Circulation 2008 Chan 2286 97

Mark Y. Chan, Felicita Andreotti and Richard C. BeckerHypercoagulable States in Cardiovascular Disease

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Hypercoagulable States in Cardiovascular DiseaseMark Y. Chan, MD, MHS; Felicita Andreotti, MD, PhD; Richard C. Becker, MD

Certain individuals may have an abnormal propensity todevelop venous or arterial thrombosis and either expe-

rience thromboembolic events relatively early in life or sufferrecurring events.1 This well-described clinical phenomenon,paralleled by familial clustering of thrombotic phenotypes,has led to a comprehensive search for inherited and acquiredforms of hypercoagulability as part of the condition known asthrombophilia. Although clearly defined associations havebeen described for hypercoagulable states and thrombosiswithin the venous system, the establishment of causative orcontributing roles for these same thrombophilic conditionsand the occurrence of arterial thrombosis has been consider-ably more elusive.2

The World Health Organization/International Society ofThrombosis and Hemostasis in 1995 defined thrombophiliaas an unusual tendency toward thrombosis.1 Frequently citedfeatures traditionally include (1) early age of onset; (2) recurrentepisodes; (3) strong family history; (4) unusual, migratory, orwidespread locations; and (5) severity out of proportion toany recognized stimulus. Here, we provide an updated reviewof hypercoagulable states in cardiovascular disease in 3sections: (1) inherited hypercoagulable states; (2) acquiredhypercoagulable states; and (3) diagnosis and management.

Inherited Hypercoagulable StatesEstablishment of the role of pathways that lead to heritablehypercoagulable phenotypes in multifactorial disorders suchas cardiovascular diseases is complicated by the inability toadequately discern the necessity and sufficiency of proposedmediators of hypercoagulability (Figure 1).2 Hyperhomocys-teinemia is a good example of the challenges faced.3 Elevatedhomocysteine levels exert numerous vasotoxic effects on theendothelium, which lead to endothelial cell dysfunction,platelet activation, and thrombus formation and an increasedrisk of thrombotic events.4 A C677T point mutation withinthe coding region of the methylenetetrahydrofolate reductase(MTHFR) gene is the most common genetic cause of hyper-homocysteinemia, with homozygotes for the 677T alleleexhibiting mild to moderate elevations of serum homocys-teine and a varying propensity for symptomatic arterialthrombosis.5 However, despite studies showing a clear associ-ation between the 677TT genotype and hyperhomocysteinemia(gene-intermediate phenotype association), and other studies

demonstrating a relationship between hyperhomocysteinemiaand arterial thrombosis (intermediate phenotype-disease as-sociation), studies attempting to establish a conclusive linkbetween genotype and clinical disease (genotype-diseaseassociation) have yielded conflicting results.6 Additionally,the lowering of plasma homocysteine levels has failed toreduce ischemic events in large randomized trials.7–10 It istherefore uncertain whether hyperhomocysteinemia plays acausative role or is merely an epiphenomenon or nonfunc-tional biomarker among individuals at risk for atherothrom-bosis and related events. These observations illustrate some ofthe major challenges in determining the biological and clinicalrelevance of putative hypercoagulable gene variants.

The difficulty in establishing a clear link between genotypeand the risk of multifactorial disease in small case-controlstudies is frequently the result of limited statistical power,because individual polymorphisms only impart a small over-all risk toward clinical events. This may be resolved bypooling multiple smaller studies in a well-designed meta-analysis, as demonstrated in a study of the coronary diseaserisk conferred by 7 hemostatic polymorphisms. Althoughnumerous smaller studies investigating the association of thefactor V Leiden and prothrombin G20210A gene mutationswith arterial thrombosis show conflicting results, Ye et al11

demonstrated in a very large meta-analysis of 66 155 casesand 91 307 control subjects across multiple heterogeneouspopulations that these 2 mutations were associated with amodest but significantly increased risk of coronary arterydisease and myocardial infarction (MI), with point estimatesof 1.17 and 1.31, respectively.

Procoagulant and Fibrinolytic SystemsThe complex network of biochemical events regulating mam-malian coagulation comprises 5 proteases (factors II, VII, IX,and X and protein C) that interface with 5 cofactors (tissuefactor, factor V, factor VIII, thrombomodulin, and surfacemembrane proteins) to generate fibrin. A delicate balanceexists between powerful endogenous procoagulant andthromboresistant forces to ensure the fluidity of blood.12

The direct influence of genetic factors on hemostaticplasma protein concentrations is supported by studies includ-ing monozygotic and dizygotic twin pairs.13 Twin studiespresent a unique opportunity to study gene-environment

From Duke Clinical Research Institute (M.Y.C., R.C.B.), Durham, NC; National University Hospital (M.Y.C.), Singapore, Singapore; Institute ofCardiology (F.A.), Catholic University, Rome, Italy; and Divisions of Cardiology and Hematology (R.C.B.), Duke University School of Medicine,Durham, NC.

Correspondence to Richard C. Becker, MD, Professor of Medicine, Divisions of Cardiology and Hematology, Duke University School of Medicine,Director, Cardiovascular Thrombosis Center, Duke Clinical Research Institute, 2400 Pratt St, Terrace Level Room 0311, Durham, NC 27705.

(Circulation. 2008;118:2286-2297.)© 2008 American Heart Association, Inc.

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interactions, because monozygotic twins share 100% oftheir genes, whereas dizygotic twins on average share only50% of their genome. Genetic model fitting showed thatgene coding is responsible for 41% to 75% of the variationin fibrinogen, factor VII, factor VIII, plasminogen activatorinhibitor type 1 (PAI-1), factor XIII A and B subunits, andvon Willebrand factor (vWF), with a higher monozygoticthan dizygotic correlation. Similarly, factor XII, factor II(prothrombin), and factor V plasma levels are altered by thepresence of the factor XII C46T14,15 and factor XII16 poly-morphisms within the factor XII gene, the prothrombinG20210A polymorphism within the factor II gene,17 and thefactor V Leiden18 polymorphism, respectively.

The correlation between circulating procoagulant factorsand the risk of arterial thrombosis was first described instudies reporting the association of elevated concentrations offibrinogen, factor VII, and vWF with vascular risk andcardiovascular outcomes.19 Subsequently, elevated levels oftissue factor and factors VIII, IX, XI, and XII were reportedas markers of heightened thrombotic risk20–23 (Table). Morerecently, abnormalities in the kallikrein-kinin system havealso been shown to increase the risk of arterial events, as seenin the Second Northwick Park Heart Study, which showedthat lower levels of inhibitory complexes of the kallikrein-kinin system enzymes, factor XIIa-CI esterase inhibitor, andkallikrein-C1–inhibitor complexes were more common inmen who experienced an MI within 10 years of follow-up.25

Disorders of the fibrinolytic system have also been linkedto an increased risk of arterial thrombosis. Increased levels ofPAI-1 and tissue plasminogen activator are found morecommonly in patients with acute MI than in control subjects26

(Table). Similarly, in the Prospective Epidemiological Studyof Myocardial Infarction, individuals with tissue factor path-way inhibitor levels below the 10th percentile had a 2.13-fold

increased risk of coronary events compared with those withlevels above it (95% confidence interval 1.08 to 4.18).27

PlateletsPlatelets show substantial interindividual variation in activa-tion, aggregation, their surface receptors, and secreted con-tents, as well as in their interaction with numerous othercirculatory components.28 Given the critical role of plateletsin arterial thrombosis, this variability may influence the riskof atherothrombosis.29

Heterogeneity of platelet responses to a procoagulantstimulus occurs not only at the interindividual level but alsothe intraindividual level.30 Subpopulations of platelets withincreased binding of factor V, factor VIII, factor IX, andfactor X in response to thrombin and convulxin (a stimulusfor collagen receptor activation) stimulation have been iden-tified.31 As the percentage of platelets with greater coagula-tion protein binding increased, factor Xa and thrombingeneration increased accordingly. However, despite maximalconvulxin concentrations, only half of the platelets identifiedin the subpopulations increased coagulation protein binding,which indicates intraindividual heterogeneity.30

Several studies have demonstrated the heritability of plate-let function within families. The Framingham Heart Studyshowed that heritable factors were key determinants of theplatelet aggregation response, contributing more stronglythan environmental covariates to ADP- and epinephrine–induced aggregation and collagen-stimulated lag time.28 Brayand colleagues31 established the role of heritability factors indetermining platelet response to agonists using extended familystructures in white and black subjects with a documentedfamily history of premature coronary artery disease. A sepa-rate study in the same population found that heritability

Genetic Factors Phenotype/Biological Effects Environmental Factors

Gene-environment interactions

Atherothrombosis (clinical disease)-Acute Coronary Syndrome-Ischemic Stroke-?Acute limb, visceral ischemia

DM/Metabolic syndrome

Diet (folate, vitamin B12 deficiency, western diet)

Smoking

Sedentary lifestyle

Oral contraceptives, hormone replacement

Pregnancy and Puerperium

Air Pollution

Coagulation Proteins-Factor V Leiden (G1691A)-G20210A prothrombin variant-Fibrinogen β-chain -455 G/A.854 G/A and Bc/1, α-chain

Thr312Ala

Fibrinolytic system-PAI-1 -6754G/5G-TAFI Ala147Thr, TAFI 1542C/G

Platelet receptors-GPIIIa Leu33Pro, GP1BA -5T/C,GP6 13254T/C

Metabolic-MTHFR 677C/T (homocysteine)

Gen

e-ge

ne in

tera

ctio

ns

Activated Protein C resistance (Factor V Leiden) ↑fibrinogen, thrombin, factor VII, factor VIIIPAI-1, VWF (coagulation and fibrinolytic protein polymorphisms)

↑platelet activation/aggregation (GP polymorphisms) hyperhomocysteinemia (MTHFR 677C/T)

Pathophysiology of Inherited Hypercoagulable States

Figure 1. Pathophysiology of inherited hypercoagulable states. MTHFR indicates methyltetrahydrofolate reductase. This figure onlydepicts inherited hypercoagulable states with well-described associations of genotype with phenotype and of phenotype with clinicaldisease. Other inherited hypercoagulable states are listed in the Table.

Chan et al Hypercoagulable States in Cardiovascular Disease 2287




contributed more strongly than clinical covariates to variabil-ity in the platelet response to aspirin.32

Moreover, the ability of glycoprotein (GP) Ib� and VIgenetic polymorphisms to predict the clinical response tohormone replacement therapy (HRT) of the Heart and Estro-gen/progestin Replacement Study (HERS) is a clear indica-tion that genetic markers of susceptibility to arterial throm-botic events have the potential to inform therapeutic decisionmaking. In a subgroup analysis of HERS, HRT increased thehazard ratio of coronary events in patients with the GPIb�-5TT genotype (wild type) by 16% and reduced thehazard ratio in patients with the TC and CC genotypes by46%. HRT reduced the hazard ratio in patients with the GPVI13254TT genotype (wild type) by 17% but increased thehazard ratio in patients with the TC and CC genotypes by35%. This study was the first to show a diametrically oppositetherapeutic response with hormone therapy in subjects withspecific polymorphisms in platelet surface glycoproteinscompared with subjects possessing the wild-type genotype,thus paving the way for future strategies in pharmacog-enomic personalized medicine.33

Platelet-specific polymorphisms in the GP IIIa, GP Ib�,and GP VI genes have shown an association with an increasedrisk of cardiovascular events in some but not all studies(Table). The large meta-analysis by Ye et al11 did not showsignificant overall associations between the GP Ia 807T, GPIb� [-5]C, and GP IIIa 1565T gene variants and coronary

Table. Hypercoagulable States

Inherited Hypercoagulable StatesAssociation WithArterial Disease

Coagulation proteins

Fibrinogen level CAD,* stroke*

�-Chain �455 G/A CAD,* stroke‡

�-Chain �854 G/A CAD†

�-Chain �1420 G/A CAD†

�-Chain Bcl1 CAD,† PAD†

�-Chain C448 Stroke‡

�-Chain Thr312Ala Stroke‡

Prothrombin G20210A variant CAD,* stroke,*PAD‡

Factor V Leiden (G1691A) CAD†, stroke*

Tissue factor antigen level CAD‡

Tissue factor pathway inhibitor CAD‡

Factor VII level CAD‡

FVII Arg353Gln, FVII HRV4, FVII-401G/T,FVII-402G/A

CAD‡

Factor VIII level CAD,† stroke†

Factor IX level CAD‡

Factor XI level (paradoxical) CAD‡

Factor XII level (paradoxical) CAD‡

FXII C46T CAD,‡ stroke‡

FXIII Val34Leu CAD,† stroke‡

vWF antigen level CAD†

vWF Thr789Ala CAD‡

vWF SmaI polymorphism in intron 2 Stroke‡

Thrombomodulin antigen level CAD†

Fibrinolytic system

PAI level Stroke†

PAI-1 �6754G/5G CAD*

Thrombin activatable fibrinolysis inhibitor level CAD‡

TAFI Ala147Thr, 1542C/G CAD‡

tPA CAD,† stroke†

tPA Alu insertion/deletion CAD‡

tPA �7351C/T CAD,‡ stroke‡

Platelets

Platelet hyperreactivity CAD†

GP IIIa Leu33Pro CAD*

GP 1BA �5C/T CAD†

GP 1a C807T CAD†

GP 6 T13254C CAD†

Biochemical

Hyperhomocysteinemia§ CAD,* stroke*

MTHFR C677T CAD,* stroke*

Inflammation, endothelial function, and other heritablefactors

CAD,† stroke†

C-reactive protein MI,* stroke†

Lipoprotein(a) MI,† stroke†

Genetic polymorphisms of PON1, eNOS, apoB, apoE,ACE, 5� lipoxygenase, TGF-�1, and P-selectin

MI†, stroke†

(Continued )

Table. Continued

Inherited Hypercoagulable StatesAssociation WithArterial Disease

Acquired hypercoagulable states

Thrombotic thrombocytopenic purpura MI,† stroke,† MV†

Heparin-induced thrombocytopenia MI,† stroke†

Antiphospholipid syndrome/systemic lupuserythematosus

CAD,† stroke†

Rheumatoid arthritis CAD,† stroke†

Nephrotic syndrome MI†

Solid organ malignancy MI,‡ stroke‡

Myeloproliferative disorders: essentialthrombocytosis, polycythemia vera, chronic myeloidleukemia and myelofibrosis

MI,† stroke,† MV†

Oral contraceptives MI,* stroke*

HRT CAD,† stroke*

Pregnancy and puerperium MI†

Air pollution CAD†

History of venous thrombosis CAD†, stroke†

CAD indicates coronary artery disease; PAD, peripheral arterial disease;TAFI, thrombin activatable fibrinolysis inhibitor; tPA, tissue plasminogenactivator; MV, microvascular disease; MTHFR, methylenetetrahydrofolate re-ductase; PON1, paraoxonase 1; eNOS, endothelial nitric oxide synthase; apo,apolipoprotein; and TGF, transforming growth factor.

Reported as 3 arbitrary levels of association: *probable, †possible, and‡equivocal.

§Does not denote homocysteinuria, which is an inborn error of metabolismwith mental retardation and growth abnormalities.

Modified from Endler and Mannhalter,24 copyright © 2003, with permissionfrom Elsevier.

2288 Circulation November 25, 2008




disease, yielding a per-allele relative risk of 1.02 (confidenceinterval 0.97 to 1.08), 1.05 (confidence interval 0.96 to 1.13),and 1.03 (confidence interval 0.98 to 1.07), respectively.Abnormal platelet activation or aggregation has been linkedto at least 3 genetic variants, including a polymorphism of thegene encoding the �-subunit of G proteins (GNB3),33 adimorphism within the P2Y1 gene,34 and 2 haplotypes withinthe P2Y12 gene.35 In small case-control studies, geneticvariation of VAMP8, which is involved in platelet degranu-lation, has also shown an association with early-onset MI(P�0.025),36 whereas the minor sequence haplotype of theGP6 gene has been associated with an increased risk of MIamong elderly individuals (P�0.009).37

Although not traditionally considered a hypercoagulablestate, resistance to treatment with aspirin and thienopyridinesrepresents an important potential obstacle to the managementof patients with arterial thrombosis. Because pathway-specific inhibitors of platelet function are frequently used inthe treatment and prophylaxis of atherothrombosis, a patientexhibiting a limited pharmacological response to these med-ications may be at substantial risk of recurrent atherothrom-botic events.38 The biggest challenge to the diagnosis ofantiplatelet resistance is that using different tests of plateletfunction, the same patient can be classified either as resistantor not resistant to antiplatelet therapy.39 Moreover, no ran-domized trials have been published that show an improve-ment in clinical outcomes with a strategy of modifyingantiplatelet therapy according to the results of a plateletfunction test. Ongoing studies such as Gauging Responsivenesswith a VerifyNow Assay-Impact on Thrombosis and Safety(GRAVITAS; ClinicalTrials.gov identifier NCT00645918),which has been designed to test the hypothesis that tailoredantiplatelet therapy with the Accumetrics VerifyNow P2Y12assay reduces major adverse cardiovascular events afterdrug-eluting stent implantation, may provide future insightsinto appropriate testing strategies.

Overall, these data support the existence of heritable differ-ences in platelet biology that may increase the individual risk ofatherothrombosis. Further answers may be provided by ongoingefforts of the Bloodomics consortium (www.bloodomics.org), asystems biology working group that aims to identify sequencevariations in platelet genes associated with atherothromboticrisk, through the application of platelet transcriptomic andproteomic data, gleaned from functional studies in healthyvolunteers, to large genotyping case-control studies of pa-tients with the acute coronary syndrome.

The Vessel WallThe link between atherogenic risk factors and the hemo-static system is exemplified by the biologically diverseeffects of lipoprotein(a).40 Although proatherosclerotic ef-fects were originally considered to account for the increasedthrombotic risk in patients with elevated levels of lipopro-tein(a), the discovery of its adverse effects on endothelialfunction, fibrinolysis, and PAI-1 levels suggests that the riskof thrombosis is mediated in part through a direct effect onthe hemostatic system.

Polymorphisms of genes regulating endothelial functionhave been positively associated with an increased risk of

atherosclerotic disease, MI, or stroke, although their specificeffects on the hemostatic system remain unknown. Thesegenetic polymorphisms include paraoxonase 1, endothelialnitric oxide synthase, apolipoprotein B, apolipoprotein E,angiotensin-converting enzyme, and 5�-lipoxygenase poly-morphisms.41 Paraoxonase 1Q192R and endothelial nitricoxide synthase E298D polymorphisms were independentlyassociated with onset of a first MI at age �50 years in theThrombogenic Factors and Recurrent Coronary Events Study,which suggests a role for these genotypes in the pathogenesisof early-onset MI.42 More research is needed to ascertain themechanism through which these polymorphisms influenceclinical events, because it is presently unknown whether theincrease in early-onset MI is caused solely by a deleteriouseffect on endothelial function or whether a more direct effecton hemostatic system exists.

Inflammation and Other Heritable FactorsOther risk markers for atherothrombosis not traditionallyconsidered part of the coagulation system, including inflam-matory mediators, increasingly have been shown to directlyinfluence coagulation pathways (Table). C-reactive protein,an inflammatory marker that is increased in both asymptom-atic and symptomatic arterial disease, has been found toincrease macrophage tissue factor expression.43 The deCODEGenetics Investigators described an association between MIand a common sequence variant on chromosome 9p21 adja-cent to the tumor suppressor genes CDKN2A and CDKN2Bin a study of 4587 cases and 12 767 control subjects.44

Homozygotes for this variant had an estimated risk of MI thatwas 1.64 times as great as that of noncarriers, and the risk forearly-onset cases was 2.02. In a study of 3657 patients withMI and 1211 control subjects, 2 specific transforming growthfactor-�1 variants, the �509C/T polymorphism and �509C/868T/913G/11929C (CTGC) haplotype, were independentlyassociated with MI in men, whereas lower risks of MI wereobserved among carriers of the �509CC genotype.45 More-over, for MI, data exist that suggest protection for carriers ofthe P-selectin Pro715 allele and increased risk for specificgroups carrying CD14 variants.46 Although preliminary andconflicting in part, the data support a possible influence ofheritable nonhemostatic factors on coagulation pathways thatlead to atherothrombosis.

Gene–Environment and Gene–Gene Interactions:Phenotypic ModifiersThe complexity of gene–gene and gene–environment rela-tionships is expected to confer significant plasticity to thehypercoagulable phenotype, given that an estimated 20 000 to25 000 coding genes exist in the human genome.41 Theavailable evidence suggests strongly that coronary athero-thrombosis is a complex disorder governed by multiplegene–gene and gene–environment interactions.2,19,41

Age contributes 1.5% to 14.5% of the observed variabilityin plasma hemostatic protein concentrations.2 The overallinfluence of inherited factors on arterial (and possibly ve-nous) thrombosis is expected to decline with age, whereasacquired factors become more operational (Figure 2). How-ever, in a study of 130 monozygotic and 155 dizygotic





same-sex twin pairs 73 to 94 years of age, genetic factors stillhad a major effect on variation in hemostatic protein levels,ranging from 33% for D-dimer to 71% for thrombin activat-able fibrinolysis inhibitor,47 which suggests that heritablefactors remain an important consideration in elderly individ-uals with suspected hypercoagulable states.

Ethnic differences in the allelic frequencies of hemostaticgene polymorphisms add another layer of complexity todeciphering the genetic basis of arterial thrombosis. Theincidence of clinical thrombotic disorders varies widelybetween races.48,49 The Atherosclerosis Risk in CommunityStudy reported that black individuals had a 3-fold highermultivariable-adjusted risk of lacunar stroke than white indi-viduals.50 Additionally, the Multi-Ethnic Study of Athero-sclerosis identified distinct profiles in hemostatic and endo-thelial cell markers among white, black, Hispanic, andAsian-American subjects. Black subjects had the highestlevels of factor VIII, D-dimer, plasmin-antiplasmin com-plexes, and vWF, whereas whites and Hispanics had inter-mediate levels. Although Asians had the lowest levels ofthese markers, they also had the highest levels of PAI-1. Theprevalence of several hemostatic gene polymorphisms alsovaries widely between ethnic groups, as noted in the Phar-macogenetic Optimization of Anticoagulation Study, whichdetermined racial differences in prothrombotic genotype fre-quency among white and black patients receiving anticoagu-lant therapy.51 The factor V Leiden GA genotype wasdocumented in 8.6% and 1.4% of white and black patients,respectively; in whites, the genotype was a significant riskfactor for venous thromboembolism but not arterial thrombo-sis, whereas in blacks, it was an equal risk factor for bothvenous thromboembolism and arterial thrombosis. The impli-cations for diagnostic testing based on race remain to bedefined, and further research is needed to establish thepresence of gene-ethnicity relationships.

Acquired Hypercoagulable StatesThe acquired thrombophilic disorders include uncommon butnot rare conditions, such as drug-induced thrombocytopenia,

autoimmune diseases, and myeloproliferative disorders (Ta-ble). In some cases, familial clustering and genetic influencesare discernible52 (Figure 3). Pregnancy, estrogen intake,smoking,53 and, more recently, fine particulate air pollutioncan cause profound changes in coagulation.54 Consumptionof a triglyceride-rich meal is associated with an acute eleva-tion of factor VIIa,55 although it remains uncertain whetherthis increase depends on the actual fatty acid composition ofingested triglycerides.56

Disorders Associated With ThrombocytopeniaHeparin-induced thrombocytopenia occurs in 1% to 3% ofpatients receiving unfractionated heparin for 5 or moreconsecutive days.57 Recent hospital-based registries suggestthat the true incidence has been underestimated due tounderrecognition in clinical practice.58 Although heparin-induced thrombocytopenia traditionally is associated with anincreased risk of thromboembolic complications, recent dataindicate that up to 6% of patients with heparin-inducedthrombocytopenia may experience major bleeding.59 Patientsdeveloping thrombocytopenia during treatment with heparinin the Complication After Thrombocytopenia Caused byHeparin registry commonly experienced bleeding, and anincreased risk of major bleeding and subsequent mortalitywas seen when platelet counts fell below 125�109/L.

Many patients with anti-platelet factor (PF) 4/heparinantibodies remain asymptomatic,57 which implies that otherhost-specific factors influence the development of clinicalthrombosis in heparin-induced thrombocytopenia. In a mousemodel transgenic for human Fc� RIIa and PF4 and null formouse PF4, mice fed a hypercholesterolemic diet and treatedwith an anti-PF4/heparin antibody and heparin developedmore severe thrombocytopenia and more extensive thrombo-sis than similarly treated mice fed a normal diet.60 The miceon a hypercholesterolemic diet also had greater prothrom-botic changes in platelet reactivity and endothelial activation,which suggests that diet and other host-specific factors mayinfluence the development of thrombosis in a subset ofpatients who develop anti-PF4/heparin antibodies.

Thrombotic thrombocytopenic purpura (TTP) is a severethrombotic microangiopathy characterized by profoundthrombocytopenia, systemic platelet aggregation, erythrocytefragmentation, and multiorgan ischemia.60 TTP must beconsidered in any patient receiving ticlopidine (or rarelyclopidogrel) who develops a platelet count �100�109/L, andMI is an early, frequent, and severe complication of TTP.61

Most cases of TTP are caused by a severe functional defect ofthe plasma metalloprotease ADAMTS13, which fails todegrade unusually large vWF multimers.62 ADAMTS13 reg-ulates platelet adhesion and aggregation through cleavage ofvWF multimers. Two recent studies have demonstrated theprognostic value of inhibitory anti-ADAMTS13 antibodies inadult-acquired TTP.62,63 Patients with TTP and detectableinhibitory anti-ADAMTS13 antibodies had delayed plateletcount recovery, higher plasma exchange volume require-ments, and a trend toward more frequent flare-ups. Highlevels of inhibitory anti-ADAMTS13 IgG at presentationwere associated with the persistence of an undetectable

Inheritedfactors

Male

Female

Rel

ativ

e co

ntrib

utio

n

Age

OCP usePregnancy/puerperium

6th decade of life

Menopause

Singlegene

Polygenic

Acquiredfactors

Relative Influence of Inherited and Acquired Factors with Age

Figure 2. Relative influence of inherited and acquired factors indetermining hypercoagulable risk with age. Because of theunique contribution of pregnancy, puerperium, and menopause,women may have a distinct age-dependent risk profile com-pared with men.





ADAMTS13 activity in remission, the latter being predictivefor relapses within an 18-month period.63

Autoimmune Disorders, MyeloproliferativeDisorders, and MalignancyThe antiphospholipid syndrome is strongly associated withatherothrombosis, with several studies indicating that patientswith antiphospholipid syndrome experience an increasedincidence of atherosclerosis compared with the general com-munity.64 Anti-�2-GP I antibodies bind to oxidized LDL inantiphospholipid syndrome patients and lead to enhanceduptake of oxidized LDL by macrophages in vitro.65 Anti-prothrombin antibodies have been detected in asymptomaticdyslipidemic middle-aged men and have been shown topredict MI among patients with antiphospholipid syndrome.64

Although 2 cross-sectional studies have described a 2- to3-fold increase in the prevalence of carotid plaque or coro-nary artery calcification in patients with systemic lupuserythematosus,65,66 evidence supporting an increased risk ofthrombosis in the absence of antiphospholipid antibodies isless strong.

The diagnostic workup for suspected antiphospholipidsyndrome traditionally encompasses testing for antiphospho-

lipid antibodies, lupus anticoagulant anticardiolipin, and anti-�2-GP I. However, in the recent Warfarin in the AntiPhos-pholipid Syndrome study, IgG antibodies to �2-GP I and toprothrombin were associated with anamnestic arterial andvenous thrombosis, respectively, and those to annexin AVwere associated with spontaneous abortions, which supportsthe role of anti-�2-GP I antibodies in the diagnostic workupof the syndrome and the possible role of anti-prothrombin andannexin AV antibody measurements.67

Rheumatoid arthritis is associated with an increased risk ofcoronary and cerebrovascular atherosclerotic disease, MI, andischemic stroke.68 In the Nurses’ Health Study, the incidenceof the composite end point of MI and stroke was significantlyhigher among those with rheumatoid arthritis of �10 years’duration than among normal control subjects (incidence of272 versus 96 per 100 000 person-years).68 An increasedincidence of coronary heart disease may also precede theonset and diagnosis of rheumatoid arthritis, as demonstratedin a population-based study in which hospitalization for MIoccurred 3-fold more often in patients who were subsequentlydiagnosed with rheumatoid arthritis.69 This increased risk ofatherothrombosis appears to be the result of heightenedinflammation and coagulation rather than concomitant rheu-

Genetic Factors

Phenotype/Biological EffectsEnvironmental Factors

Atherothrombosis (clinical disease)-Acute Coronary Syndrome-Ischemic Stroke-?Acute limb, visceral ischemia

Malignancy and myeloproliferative diseases (PRV,ET)

?Viral infections (SLE/APS)

Drugs (thienopyridines-TTP, heparin-HIT, cocaine, OCP, antifibrinolytics, prothrombin complex concentrates)

DM/Metabolic syndrome

Diet

Smoking

Sedentary lifestyle

Pregnancy and Puerperium

Air pollution

Fc gamma RIIA polymorphisms (HIT)

ADAMTS13 mutations (TTP)

SNPs of genes regulating cytokines, B cell activation, apoptosis and complement (SLE)

↑viscosity (TTP)LA, aCL, β2-GPI (APS)Fc gamma RIIA, Anti-PF4 Antibodies (HIT)↑CRP, IL-6, TNF-α, E-selectin, P-selectin,ICAM-1, VCAM-1 and oxidized LDL (DM/MS, SLE) Endothelial dysfunction, Acceleratedatherosclerosis (Smoking/DM/MS/SLE)

Pathophysiology of Acquired Hypercoagulable States

Figure 3. Pathophysiology of acquired hypercoagulable states. SNP indicates single-nucleotide polymorphism; SLE, systemic lupuserythematosus; APS, antiphospholipid syndrome; anti-PF4, antiplatelet factor 4; HIT, heparin-induced thrombocytopenia; CRP,C-reactive protein; IL-6, interleukin 6; TNF, tumor necrosis factor; ICAM, intercellular adhesion molecule; VCAM, vascular cell adhesionmolecule; DM, diabetes mellitus; MS, metabolic syndrome; PV, polycythemia vera; ET, essential thrombocythemia; and OCP, oral con-traceptive pill.





matoid vasculitis.70 Although MI as a direct consequence oflarge or medium-sized vessel vasculitis is uncommon, iso-lated reports of acute thrombosis within coronary arteryaneurysms have been reported in patients with polyarteritisnodosa71 or a history of childhood Kawasaki disease,72 butchronic angina due to progressive arterial narrowing is by farthe more common presentation of coronary or aortic arteritis.73

Patients with the nephrotic syndrome, especially membra-nous nephropathy, have a relatively high incidence of botharterial and venous thrombosis.74 In an analysis of 142patients with nephrotic syndrome and 142 matched healthycontrol subjects, the adjusted relative risk of MI and coronarydeath with nephrotic syndrome was 5.5 and 2.8, respective-ly.75 Although the actual mechanism leading to increasedcoronary thrombosis in nephrotic syndrome is unclear, pos-sible pathogenic factors include hyperlipidemia, platelet hy-perreactivity, endothelial dysfunction, and functional andquantitative changes in plasma coagulation proteins.76

The myeloproliferative disorders often elicit unique clini-cal features, such as a tendency toward both hemorrhagic andthrombotic events, splenomegaly (which is occasionally mas-sive), and clinical manifestations of microcirculatory distur-bances such as ocular migraine, Raynaud phenomenon, anderythromelalgia. Thrombocytosis (�450 000 platelets/mm3)is a main feature of essential thrombocytosis and an importantdiagnostic feature of polycythemia vera, with concomitantincreases of both erythrocyte and leukocyte cell lines in thelatter disorder. The added presence of the Janus kinase-2mutation may have important diagnostic and managementimplications.

Environmental FactorsEstrogen exerts numerous effects on the hemostatic system,including modulation of platelet function and endogenouslevels of physiological anticoagulants.77 Pregnancy and oralcontraceptive use are more prevalent in women with acute MIand normal coronaries than in those who have significantcoronary artery disease on angiography.78,79 Acute MI occursat a rate of 6.2 per 100 000 deliveries, which implies that inwomen of reproductive age, pregnancy increases the risk ofMI by 3- to 4-fold. The overall contribution of plaque ruptureand atherothrombosis to this rare but often catastrophic eventis uncertain, and other underlying mechanisms, includingvasospasm due to sympathomimetic agents and coronarydissection, have been implicated. Certain conditions, in ad-dition to age �30 years, appear to be independent risk factorsfor MI during pregnancy and are particularly important giventheir modifiable nature; these include hypertension, thrombo-philia, diabetes mellitus, smoking, transfusion, and postpar-tum infection.80

The association between HRT and arterial thrombosis isparticularly complex. In randomized trials including �20 000women followed up for 4.9 years, HRT users had a signifi-cantly increased incidence of stroke and pulmonary embolismbut no significant change in endometrial cancer or coronaryheart disease.81 Psaty and colleagues82 suggested an interac-tion with other inherited hypercoagulable states and acquiredrisk factors, whereas Rossouw et al83 found that earlyinitiation of HRT in relation to menopause might improve the

risk-benefit profile. Currently, however, the weight of theevidence indicates that older women and those with subclin-ical or overt coronary heart disease should not take HRT.81

Further data on HRT in younger women will come from theongoing Kronos Early Estrogen Prevention Study (Clinical-Trials.gov identifier NCT00154180), which is evaluating 5years of HRT versus placebo in 720 women 42 to 58 years ofage who are within 36 months of their final menstrual period,using the prevention of progression of carotid intimal medialthickness and the accrual of coronary calcium as surrogateclinical end points.

Fine particulate air pollution has been linked to cardiovas-cular disease. In a study of postmenopausal women withoutprevious cardiovascular disease who were living in citiesexposed to varying levels of air pollution, each increase of 10�g/m3 was associated with a 24% increase in the risk ofcardiovascular events and a 76% increase in the risk of deathdue to cardiovascular disease over a 6-year period.84 The riskof cardiovascular disease varied with the level of exposurebetween and within cities.85 In the Intermountain HeartCollaborative Study, short-term exposure to ambient fineparticulate pollution (particles with an aerodynamic diameter�2.5 �m) elevated by 10 �g/m3 was associated with anincreased risk of acute coronary events equal to 4.5% (95%confidence interval 1.1 to 8.0), with the most pronouncedeffects seen in patients with angiographically demonstratedcoronary artery disease.85 Controlled inhalation of dieselexhaust causes impairment of vascular and endothelial func-tion in human subjects within 2 hours,86 and the effect persistsfor at least 24 hours.87 Although diesel exhaust exposure didnot appear to affect D-dimer, platelet count, vWF, PAI-1, orC-reactive protein levels in healthy volunteers,88 it did sup-press the acute release of endothelial tissue plasminogenactivator in men with stable coronary heart disease duringexercise.89 These studies suggest that although air pollutionmay potentially have a mild prothrombotic effect, itsproatherogenic properties appear to have a more dominantrole in mediating some of its observed adverse cardiovasculareffects.

Diagnosis and Treatment ofHypercoagulable States

Diagnostic Approach to SuspectedHypercoagulable StatesPatients experiencing arterial thrombotic events are morelikely to have 1 or more traditional cardiovascular risk factorsas a provocative stimulus rather than a rare thrombophilicdisorder.53 This is because common atherosclerotic riskfactors themselves, particularly diabetes mellitus or the met-abolic syndrome, are potent mediators of thrombosis, stimu-lating the production of procoagulant proteins and/or impair-ing fibrinolysis.89 The presence of numerous procoagulantproteins within atheromatous plaques provides further evi-dence for the involvement of the hemostatic system inatherosclerosis.90

Acute thrombosis can cause false-positive results whentesting for hypercoagulable states that predispose to venousthrombosis: Protein C, protein S, and antithrombin activity





may be spuriously low, and factor VIII antigen or activitymay be abnormally high.91 When unfractionated heparin orlow-molecular-weight heparin is used, certain assays foractivated protein C resistance may be unreliable, and anti-thrombin activity may appear abnormally low. The use ofvitamin K antagonists (VKAs) may suppress protein C and Slevels, as well as factor IX activity or antigen levels, althoughantithrombin levels may appear abnormally high. This hadled to recommendations that tests for venous thrombophiliabe performed a minimum of 6 weeks after the acute throm-botic event, or for subjects prescribed VKA, a minimum of 6weeks after cessation of therapy. In contrast, tests for arterialthrombophilia are much less susceptible to the effects ofacute thrombosis and can therefore be performed soon afteran acute thrombotic event. Because of the highly variableeffect of antiphospholipid antibodies on test reagents used toperform a test of activated partial thromboplastin time, youngpatients with a first arterial thrombotic event should bescreened for antiphospholipid antibodies and the presence ofa circulating lupus anticoagulant even in the absence of aprolonged activated partial thromboplastin time. If theseantibodies are present on initial testing, tests should berepeated at a 6-week interval to ascertain persistence ofelevated antibody titers.92 If patients are being treated withanticoagulants during testing for lupus anticoagulant, test kitscontaining neutralizers that inactivate heparin or low-molecular-weight heparin should be used.91

A highly selected approach to genetic screening is verydesirable because of the marginal effect that individualgenetic polymorphisms have in determining clinical diseaseand a low overall detection rate. Nonetheless, the greaterprevalence of several thrombophilic risk markers in selectedsubgroups may provide insights into disease pathophysiologyand provide a personalized approach to patient care andgenetic counseling.93 We recommend the algorithm modifiedfrom Andreotti and Becker, in which patients who meet any1 of 5 criteria will undergo further testing53 (Figure 4).

Due consideration must be given to 2 scenarios of venousthromboembolism that occur within the arterial circulation.The first is paradoxical embolism, in which thrombosis thatoccurs in the venous circulatory system has propagated ormigrated to the arterial system via an intracardiac shunt, mostcommonly a patent foramen ovale.94,95 Patients with trueparadoxical embolism require anticoagulation with warfarinand may benefit from closure of the intracardiac shunt. Thesecond is saphenous vein graft thrombosis in the absence ofovert atherosclerosis or deficiencies of vein graft construc-tion.96 It may be prudent to perform a comprehensive screenfor both venous and arterial thrombophilia given the uniqueopportunity for interaction between the arterial and venousenvironments in these 2 circumstances.

The utility of platelet function testing remains unclear;limitations of many currently available tests include thepropensity to produce in vitro artifacts and the measurementof specific markers of platelet function without providing aglobal estimate of platelet biology in a given subject.39

Ongoing studies of antiplatelet therapy guided by standard-ized point-of-care measurements may help resolve this com-plex issue.

Therapeutic PerspectivesPatients presenting with a first episode of arterial thrombosiswho are subsequently found to have an inherited thrombo-philic condition should receive standard treatment for theacute thrombotic episode. Family screening is recommended,and HRT should be discouraged among women found to becarriers of procoagulant gene variants.97 A treatment dilemmaarises when patients with known or highly suspected arterialthrombophilia experience recurring thrombotic events. Al-though long-term anticoagulation with a VKA may intu-itively represent an attractive treatment option, data aresparse. Most clinicians would consider long-term VKA ther-apy with a target international normalized ratio of 2 to 3 oraspirin-VKA combination therapy based on extrapolateddata.98,99 Dual antiplatelet therapy with aspirin and a thien-opyridine may be a reasonable option for events restricted tothe coronary bed, although dedicated studies have not beenperformed in patients with arterial thrombophilia. In thefuture, ongoing studies to evaluate the clinical utility ofassessing platelet responsiveness to antiplatelet therapy andstudies examining the role of genotype-guided treatmentstrategies, such as the recent Randomized Trial of Genotype-Guided versus Standard Warfarin Dosing in Patients Initiat-ing Oral Anticoagulation (COUMA-GEN) study,100 may helpinform selection of the appropriate antithrombotic regimen inpatients with hypercoagulable states.

Despite an association between elevated serum homocysteinelevels and clinical end points, no convincing evidence existsof a reduction in adverse clinical events with vitamin supple-mentation in patients with a modest elevation.7–10 However, itmay be reasonable to implement vitamin B12, vitamin B6,

An episode of arterial thrombosis with any of the following clinical features:

1.Previous arterial thrombosis and age ≤ 50 (male) or ≤ 55 (female)

2.Age ≤ 55 (male) or ≤ 60 (female) with no other traditional risk factors present*

3.No significant coronary stenosis on angiography

4.Age ≤ 55 (male) or ≤ 60 (female) + strong family history†

Consider screening for:

Antiphospholipid antibodies

ET, PV, malignancy

Cocaine metabolites

Consider screening for:

Serum or plasma homocysteine

Factor V Leiden, PT 20210 and other candidate gene variants

?Platelet hyperreactivity

Figure 4. Clinical features suggesting underlying thrombophilia.*Assuming that the following risk factors have been excluded:general (hypertension, diabetes mellitus, smoking, and hyperlip-idemia), MI (recent coronary stenting with suboptimal angio-graphic result or antiplatelet nonadherence), cardioembolicstroke (atrial fibrillation, valvular or other structural heart dis-ease, or carotid artery disease). †May be defined as at least 1first-degree relative affected at age �50 years if male or �55years if female. ET indicates essential thrombocythemia; PV,polycythemia vera. Modified with permission from Andreotti andBecker.53 Copyright © 2005, the American Heart Association.





and folic acid supplementation among patients with markedlyelevated homocysteine concentrations(�100 �mol/L).

The importance of recognizing acquired causes of arterialthrombophilia relates directly to the availability of beneficialtreatments and management strategies for many of theseconditions (Figure 5). Long-term, intermediate-intensity an-ticoagulation with VKA (international normalized ratio of 2.0to 3.0) reduces the likelihood of recurrent arterial thrombosisin patients with the antiphospholipid syndrome.102 In essen-tial thrombocythemia and polycythemia vera, increased plate-let biosynthesis of thromboxane A2 is suppressible by low-dose aspirin.76 Moreover, anagrelide or hydroxyurea added tomaintenance antiplatelet therapy reduced the number ofthrombotic events, compared with antiplatelet therapy with-out myelosuppressive therapy, in patients with essentialthrombocythemia and high-risk clinical features forthrombosis.

Future DirectionsThe polygenic nature of inherited arterial thrombophilia andthe complex interaction between genetic and environmentalfactors necessitate a paradigm shift in applied researchconstructs.2 A careful phenotypic characterization of patientsis fundamental, especially when looking for new genetic riskfactors. Indeed, families, which on average share a number ofphenotypic traits, are the object of genetic studies par excel-lence. As a consequence, a distinction should be madebetween patients who develop an acute coronary syndrome,especially without premonitory symptoms (in which throm-bosis is considered to play a pivotal role), and patients withcoronary atherosclerotic disease who never develop an acuteischemic episode.46

Linkage studies that use genetic markers in extendedpedigrees alone may not give a complete answer because ofthe low penetrance of individual polymorphisms and theheterogeneity in loss-of-function mutations underlying vari-ability within the coagulation system.2 Because the geneticsof the coagulation system are well characterized, genome-wide association studies on large populations have emergedas an attractive platform for understanding the contribution ofknown single-nucleotide polymorphisms to clinical disease.2

The potential for deep resequencing to further fill in the gapsby identifying unknown polymorphisms may soon be realizedwith the availability of very-high-throughput commercial

sequencing technology, such as the 454 pyrosequencing(http://www.454.com) and Solexa sequencing-by-synthesis(http://www.illumina.com) platforms. This paradigm mustalso be expanded to include the tremendous variability intranscription, translation, and posttranslation patterns throughthe use of gene expression profiling and proteomic studies.2

Additionally, robust analytical methods are required to reli-ably process large volumes of high-dimensionality data.Examples of such analytic platforms include artificial neuralnetworks, which outperformed standard methods of regres-sion analysis in a study testing the association between 62single-nucleotide polymorphisms and venous thromboembo-lism.103 Investigators around the world will also be wellserved by the development of a strong collaborative network,such as the National Institutes of Health–sponsored RareThrombotic Disorders Network, to provide large data setswith sufficient imputational power.104

The large sample size and systematic collection of clinicaldata in phase III randomized clinical trials is an attractiveplatform for performing parallel group mechanistic studies.The prospective acquisition of biological samples at baselineand after treatment implementation allows the use of power-ful, unbiased molecular technologies, including microarray-based genome-wide genotyping and gene expression profil-ing, platelet proteomics, and molecular imaging, which maylead to a deeper understanding of hypercoagulable states andtheir appropriate treatment. Global genomic discovery effortshold the promise of useful bench-to-bedside applications thatguide patient therapy, as exemplified by the recent Food andDrug Administration approval of the Verigene F5/F2/MTHFR Nucleic Acid Test (Nanosphere Inc, Northbrook, Ill)for selected patients with venous or arterial thrombosis.105

ConclusionsThe concept of arterial thrombophilia continues to evolve asthe discovery of new pathways involved in human coagula-tion uncovers novel molecular candidates associated with aheightened risk of clinical thrombosis. Moreover, it is nolonger appropriate to consider specific markers of hyperco-agulability in isolation. Rather, a systems approach thataccounts for the additive and possibly multiplicative effectsof all potentially biologically relevant markers is preferred. Inparticular, better methods are needed to study the interaction

Offending drug identified ? No

Specific cause identified

YesNo

Referthrombosis

clinic

Homocysteinemia

Yes

APS Hematological cause

Inherited

Family screeningAntiplatelet, other standard therapies

?Coumadin

Acquired

HIT TTP PV ET

Directthrombininhibitors

Plasmaph-aresis

Phlebotomy +/- chemotherapy

Aspirin

Chemo-therapy

+/-Aspirin

Figure 5. Treatment algorithm. ET indicatesessential thrombocytosis; PV, polycythemiavera; HIT, heparin-induced thrombocytopenia;and APS, antiphospholipid syndrome.Reprinted from Chan and Becker,101 copyright© 2008, with permission from Elsevier.





between inherited, demographic, and acquired or environ-mental predisposing conditions.

The vascular-bed specificity and complex genotype-phe-notype relationships of hypercoagulable states mandate aselective approach to cost-effective and practical screening.An appropriate index of suspicion and carefully constructeddiagnostic algorithms are essential components in the evalu-ation and management of patients with suspected arterialthrombophilia.

AcknowledgmentsThe authors thank Penny Hodgson for editorial review of themanuscript and Elizabeth Foust for her editorial assistance.

Sources of FundingDr Chan is supported by a medical research fellowship award fromthe National Medical Research Council of Singapore and by aresearch award from The Snyderman Foundation, Duke ClinicalResearch Institute.

DisclosuresDr Chan receives research support from Regado Biosciences, EliLilly, and Sanofi-Aventis. Dr Becker receives research support fromRegado Biosciences, The Medicines Company, Bristol-MyersSquibb, AstraZeneca, and Bayer. Dr Becker is employed by DukeUniversity, which financed development of aptamer technology. DrAndreotti reports no conflicts.

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KEY WORDS: coagulation � platelets � thrombosis





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