J Am Board Fam Pract: first published as 10.3122/15572625-13-2-111 on 1 March 2000. Downloaded from

CLINICAL REVIEW Activated Protein C Resistance: The Most Common Risk Factor for Venous Thromboembolism

Dawn R. Sheppard, DO

Background: Venous thromboembolism is a major cause of morbidity and mortality. Although activated protein C resistance (APC-R) is the most commonly recognized inherited risk factor for venous throm­ boembolism, little is known about its long-tenn implications on health. Methods: MEDLINE was searched from January 1989 through August 1999 using the key words ''thromboembolism," ''thrombosis," "activated protein C resistance," and "factor V Leiden." Results: One in 1000 people in the United States is affected by venous thromboembolism annually. APC-R is now understood to be responsible for up to 64% of these cases. APC-R, which occurs widely in some ethnic groups and is nearly absent in others, is due to a single point mutation in the gene for clot­ ting factor V. As a result, inactivation of factor V by activated protein C is impaired, leading to a hyper­ coagulable state. This condition creates a lifelong increased risk of thrombosis and, possibly, anticoag- ulant therapy.. . Conclusion: Family physicians have a new tool for assessing risks for venous thromboembolism. Recognizing that up to 64% of patients with venous thromboembolism can have APe-R and treating this disorder with prophylactic and therapeutic anticoagulation might reduce patient morbidity and mortal­ ity from venous thromboembolism. Screening high-risk patients might now be indicated. (J Am Board Fam Pract 2000i13:111-5.)

Venous thromboembolism, a serious health prob­ "thromboembolism," "thrombosis," "activated pro­ lem and an important cause of morbidity, affects tein C resistance," and "factor V Leiden." about 1 in 1000 persons annually. 1-5 It can prolong a hospital stay, it can expose patients to medications and increase their risk of developing an adverse Background reaction, and it is sometimes fatal. Patients who Dahlback discovered a novel mechanism for famil- http://www.jabfm.org/ have spontaneous or recurrent venous thromboem­ . ial thrombosis in 1993. It is characterized by an bolism could have an underlying inherited or ac­ inherited resistance to the anticoagulant action of quired hypercoagulable state. Although patients activated protein C (APC).2,S Studies report that with venous thromboembolism frequently have the discovery of activated protein C resistance family histories of thrombosis, well-defined defects, (APC-R) has raised the yield of diagnosed coagu­ such as inherited deficiencies of anticoagulant pro­ lation abnormalities up to 64% in thrombosis pa­ on 26 September 2021 by guest. Protected copyright. teins, were found only in a minority (5% to 10%) of tients and up to 8% in the general population. The 4 6 cases. - wide range is postulated because of differences in selection criteria, ethnic background of the popu­ lations studied, and laboratory methods Methods used.1.3·5.7-9 APC-R is by far the most common MEDLINE was searched from January 1989 inherited thrombophilia. through August 1999 using the search terms Physiology and Pathophysiology \Vithin intact vessels, thrombin binds to thrombo­ Submitted, revised, 23 September 1999. From General Leonard Wood Army Community Hospi­ modulin on the endothelial cell. This bound tal, Ft Leonard Wood, Mo. Address reprint requests to thrombin functions as an anticoagulant by activat­ Dawn R. Sheppard, DO, General Leonard Wood Army Community Hospital, 126 Missouri Ave, Ft Leonard \Vood, ing the protein C system. APC potentiated by co­ MO 65473. factor protein S down-regulates the activity of the

Activated Protein C Resistance 111 J Am Board Fam Pract: first published as 10.3122/15572625-13-2-111 on 1 March 2000. Downloaded from coagulation system (limits clot fonnation) by cleav­ pulmonary embolism and superficial thrombophle­ ing and inhibiting factors V (FV) and VITI.2,7,8.10-13 bitis are found in many cases.',8 Rare thrombotic APC-R is caused by a single point mutation in manifestations and arterial thromboses are not 2 the FV gene. ,ll This mutated FV may be referred commonly reported as in other inherited thrombo­ 7 to as factor V Leiden (FVL), FV:Q506 allele, or as philias. Clinically APC-R occurs with equal risk to APC_R.l,2,13,l4 This mutated gene is less efficiently . both sexes,5,l7 at any age, and in a variety of man­ degraded by APC (therefore potentiating clot for­ ifestations. mation). Genotypic carriers of this allele, both het­ FVL is inherited in an autosomal-dominant erozygous and homozygous, are at greater risk for fashion; but penetrance is highly variable.4,7,8 Al­ venous thromboembolism. though some never experience thrombotic events, others suffer from recurrent, severe thrombosis at a l Etiology young age. ,Z,4,7-9,14 In general, homozygous pa- It is not known what posltlVe genetic selection tients experience thrombosis at a much younger pressure has been involved in maintaining APC-R age than do heterozygotes (median 31 years com­ in the population.2 Some experts suggest that the pared with 47 years).9 Thrombotic risk is increased high frequency of FVL allele has conferred a sur­ 5 to 10 times more than nonnal in heterozygotes and 50 to 100 times in homozygotes.1,2,9,15 This vival advantage during evolution. For instance, a risk is compounded by the coexistence of other thrombophilic state might have provided protec­ 7 tion against severe bleeding episodes in association genetic or acquired risk factors. ,8,14 with postpartum hemorrhage or life-threatening Persons with combinations of FVL and another trauma, or it might have protected against iron clotting defect have a much higher risk of throm­ deficiency by reducing menstrual blood loss.4,7 bosis than do those with just one genetic de­ fec~,3,14,18(72% and 19% APC-R only, respec­ Modem-day life exposes FVL carriers to circum­ stantial venous thromboembolism risks to which tivelyI6). Researchers have reported that APC-R is our ancestors were not exposed: oral contracep­ found in up to 19% of symptomatic protein C­ deficient patients and 39% of protein S-deficient tives, major surgery, prolonged immobilization 16 during travels, extended life span, and a relatively patients. The high prevalence of this gene in the sedentary lifestyle.2,4,7,15,l6 population increases the chance that it could coex­ ist with another thrombophilia, such as prothrom­ bin gene mutation, hyperhomocystinemia, anti­ Epidemiology and Prevalence thrombin TIl deficiency, or antiphospholipid http://www.jabfm.org/ APC-R is the most common inherited risk factor syndrome. for thrombosis. Many studies report a prevalence of In addition to inherited APC-R, there can be 3% to 64%.5,13 The likelihood of this disorder precipitating factors that predispose persons to ac­ occurring is highly dependent on the population quire APC-R. Oral contraceptive intake and preg­ studied. Heterozygous FVL occurs in 3% to 8% of nancy are associated with an increased prevalence the general population of white, European de­ of thrombosis, up to 60% and 80%, respec­ 7 on 26 September 2021 by guest. Protected copyright. scent. ,l,2,4,7,8,l5 Although the carrier frequency in tively.l,8,13,14,16 Women taking oral contraceptives Hispanic, African-American, Asian, and Native have a much lower APC ratio (defined later in this American populations is substantially less, a US 9 article) than do matched controls. ,13 Two women study did find FVL in these groupS.17 Based on labeled with APC-R (without FVL) had their ratios ethnic-specific allele frequencies observed in this return to nonnal within 2 months of discontinuing study and on US census data, it can be estimated 9 contraceptive medications. ,13 The thrombosis risk that more than 11.3 million Americans carry the increases 3.8-fold in those taking oral contraceptives mutated FV geneY and 35- to 50-fold in those who are FVL carriers and taking oral contraceptives.Z,9,17 The incidence of ve­ Clinical Manifestations nous thromboembolism in young, healthy females is Venous thrombosis is the third most common car­ very low, however. If other, less successful contracep­ diovascular disease after acute ischemic heart dis­ tive methods fail, the patient could be at greater risk ease and stroke.8 Deep venous thrombosis is the of venous thromboembolism from an unintended most prevalent manifestation of APC-R, although pregnancy.17 Currently the literature suggests hor-

112 JABFP March-Apri12000 Vol. 13 No.2 J Am Board Fam Pract: first published as 10.3122/15572625-13-2-111 on 1 March 2000. Downloaded from mone replacement therapy might increase venous from patients who had unexplained thrombosis. thromboembolism risk up to twofold,19 and hormone The APC test can be performed on anticoagulated replacement therapy combined with APC-R could blood. The patient's plasma is prediluted with FV­ 20 9 12 increase risk up to threefold. The risk of venous deficient plasma. • (FV-deficient plasma is able to thromboembolism is very small, however, compared correct the deficiency of the vitamin K-dependent with the cardiovascular and other benefits from hor­ factors without affecting the patient's endogenous mone replacement therapy. M. A carefully standardized amount of APC is Moreover, 20% of recurrent miscarriage losses added in an activated partial thromboplastin time in the second trimester have been associated with (aPTT) reaction. An aPTT test without APC is FVL.16 This information has led some researchers also performed, and results are expressed as the to examine the role of APC-R in conjunction with quotient (APC ratio) of the former clotting time anti phospholipid syndrome. Anticardiolipin anti­ divided by the latter.2.10 bodies from some anti phospholipid syndrome pa­ tients down-regulate APC activity, in tum creating [aPTT + APC (sec)]/[aPTT(sec)] the thrombophilia associated with antiphospholipid syndromeP Patients with thrombophilia should be = APC resistance ratio screened for APC-R even if antiphospholipid syn­ drome has been previously diagnosed.22 Patients with APC-R usually have a ratio of <2.0 compared with a ratio of >2.0 for patients without Differential Diagnoses APC_R.'·10 The above procedure is rapid, relatively Consideration should be given to ruling out other inexpensive, and highly reproducible if performed clinical conditions known to be associated with under standardized conditions.' The APC-ratio in­ thrombosis, such as immobilization, obesity, oral dicates the severity of the APC-R and also detects contraceptive use, congestive heart failure, preg­ thrombosis-prone APC-R cases without the FV nancy, infection, malignancy, myeloproliferative gene mutation.3 The high sensitivity and specificity disorder, hyperlipidemia, postsurgical state, and of the APC ratio (approaching 100%3.7.8.14), to­ 1 nephrotic syndrome. Attendant circumstantial fac­ gether with its reliability and ease with which it is tors, however, should not preclude an evaluation performed, make it an adequate screening method. 14 for inherited thrombophilia. A precipitating fac­ Even so, a certain number of cases fall within a zone tor is often observed in heterozygous and homozy­ 3

that is borderline for diagnosis. Those who have a http://www.jabfm.org/ 14 gous persons. Other coagulation pathway abnor­ . borderline test or a positive test can then be ana­ malities that increase the risk for thrombosis lyzed with direct genotyping to confirm the pres­ include a deficiency of antithrombin III, protein C ence of FVL allele.8 and protein S deficiencies, abnormalities of the fibrinolytic system (plasminogen, tissue plasmino­ gen activator, and plasminogen activator inhibitor), FV6enotype fibrinogen deficiencies, homocystinemia, pro­ DNA genotyping gives a distinct and certain result: on 26 September 2021 by guest. Protected copyright. thrombin DNA mutation, and antiphospholipid the patient is normal, heterozygous, or homozy­ gous. 3 Confirming genotype is important to differ­ syndrome. 1 entiate acquired from inherited APC-R. An inher­ ent disadvantage of proceeding directly to a Laboratory Testing molecular test is that with approximately 10% of Approximately 10% of all persons afflicted with the APC-R (phenotype), patients lack the FV mutation APC-R phenotype do not have the APC-R geno­ (genotype),1 and the diagnosis of APC-R in these 2 14 type, or FVL. • As a result, several different patients will be missed. The genotyping technique methods are used for screening and confirming is not designed to measure function and will not APC-R and its mutated FV allele. detect other anticoagulant protein deficiencies that stand alone or that add to the severity of APC-R.3 APe Test The resulting combination of phenotypic and ge­ The APC test was developed to investigate the notypic information will aid in establishing prophy­ anticoagulant response to APC in plasma samples lactic and therapeutic guidelines.

Activated Protein C Resistance 113 J Am Board Fam Pract: first published as 10.3122/15572625-13-2-111 on 1 March 2000. Downloaded from

Medical Treatment and Preventive Measures out obvious precipitating factors; recurrent throm­ Although in patients with APC-R, venous throm­ bosis despite adequate anticoagulant therapy; and boembolism requires much the same treatment and thrombosis at an unusual site (such as the hepatic, follow-up as it does for in other patients, some mesentery, or axillary vein or sagittal sinus).l,16,23 management considerations need to be addressed. Screening for an inherited thrombophilia (includ­ The prophylactic and therapeutic treatment of ing, but not limited to APC-R) is also indicated for APC-R is not well established. The number of sites any woman who experiences a deep vein thrombo­ involved, the severity of the thrombosis, and sis during pregnancy or oral contraceptive use, and whether the thrombosis was spontaneous or sec­ screening must be considered in managing recur­ ondary to a precipitating event1 will influence the rent fetal losses. physician and the patient as they make difficult In the past, general screening for inherited therapeutic decisions. Family history (frequency of thrombophilia before circumstances warranted has venous thromboembolism among family members not been judged to be cost-effective, in part because and their genotypes), occupational history (risk of clotting defects are uncommon. The clear associa­ trauma), and social history (sedentary lifestyle, re­ tion between APC-R and increased risk of throm­ productive desires) are also important when initi­ bosis, together with a 3 % to 64% prevalence of ating or maintaining antithrombotic therapy. 1,2,8 APC-R in the general population, mandate the Asymptomatic patients with APC-R who have need for more prospective data. These data will never had a thromboembolic event, as well as their help determine the benefits of general screening in family members, have special needs. They should association with surgery, oral contraceptive use, receive counseling regarding the implication of the pregnancy, and other high-risk situations.2,3,7 It diagnosis and information concerning the signs and will provide important information to family mem­ symptoms of venous thromboembolism. 1 Short­ bers and help determine management options. For term prophylaxis with heparin must be considered example, should women have APC-R screening in for certain high-risk circumstances known to pro­ association with oral contraceptive use? If a woman voke thrombosis, such as immobilization, surgery, is found to be phenotype positive and genotype trauma, or obstetric procedures. 1,8 negative while taking oral contraceptives, she Heterozygotes, homozygotes, and those with might elect to choose another contraceptive another coagulation defect should be given preven­ method, thus potentially avoiding a venous throm­ tive therapy for circumstantial risks18 and extended boembolism or long-term anticoagulation. Ques­ 8 anticoagulation after a thrombotic event. The tions such as these will need to be answered. http://www.jabfm.org/ physician and the patient must balance the risk of bleeding against the risk of recurrence when ther­ apy is discontinued. Retrospective data have shown Conclusion a long period between treatment interruption and The efficacy, safety, and need for APC-R screening recurrence (mean 10 years).14 Even so, many phy­ of high-risk patients might now be indicated. The sicians empirically treat patients for at least 1 year widely ranging prevalence of APC-R and the avail­ on 26 September 2021 by guest. Protected copyright. after two episodes of venous thromboembolism and ability of laboratory testing will have a profound prescribe life-long treatment after three episodes.23 influence on the development of therapeutic and Further studies are needed to define the optimal prophylactic regimens. A number of unresolved type, intensity, and duration of prophylactic and issues must be addressed, however, before wide­ therapeutic options. spread screening can be implemented. Clinical trials are needed to determine the optimal antico­ agulation needed to reduce morbidity and mortal­ Screening and Future Direction ity from APC-R-induced venous thromboembo­ Patients with venous thromboembolism should be lism. Our understanding of APC-R is advancing, screened for an underlying coagulation abnormal­ but testing for APC-R is ordered far less frequently ity (including, but not limited to APC-R) when any than for other inherited thrombophilia,16 which of the following conditions are encountered: family suggest routine testing might not be available or history of thrombosis; thrombosis at an early age practicing clinicians are unaware of this entity. Ed­ «45 years); recurrent thrombosis, especially with- ucating ourselves, our patients, and our fellow phy-

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Activated Protein C Resistance 115