activated protein c resistance


Summary: A hemostatic disorder characterized by a poor anticoagulant response to activated protein C (APC). The activated form of Factor V (Factor Va) is more slowly degraded by activated protein C. Factor V Leiden mutation (R506Q) is the most common cause of APC resistance.

Top Publications

  1. Prochazka M, Krcova V, Hrachovec P, Kudela M, Slavik L. [Activated protein C resistance and deep venous thrombosis in pregnancy]. Ceska Gynekol. 2002;67:251-4 pubmed
    ..Factor V appeared in II (33.3%) women, in comparison to 3 (5.9%) women in the control group. APC resistance and factor V. Leiden represent as important factors in the aetiology of deep venous thrombosis in pregnancy. ..
  2. Nagy V, Facsko A, Takacs L, Balazs E, Berta A, Balogh I, et al. Activated protein C resistance in anterior ischaemic optic neuropathy. Acta Ophthalmol Scand. 2004;82:140-3 pubmed
    ..021). The high frequency of Leiden mutation in NAION suggests a pathogenic role of the mutation in the disease. ..
  3. Naudziunas A, Miliauskas S. Factor V Leiden and post thromboembolic pulmonary hypertension. Medicina (Kaunas). 2003;39:1171-4 pubmed
    Literature review and original data concerning the most common cause of inherited thrombophilia - activated protein C resistance have been presented...
  4. Mahieu B, Jacobs N, Mahieu S, Naelaerts K, Vertessen F, Weyler J, et al. Haemostatic changes and acquired activated protein C resistance in normal pregnancy. Blood Coagul Fibrinolysis. 2007;18:685-8 pubmed
    ..The clinical significance of this finding should be determined because it complicates the interpretation of lowered APC-SR. ..
  5. Mosnier L, Zlokovic B, Griffin J. The cytoprotective protein C pathway. Blood. 2007;109:3161-72 pubmed
  6. Kassis J, Neville C, Rauch J, Busque L, Chang E, Joseph L, et al. Antiphospholipid antibodies and thrombosis: association with acquired activated protein C resistance in venous thrombosis and with hyperhomocysteinemia in arterial thrombosis. Thromb Haemost. 2004;92:1312-9 pubmed
    ..between factor V Leiden and venous thrombosis, hyperhomocysteinemia and arterial thrombosis, and activated protein C resistance (APCR) and venous thrombosis (OR, 95% CI = 4.00, 1.35-11.91; 4.79, 2.03-11.33; and 2.03, 1.03-3...
  7. Dawood F, Mountford R, Farquharson R, Quenby S. Genetic polymorphisms on the factor V gene in women with recurrent miscarriage and acquired APCR. Hum Reprod. 2007;22:2546-53 pubmed
    Recurrent miscarriage (RM) has been associated with the thrombophilia, activated protein C resistance (APCR)...
  8. Benedetto C, Marozio L, Tavella A, Maulà V, Carmignani D, Curti A. Response to activated protein C decreases throughout pregnancy. Acta Obstet Gynecol Scand. 2002;81:1028-32 pubmed
    ..Our data confirm a reduction in the APC ratio throughout pregnancy. In our series, an APC ratio of less than 2.0 according to the cut-off point of our laboratory). ..
  9. Scanavini D, Legnani C, Lunghi B, Mingozzi F, Palareti G, Bernardi F. The factor VIII D1241E polymorphism is associated with decreased factor VIII activity and not with activated protein C resistance levels. Thromb Haemost. 2005;93:453-6 pubmed
    ..Our findings point toward the presence of genetic determinant of coagulation factor levels with a biologically significant role, but with a poor predictive value to estimate thrombotic risk beyond established risk factors. ..

More Information


  1. Sedano S, Gaffney G, Mortimer G, Lyons M, Cleary B, Murray M, et al. Activated protein C resistance (APCR) and placental fibrin deposition. Placenta. 2008;29:833-7 pubmed publisher
    b>Activated protein C resistance (APCR) results in an ineffective anticoagulant response leading to an increased risk of thrombosis, particularly during pregnancy...
  2. Soria J, Almasy L, Souto J, Buil A, Martinez Sanchez E, Mateo J, et al. A new locus on chromosome 18 that influences normal variation in activated protein C resistance phenotype and factor VIII activity and its relation to thrombosis susceptibility. Blood. 2003;101:163-7 pubmed
    b>Activated protein C resistance (APCR) is the most prevalent risk factor for thrombosis, accounting for 20% to 60% of familial thrombophilia...
  3. Negaard H, Iversen P, Ostenstad B, Mowinckel M, Sandset P. Increased acquired activated protein C resistance in unselected patients with hematological malignancies. J Thromb Haemost. 2008;6:1482-7 pubmed publisher
    ..Decreased levels of protein S and TF pathway inhibitor were inversely correlated to APC resistance. APC resistance may contribute to the hypercoagulable state in hematological malignancies. ..
  4. Tans G, van Hylckama Vlieg A, Thomassen M, Curvers J, Bertina R, Rosing J, et al. Activated protein C resistance determined with a thrombin generation-based test predicts for venous thrombosis in men and women. Br J Haematol. 2003;122:465-70 pubmed
    ..In addition, acquired APC resistance resulting from OC use predicts an increased risk for venous thrombosis independent of factor V Leiden. ..
  5. Santamaria A, Soria J, Tirado I, Mateo J, Coll I, Souto J, et al. Double heterozygosity for Factor V Leiden and Factor V Cambridge mutations associated with low levels of activated protein C resistance in a Spanish thrombophilic family. Thromb Haemost. 2005;93:1193-5 pubmed
  6. Harvey D, Lowe G. Factor V Leiden: association with venous thromboembolism in pregnancy and screening issues. Br J Biomed Sci. 2004;61:157-64 pubmed
    ..Pregnant women with a history of VTE or with a family history of the mutation are investigated. Whether or not the introduction of a routine screening plan for this mutation is justified remains a matter for debate. ..
  7. Jadaon M, Dashti A, Lewis H. High prevalence of activated protein C resistance and factor V Leiden mutation in an Arab population and patients with venous thrombosis in Kuwait. Diagn Mol Pathol. 2010;19:180-3 pubmed
    b>Activated protein C resistance (APC-R) because of clotting factor V Leiden mutation (FVL; Arg506Gln; G1691A) is a risk factor for the development of venous thromboembolic disorders (VTE)...
  8. Chegeni R, Kazemi B, Hajifathali A, Pourfathollah A, Lari G. Factor V mutations in Iranian patients with activated protein C resistance and venous thrombosis. Thromb Res. 2007;119:189-93 pubmed
  9. de Visser M, Guasch J, Kamphuisen P, Vos H, Rosendaal F, Bertina R. The HR2 haplotype of factor V: effects on factor V levels, normalized activated protein C sensitivity ratios and the risk of venous thrombosis. Thromb Haemost. 2000;83:577-82 pubmed
    ..However, the HR2 haplotype is associated with a reduced sensitivity for APC in carriers of FVL and with reduced factor V antigen levels. ..
  10. Hoekema L, Castoldi E, Tans G, Girelli D, Gemmati D, Bernardi F, et al. Functional properties of factor V and factor Va encoded by the R2-gene. Thromb Haemost. 2001;85:75-81 pubmed
  11. Kostka H, Siegert G, Schwarz T, Gehrisch S, Kuhlisch E, Schellong S, et al. Frequency of polymorphisms in the B-domain of factor V gene in APC-resistant patients. Thromb Res. 2000;99:539-47 pubmed
    ..We suggest that the G allele, which is not associated with the FV Leiden mutation, as well as the [2379G; 2540C; 4070G] allele have no influence on the APC cofactor function itself, or only subtly as determined in the test systems used. ..
  12. Cui J, Eitzman D, Westrick R, Christie P, Xu Z, Yang A, et al. Spontaneous thrombosis in mice carrying the factor V Leiden mutation. Blood. 2000;96:4222-6 pubmed
    ..Blood. 2000;96:4222-4226) ..
  13. Laberge A, Psaty B, Hindorff L, Burke W. Use of Factor V Leiden genetic testing in practice and impact on management. Genet Med. 2009;11:750-6 pubmed publisher
    ..These results underscore the importance of further research concerning effective prevention and treatment strategies for patients with genetic risk to help translate genetic risk information into improved health outcomes. ..
  14. Nojima J, Kuratsune H, Suehisa E, Kawasaki T, Machii T, Kitani T, et al. Acquired activated protein C resistance associated with anti-protein S antibody as a strong risk factor for DVT in non-SLE patients. Thromb Haemost. 2002;88:716-22 pubmed
    ..vein thrombosis (DVT) by using objective tests for diagnosing DVT and laboratory tests including the activated protein C resistance (APC-R) test, the factor V Leiden test, and various aPL Abs...
  15. Herskovits A, Morgan E, Lemire S, Lindeman N, Dorfman D. An improved algorithm for activated protein C resistance and factor V Leiden screening. Am J Clin Pathol. 2013;140:379-86 pubmed publisher
    To evaluate the performance of a Russell viper venom-based activated protein C resistance (APCR) screening test relative to DNA analysis for the factor V Leiden mutation...
  16. Zarychanski R, Houston D. Plasma homocysteine concentration is not associated with activated protein C resistance in patients investigated for hypercoagulability. Thromb Haemost. 2004;91:1115-22 pubmed
    ..In these patients, elevated plasma homocysteine levels is not associated with aPC resistance regardless of FV Leiden genotype suggesting that this is not the mechanism by which homocysteine exerts a prothrombotic effect. ..
  17. Cappuccio G, Valesio R, Lamorgese V, Massucco S, Varetto G, Conforti M, et al. [Femoropopliteal arterial thrombosis in a young patient with heterozygous V Leiden factor mutation. Case report]. Minerva Med. 2007;98:77-80 pubmed
    ..The criticality of lower limb ischemia in an otherwise healthy young patient underscores the grave impact this condition can have on the patient's quality of life and on health care costs. ..
  18. Bossone A, Margaglione M. More on: does the factor V Asp79His (409 G/C) polymorphism influence Factor V and APC resistance levels?. J Thromb Haemost. 2005;3:417 pubmed
  19. Zanardo V, Savio V, Sabrina G, Franzoi M, Zerbinati P, Fadin M, et al. The effect of pre-eclampsia on the levels of coagulation and fibrinolysis factors in umbilical cord blood of newborns. Blood Coagul Fibrinolysis. 2005;16:177-81 pubmed
    ..01) as compared with neonates from normotensive women. Cord blood protein C antigen and activated protein C resistance mean levels were slightly higher in the group of neonates from pre-eclamptic mothers...
  20. Shaikh S, Van Cott E. The effect of argatroban on activated protein C resistance. Am J Clin Pathol. 2009;131:828-33 pubmed publisher
    ..Argatroban increases the APC resistance ratio, which can mask a diagnosis of APC resistance and, therefore, factor V Leiden. Clinicians should be advised that APC resistance testing for patients receiving argatroban is not valid. ..
  21. Kalpage H, Sumathipala D, Goonasekara H, Dissanayake V. A Study on Hereditary Thrombophilia and Stroke in a Cohort from Sri Lanka. J Stroke Cerebrovasc Dis. 2016;25:102-9 pubmed publisher
    ..6) years, respectively. MTHFR c.677C>T is the predominant mutation and the only mutation that had patients with the homozygous mutant genotype. Venous thrombosis showed a significant association with the F5 c.1691G>A mutation. ..
  22. Wan Ab Rahman W, Abdullah W, Hassan M, Hussin A, Zulkafli Z, Haron J. Familial antithrombin III deficiency in a Malay patient with massive thrombosis. Malays J Pathol. 2017;39:197-200 pubmed showed reduced AT III activity (38?l/dl) and normal results for protein C, protein S, activated protein C resistance and lupus anticoagulant assays...
  23. Rodger M, Carrier M, Gervais M, Rock G. Normal functional protein S activity does not exclude protein S deficiency. Pathophysiol Haemost Thromb. 2003;33:202-5 pubmed
    ..Functional PS activity testing should not be used as a screening test to eliminate free antigenic PS testing for the laboratory diagnosis of PS deficiency. ..
  24. Ku D, Arkel Y, Paidas M, Lockwood C. Circulating levels of inflammatory cytokines (IL-1 beta and TNF-alpha), resistance to activated protein C, thrombin and fibrin generation in uncomplicated pregnancies. Thromb Haemost. 2003;90:1074-9 pubmed
    ..A sub-group of pregnancies with APC resistance had increased levels of TNF-alpha and may be important in the risk for adverse pregnancy outcomes. ..
  25. Gaunt T, Lowe G, Lawlor D, Casas J, Day I. A gene-centric analysis of activated partial thromboplastin time and activated protein C resistance using the HumanCVD focused genotyping array. Eur J Hum Genet. 2013;21:779-83 pubmed publisher
    ..In conclusion, variation at several genetic loci influences intrinsic blood coagulation as measured by both aPTT and APC resistance. ..
  26. Castoldi E, Rosing J. APC resistance: biological basis and acquired influences. J Thromb Haemost. 2010;8:445-53 pubmed publisher
    ..This paper reviews the multifactorial etiology of APC resistance and discusses its clinical implications. ..
  27. Alakoc Y, Aka P, Egin Y, Akar N. Factor V Leiden in an Urartian, dating back to 1000 BC. Clin Appl Thromb Hemost. 2010;16:679-83 pubmed publisher
    ..To date, the age of this mutation was estimated based on statistical calculations using haplotype frequencies; here for the first time, we report FVL in an ancient population of 3000 years. ..
  28. Stölzel K, Jovanovic S, Albers A. [Jugular vein thrombosis caused by hypercoagulability following in-vitro fertilization-activated protein C resistance and immobilization]. HNO. 2013;61:250-5 pubmed publisher
    ..It also discusses the current literature that forms the basis for recommendations regarding the diagnosis, therapy and interdisciplinary management. ..
  29. el Haddad R, Kaprál A, Zivny J. [Internal jugular vein thrombosis in a patient with ovarian hyperstimulation syndrome]. Ceska Gynekol. 2003;68:114-7 pubmed
    ..Case report. 1st Medical Faculty, Charles University and General Faculty Hospital, Prague. A 27-year-old primiparous woman undergoing in vitro fertilisation (IVF). ..
  30. Muwakkit S, Saab R, Sanjad S, Bhar S, Ishak R, Samad Z, et al. Renal venous thrombosis in a newborn with prothrombotic risk factors. Blood Coagul Fibrinolysis. 2009;20:458-60 pubmed publisher
    ..This case and other studies clearly demonstrate that neonatal RVT should be evaluated for thrombophilia conditions. ..
  31. Mahmood A, Needham J, Prosser J, Mainwaring J, Trebble T, Mahy G, et al. Prevalence of hyperhomocysteinaemia, activated protein C resistance and prothrombin gene mutation in inflammatory bowel disease. Eur J Gastroenterol Hepatol. 2005;17:739-44 pubmed
    ..Both hyperhomocysteinaemia and a low APC ratio may contribute to an increased risk of thromboembolic disease in IBD patients. ..
  32. Weingarz L, Schwonberg J, Schindewolf M, Hecking C, Wolf Z, Erbe M, et al. Prevalence of thrombophilia according to age at the first manifestation of venous thromboembolism: results from the MAISTHRO registry. Br J Haematol. 2013;163:655-65 pubmed publisher
    ..The decline in the prevalence of hereditary thrombophilia with older ages supports the use of a selected thrombophilia screening strategy dependent on age and the presence or absence of additional VTE risk factors. ..
  33. Welbourn J, Maiti S, Paley J. Factor V Leiden detection by polymerase chain reaction-restriction fragment length polymorphism with mutagenic primers in a multiplex reaction with Pro G20210A--a novel technique. Hematology. 2003;8:73-5 pubmed
    ..This multiplex PCR/RFLP reaction is rapid, robust and dependable. ..
  34. Prochazka M, Krcova V, Kudela M, Slavik L. [Occurrence of gene mutations in factor V Leiden, prothrombin and methylenetetrahydrofolate reductase in patients with pre-eclampsia]. Ceska Gynekol. 2003;68:162-6 pubmed
    ..The prevalence of APC resistance was statistically higher in preeclamptic patients compared to the control group. ..
  35. Canonico M, Alhenc Gelas M, Plu Bureau G, Olié V, Scarabin P. Activated protein C resistance among postmenopausal women using transdermal estrogens: importance of progestogen. Menopause. 2010;17:1122-7 pubmed publisher
    ..These results provide a biological support to epidemiological data regarding the potential thrombogenic effects of norpregnanes. However, these findings need to be confirmed in a randomized trial. ..
  36. Verspyck E, Marpeau L. [Thrombophilias and vascular placental pathology. A survey of the literature]. Rev Med Interne. 2005;26:103-8 pubmed
    ..To determine by controlled studies the role for a prophylactic low molecular weight heparin regimens in patients with haemostatic abnormalities and previous pregnancy complications. ..
  37. Olsson E, Höijer P. Activated protein C resistance due to factor V Leiden, elevated coagulation factor VIII and postoperative deep vein thrombosis in late breast reconstruction with a free TRAM flap: a report of two cases. Br J Plast Surg. 2005;58:720-3 pubmed
    ..Both showed APC resistance due to factor V Leiden and elevated coagulation factor VIII. One of the patients also had an event of both arterial and venous anastomotic thrombosis postoperatively. ..
  38. Thuemer O, Huttemann E, Sakka S. [Procalcitonin as an early marker of sepsis]. Anaesthesist. 2006;55:650-4 pubmed
    ..The patient was transferred to the normal ward on the 2nd postoperative day. This case shows that procalcitonin allows early and reliable diagnosis of sepsis in patients with undefined shock. ..
  39. Locke C, Evans N. Evaluating idiopathic venous thromboembolism: what is necessary, what is not. J Fam Pract. 2003;52:770-7 pubmed
  40. Zavala Hernández C, Hernández Zamora E, Martinez Murillo C, Arenas Sordo M, González Orozco A, Reyes Maldonado E. Association of resistance to activated protein with the presence of Leiden and Cambridge Factor V mutations in Mexican patients with primary thrombophilia. Cir Cir. 2010;78:127-32 pubmed
    Leiden and Cambridge factor V coagulation mutations and activated protein C resistance (RaPC) are alterations related with vein and artery thrombosis...
  41. Schouten M, Van T Veer C, Roelofs J, Levi M, van der Poll T. Impact of the factor V Leiden mutation on the outcome of pneumococcal pneumonia: a controlled laboratory study. Crit Care. 2010;14:R145 pubmed publisher
    ..Homozygosity for the FVL mutation protects against lethality due to pneumococcal pneumonia in mice treated with antibiotics. ..
  42. Povýsil P, Sankot J, Rohlík P, Miculka P. [Thrombosis in the area of the superior mesenteric vein in a female patient positive for APC resistance]. Rozhl Chir. 2001;80:72-6 pubmed
    ..The authors examined thrombophil markers and assessed APV resistance. Relapse of TEN in the form of bilateral massive pulmonary embolization with subsequent anticoagulation. ..
  43. Lambert M. [Thromboembolic diseases. XVIIIth Congress of the International Society on Thrombosis and Haemostasis, Paris, 6-12 July 2001]. Rev Med Interne. 2002;23:238-42 pubmed
  44. Tan X, Yu Z, Sao J, Chen L, Shen Y, Ding J, et al. Association between in vitro fertilization outcomes and inherited thrombophilias: a meta-analysis. J Assist Reprod Genet. 2016;33:1093-8 pubmed publisher
    ..gene G20210A mutation (PGM), 5,10-methylentetrahydrofolate reductase (MTHFR) C677T, MTHFR (A1298C) and activated protein C resistance (APCR). The main outcome measures included CPR and implantation rate (IR)...
  45. Martinelli I, Battaglioli T, Bucciarelli P, Passamonti S, Mannucci P. Risk factors and recurrence rate of primary deep vein thrombosis of the upper extremities. Circulation. 2004;110:566-70 pubmed
    ..Oral contraceptives increase the risk only when combined with inherited thrombophilia. The recurrence rate of primary upper-extremity DVT is low but tends to be higher in patients with thrombophilia than in those without. ..
  46. Elice F, Fink L, Tricot G, Barlogie B, Zangari M. Acquired resistance to activated protein C (aAPCR) in multiple myeloma is a transitory abnormality associated with an increased risk of venous thromboembolism. Br J Haematol. 2006;134:399-405 pubmed
    Acquired activated protein C resistance (aAPCR), not associated with factor V Leiden, has been described in cancer patients with an increased risk of venous thromboembolism (VTE)...
  47. VanWijk M, Boer K, Berckmans R, Meijers J, van Der Post J, Sturk A, et al. Enhanced coagulation activation in preeclampsia: the role of APC resistance, microparticles and other plasma constituents. Thromb Haemost. 2002;88:415-20 pubmed
    ..In pregnancy and preeclampsia, increased activated protein C resistance occuffed (APC sensitivity ratio: 3.3 +/- 0.8 and 2.5 +/- 0.8, both P <0.001 vs. nonpregnant)...
  48. Djordjevic V, Rakicevic L, Radojkovic D. An overview of genetic risk factors in thrombophilia. Srp Arh Celok Lek. 2010;138 Suppl 1:79-81 pubmed
    ..The breakthrough came with the discovery of activated protein C resistance and Factor V Leiden mutation...
  49. Kassir R, Debs T, Blanc P, Gugenheim J, Ben Amor I, Boutet C, et al. Complications of bariatric surgery: Presentation and emergency management. Int J Surg. 2016;27:77-81 pubmed publisher
    ..assessment is performed (measurement of antithrombin III and of protein C and protein S, testing for activated protein C resistance)...
  50. Prochazka M, Lubusky M, Slavik L, Hrachovec P, Zielina P, Kudela M, et al. Frequency of selected thrombophilias in women with placental abruption. Aust N Z J Obstet Gynaecol. 2007;47:297-301 pubmed
    ..1%) in the placental abruption group, compared to ten of 196 (5.1%) in the control group (odds ratio 3.0, 95% confidence interval 1.4-6.7). We found that factor V Leiden is a significant risk factor for placental abruption. ..
  51. Ruiz Arguelles G, López Martínez B, Cruz Cruz D, Esparza Silva L, Reyes Aulis M. Primary thrombophilia in Mexico III: A prospective study of the sticky platelet syndrome. Clin Appl Thromb Hemost. 2002;8:273-7 pubmed
    ..In addition, the activated protein C resistance phenotype, coagulation protein C activity and antigen, coagulation protein S, antithrombin III, ..
  52. Nogami K, Shinozawa K, Ogiwara K, Matsumoto T, Amano K, Fukutake K, et al. Novel FV mutation (W1920R, FVNara) associated with serious deep vein thrombosis and more potent APC resistance relative to FVLeiden. Blood. 2014;123:2420-8 pubmed publisher
    ..In conclusion, relative to FVLeiden, the more potent APCR of FVNara resulted from significant loss of FVa susceptibility to APC and APC cofactor activity, mediated by possible failure of interaction with APC and/or protein S. ..
  53. Favaloro E, Mohammed S, Pati N, Ho M, McDonald D. A clinical audit of congenital thrombophilia investigation in tertiary practice. Pathology. 2011;43:266-72 pubmed publisher
    ..cases following evaluation of a range of markers, primarily comprising factor V Leiden (FVL), activated protein C resistance (APCR), protein C (PC), protein S (PS) and antithrombin (AT)...