (05) 731-738
    CrossrefPubMedGoogle Scholar
  • 43 Castaman G, Giacomelli SH, Biasoli C, Contino L, Radossi P. Risk of bleeding and thrombosis in inherited qualitative fibrinogen disorders. Eur J Haematol 2019; 103 (04) 379-384
    CrossrefPubMedGoogle Scholar
  • 44 Jiang J, Liu K, Zou J. et al. Associations between polymorphisms in coagulation-related genes and venous thromboembolism: a meta-analysis with trial sequential analysis. Medicine (Baltimore) 2017; 96 (13) e6537
    CrossrefPubMedGoogle Scholar
  • 45 Ye Z, Zhang Q, Li Y. et al. High prevalence of hyperhomocysteinemia and its association with target organ damage in chinese patients with chronic kidney disease. Nutrients 2016; 8 (10) 645
    CrossrefPubMedGoogle Scholar
  • 46 Kumari B, Srivastava S, Chatterjee T. et al. Study of associated genetic variants in Indian subjects reveals the basis of ethnicity related differences in susceptibility to venous thromboembolism. Thrombosis 2014; 2014: 182762
    CrossrefPubMedGoogle Scholar
  • 47 Kamdi SP, Palkar P. Prevalence of hyperhomocysteinemia in healthy Indian doctors. Bioinformation 2013; 9 (04) 193-196
    CrossrefPubMedGoogle Scholar
  • 48 Zavala-Hernández C, Hernández-Zamora E, Martínez-Murillo C. et al. Risk factors for thrombosis development in Mexican patients. Ann Vasc Surg 2015; 29 (08) 1625-1632
    CrossrefPubMedGoogle Scholar
  • 49 Islam MA, Khandker SS, Alam F, Kamal MA, Gan SH. Genetic risk factors in thrombotic primary antiphospholipid syndrome: a systematic review with bioinformatic analyses. Autoimmun Rev 2018; 17 (03) 226-243
    CrossrefPubMedGoogle Scholar
  • 50 Iuliano A, Galeazzi M, Sebastiani GD. Antiphospholipid syndrome's genetic and epigenetic aspects. Autoimmun Rev 2019; 18 (09) 102352
    CrossrefPubMedGoogle Scholar
  • 51 Duarte-García A, Pham MM, Crowson CS. et al. The epidemiology of antiphospholipid syndrome: a population-based study. Arthritis Rheumatol 2019; 71 (09) 1545-1552
    Google Scholar
  • 52 Ding Q, Yang L, Hassanian SM, Rezaie AR. Expression and functional characterisation of natural R147W and K150del variants of protein C in the Chinese population. Thromb Haemost 2013; 109 (04) 614-624
    Article in Thieme ConnectPubMedGoogle Scholar
  • 53 Tang L, Guo T, Yang R. et al. Genetic background analysis of protein C deficiency demonstrates a recurrent mutation associated with venous thrombosis in Chinese population. PLoS One 2012; 7 (04) e35773
    CrossrefPubMedGoogle Scholar
  • 54 Tang L, Lu X, Yu JM. et al. PROC c.574_576del polymorphism: a common genetic risk factor for venous thrombosis in the Chinese population. J Thromb Haemost 2012; 10 (10) 2019-2026
    CrossrefPubMedGoogle Scholar
  • 55 Zhu T, Ding Q, Bai X. et al. Normal ranges and genetic variants of antithrombin, protein C and protein S in the general Chinese population. Results of the Chinese Hemostasis Investigation on Natural Anticoagulants Study I Group. Haematologica 2011; 96 (07) 1033-1040
    CrossrefPubMedGoogle Scholar
  • 56 Miyata T, Sato Y, Ishikawa J. et al. Prevalence of genetic mutations in protein S, protein C and antithrombin genes in Japanese patients with deep vein thrombosis. Thromb Res 2009; 124 (01) 14-18
    CrossrefPubMedGoogle Scholar
  • 57 Fall AO, Proulle V, Sall A. et al. Risk factors for thrombosis in an african population. Clin Med Insights Blood Disord 2014; 7: 1-6
    PubMedGoogle Scholar
  • 58 Crowley MP, Hunt BJ. Venous thromboembolism and thrombophilia testing. Medicine (Baltimore) 2017; 45 (04) 233-238
    CrossrefPubMedGoogle Scholar
  • 59 Tang L, Wang HF, Lu X. et al. Common genetic risk factors for venous thrombosis in the Chinese population. Am J Hum Genet 2013; 92 (02) 177-187
    CrossrefPubMedGoogle Scholar
  • 60 Hernandez W, Gamazon ER, Smithberger E. et al. Novel genetic predictors of venous thromboembolism risk in African Americans. Blood 2016; 127 (15) 1923-1929
    CrossrefPubMedGoogle Scholar