Activated protein C resistance explained

Activated protein C resistance (APCR)
Field:	Hematology

Activated protein C resistance (APCR) is a hypercoagulability (an increased tendency of the blood to clot) characterized by a lack of a response to activated protein C (APC), which normally helps prevent blood from clotting excessively. This results in an increased risk of venous thrombosis (blood clots in veins), which resulting in medical conditions such as deep vein thrombosis (usually in the leg) and pulmonary embolism (in the lung, which can cause death).^[1] The most common cause of hereditary APC resistance is factor V Leiden mutation.

Presentation

Associated conditions

An estimated 64 percent of patients with venous thromboembolism may have APC resistance.^[2]

Genetics

The disorder can be acquired or inherited, the hereditary form having an autosomal dominant inheritance pattern.^[3]

Pathophysiology

APC (with protein S as a cofactor) degrades Factor Va and Factor VIIIa. APC resistance is the inability of protein C to cleave Factor Va and/or Factor VIIIa, which allows for longer duration of thrombin generation and may lead to a hypercoagulable state. This may be hereditary or acquired.^[4] The best known and most common hereditary form is Factor V Leiden, which is responsible for more than 95% of cases. Other genetic causes include Factor V Cambridge (VThr306) and the factor V HR2 haplotype (A4070G mutation).^[5] Acquired forms of APC resistance occur in the presence of elevated Factor VIII concentrations. Antiphospholipid antibodies,^[6] pregnancy, and certain forms of estrogen therapy, such as ethinylestradiol-containing birth control pills, have been found to produce acquired APC resistance.^{[7] [8] [9] [10] [11] [12] [13] [14]}

Diagnosis

See also: Activated protein C resistance test.

APC resistance can be evaluated using an APC resistance test.^[15] There are two types of APC resistance tests with different properties: the activated partial thromboplastin (aPTT)-based test and the endogenous thrombin potential (ETP)-based test.^{[9] [10] [11] [16]}

Treatment

Asymptomatic individuals with APC resistance (e.g., heterozygous factor V Leiden) are not normally treated unless additional risk factors for thrombosis are also present.^[17] An example is surgery, in which perioperative short-term anticoagulation may be used. However, people with homozygous factor V Leiden, and people with heterozygous factor V Leiden who have an additional thrombophilic condition (e.g., antithrombin deficiency, protein C deficiency, or protein S deficiency), should be considered for lifelong oral anticoagulation therapy. People with APC resistance and initial DVT are treated with a standard anticoagulant regimen, for instance intravenous heparin therapy followed by oral anticoagulation.

Notes and References

1. Dahlbäck B . The discovery of activated protein C resistance . J. Thromb. Haemost. . 1 . 1 . 3–9 . 2003 . 12871530 . 10.1046/j.1538-7836.2003.00016.x. 2147784 . free .
2. Sheppard DR . 20016675 . Activated protein C resistance: the most common risk factor for venous thromboembolism . J Am Board Fam Pract . 13 . 2 . 111–5 . 2000 . 10764192 . 10.3122/15572625-13-2-111. free .
3. 7902898 . December 1993 . Koster T, Rosendaal FR, De Ronde H, Briët E, Vandenbroucke JP, Bertina RM . 54283312 . Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study . 342 . 8886–8887 . 1503–6 . 0140-6736 . Lancet . 10.1016/S0140-6736(05)80081-9.
4. Nicolaes GA, Dahlbäck B . Congenital and acquired activated protein C resistance . Semin Vasc Med . 3 . 1 . 33–46 . 2003 . 15199491 . 10.1055/s-2003-38331.
5. Book: Advances in Experimental Medicine and Biology . Hotoleanu . Cristina . Genetic Risk Factors in Venous Thromboembolism . 2016 . 906 . 253–272 . Springer International Publishing . 0065-2598 . 2214-8019 . 10.1007/5584_2016_120 . 27638626 . 978-3-319-22107-6 .
6. Kujovich JL . Factor V Leiden thrombophilia . Genet Med . 13 . 1 . 1–16 . January 2011 . 21116184 . 10.1097/GIM.0b013e3181faa0f2 . 220861191 . free .
7. Tchaikovski SN, Rosing J . Mechanisms of estrogen-induced venous thromboembolism . Thromb Res . 126 . 1 . 5–11 . July 2010 . 20163835 . 10.1016/j.thromres.2010.01.045 .
8. Hemelaar M, van der Mooren MJ, Rad M, Kluft C, Kenemans P . Effects of non-oral postmenopausal hormone therapy on markers of cardiovascular risk: a systematic review . Fertil Steril . 90 . 3 . 642–72 . September 2008 . 17923128 . 10.1016/j.fertnstert.2007.07.1298 . free .
9. Morimont L, Haguet H, Dogné JM, Gaspard U, Douxfils J . Combined Oral Contraceptives and Venous Thromboembolism: Review and Perspective to Mitigate the Risk . Front Endocrinol (Lausanne) . 12 . 769187 . 2021 . 34956081 . 8697849 . 10.3389/fendo.2021.769187 . free .
10. Douxfils J, Morimont L, Bouvy C . Oral Contraceptives and Venous Thromboembolism: Focus on Testing that May Enable Prediction and Assessment of the Risk . Semin Thromb Hemost . 46 . 8 . 872–886 . November 2020 . 33080636 . 10.1055/s-0040-1714140 . 224821517 .
11. Reda S, Morimont L, Douxfils J, Rühl H . Can We Measure the Individual Prothrombotic or Prohemorrhagic Tendency by Global Coagulation Tests? . Hamostaseologie . 40 . 3 . 364–378 . August 2020 . 32726831 . 10.1055/a-1153-5824 . 220878363 . free .
12. Clark P . Changes of hemostasis variables during pregnancy . Semin Vasc Med . 3 . 1 . 13–24 . February 2003 . 15199489 . 10.1055/s-2003-38329 .
13. Asscheman H, T'Sjoen G, Lemaire A, Mas M, Meriggiola MC, Mueller A, Kuhn A, Dhejne C, Morel-Journel N, Gooren LJ . Venous thrombo-embolism as a complication of cross-sex hormone treatment of male-to-female transsexual subjects: a review . Andrologia . 46 . 7 . 791–5 . September 2014 . 23944849 . 10.1111/and.12150 . 11585/413984 . 5363824 . free .
14. Toorians AW, Thomassen MC, Zweegman S, Magdeleyns EJ, Tans G, Gooren LJ, Rosing J . Venous thrombosis and changes of hemostatic variables during cross-sex hormone treatment in transsexual people . J Clin Endocrinol Metab . 88 . 12 . 5723–9 . December 2003 . 14671159 . 10.1210/jc.2003-030520 . free .
15. Amiral J, Vissac AM, Seghatchian J . Laboratory assessment of Activated Protein C Resistance/Factor V-Leiden and performance characteristics of a new quantitative assay . Transfus Apher Sci . 56 . 6 . 906–913 . December 2017 . 29162399 . 10.1016/j.transci.2017.11.021 .
16. de Visser MC, van Hylckama Vlieg A, Tans G, Rosing J, Dahm AE, Sandset PM, Rosendaal FR, Bertina RM . Determinants of the APTT- and ETP-based APC sensitivity tests . J Thromb Haemost . 3 . 7 . 1488–94 . July 2005 . 15978106 . 10.1111/j.1538-7836.2005.01430.x . 1887/5044 . 23567724 . free .
17. Nichols WL, Heit JA . Activated protein C resistance and thrombosis . Mayo Clin Proc . 71 . 9 . 897–8 . September 1996 . 8790269 . 10.4065/71.9.897 .