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REVIEW TOPIC OF THE WEEK

A Test in Context: D-Dimer

Jeffrey I. Weitz, MD,a,b,c James C. Fredenburgh, PHD,a,c John W. Eikelboom, MBBSa,c

ABSTRACT

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D-dimer is a soluble fibrin degradation product that results from ordered breakdown of thrombi by the fibrinolytic system.

Numerous studies have shown that D-dimer serves as a valuable marker of activation of coagulation and fibrinolysis.

Consequently, D-dimer has been extensively investigated for the diagnosis of venous thromboembolism (VTE) and is

used routinely for this indication. In addition, D-dimer has been evaluated for determining the optimal duration of anticoa-

gulation in VTE patients, for diagnosing and monitoring disseminated intravascular coagulation, and as an aid in the identi-

fication of medical patients at high risk for VTE. Thus, quantification of D-dimer levels serves an important role in guiding

therapy. This review: 1) describes how D-dimer is generated; 2) reviews the assays used for its detection; and 3) discusses the

role of D-dimer determination in these various conditions. (J Am Coll Cardiol 2017;70:2411–20) Crown Copyright © 2017

Published by Elsevier on behalf of the American College of Cardiology Foundation. All rights reserved.

D -dimer is a biomarker of fibrin formationand degradation that can be measured inwhole blood or in plasma. Healthy individ-

uals have low levels of circulating D-dimer, whereaselevated levels are found in conditions associatedwith thrombosis. D-dimer has been extensively inves-tigated for the diagnosis of venous thromboembolism(VTE) and is used routinely for this indication.D-dimer also has been evaluated for determining theoptimal duration of anticoagulation in VTE patients,for diagnosing and monitoring disseminated intra-vascular coagulation (DIC), and for identifyingmedical patients at high risk for VTE. The role ofD-dimer in patients with other conditions such aspredicting the risk of stroke in atrial fibrillation,identifying patients with coronary artery disease orhuman immunodeficiency virus (HIV) infection atrisk for cardiovascular events, or for ruling outacute aortic dissection is uncertain. The goals of thisnarrative review are to: 1) describe how D-dimer isgenerated; 2) review the assays used for its detection;

m the aDepartment of Medicine, McMaster University, Hamilton, On

medical Sciences, McMaster University, Hamilton, Ontario, Canada; a

titute, McMaster University, Hamilton, Ontario, Canada. Dr. Weitz has bee

stol-Myers Squibb, Boehringer Ingelheim, Daiichi-Sankyo, Janssen, Ionis,

s received honoraria or research support from Bayer, Boehringer Ingelheim,

ofi, andGlaxoSmithKline. Dr. Fredenburghhas reported that he has no relatio

nuscript received July 30, 2017; revised manuscript received September 1

and 3) discuss the role of D-dimer determination inthese various conditions.

GENERATION OF D-DIMER

D-dimer is a plasmin-derived soluble degradationproduct of cross-linked fibrin (1). Generation ofD-dimer requires the sequential activity of 3 en-zymes: thrombin, activated factor XIII (factor XIIIa),and plasmin (Figure 1). The process starts whenthrombin generated by the coagulation systemconverts soluble fibrinogen to fibrin monomers.Each fibrinogen molecule is a symmetrical dimercomposed of 3 pairs of 3 intertwined polypeptidechains, termed a, ß, and g, that extend laterally froma central core. The chains are held together by di-sulfide bonds such that fibrinogen molecules consistof a central E domain linked by coiled-coil regionsto 2 peripheral D domains (2). To form fibrinmonomers, thrombin cleaves short peptides from theNH2-termini of the a- and b-chains to expose “knobs”

tario, Canada; bDepartment of Biochemistry and

nd the cThrombosis and Atherosclerosis Research

n a consultant for and received honoraria from Bayer,

Novartis, Merck, Pfizer, and Portola. Dr. Eikelboom

Bristol-Myers Squibb/Pfizer, Daiichi-Sankyo, Janssen,

nships relevant to the contentsof thispaper todisclose.

5, 2017, accepted September 18, 2017.

ABBR EV I A T I ON S

AND ACRONYMS

DIC = disseminated

intravascular coagulation

DVT = deep-vein thrombosis

ELFA = enzyme-linked

immunofluorescence assay

ELISA = enzyme-linked

immunosorbent assay

HIV = human immunodeficiency

virus

PE = pulmonary embolism

VTE = venous

thromboembolism

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in the E domains. The knobs insert intopre-existing “holes” in the D domains, suchthat the fibrin monomers spontaneouslypolymerize end to end in a half-staggered,overlapping manner to form double-stranded fibrin protofibrils. Individual pro-tofibrils associate with each other to formfibrils composed of hundreds of strands.Because the monomers and protofibrils areassociated noncovalently, the fibrin networkis unstable. Fibrin strength is enhanced byfactor XIIIa, a transglutaminase activatedby thrombin, which cross-links the D do-mains of adjacent fibrin monomers, as well

as the a-chains of opposing monomers to formD-dimer and a-polymers, respectively (3). Therefore,formation of cross-linked fibrin, the substrate forD-dimer formation, requires activation of coagulationwith the resultant generation of thrombin, conversionof fibrinogen to fibrin monomers, polymerization ofthe fibrin monomers to form fibrin polymers, andcross-linking of the fibrin polymers by factor XIIIa.

D-dimer is generated when the cross-linked fibrinnetwork undergoes plasmin-mediated degradation.The degradation process starts when fibrin-boundplasminogen is converted to plasmin by tissue plas-minogen activator. Whereas plasminogen circulatesin plasma, tissue plasminogen activator is releasedlocally from endothelial cells in response to injury.Plasminogen and tissue plasminogen activator bindto the fibrin surface to form a ternary complex thatpromotes plasminogen activation (4). Thus, plasminformation is localized to fibrin, ensuring thatdegradation of circulating fibrinogen is minimal.

Fibrin-bound plasmin degrades the fibrin networkinto soluble fragments, the building block of whichis (DD)E: a complex consisting of D-dimer generatedfrom cross-linked adjacent D domains (DD) non-covalently bound to fragment E (5). Further plasmin-mediated proteolysis of fragment E releases it fromthe (DD)E complex, and D-dimer then circulates inplasma with a half-life of approximately 8 h until itis cleared by the kidneys and the reticuloendothelialsystem (6). Therefore, because it can only be gener-ated when there is formation and degradation ofcross-linked fibrin, D-dimer provides a global markerof activation of the coagulation and fibrinolytic sys-tems, and serves as an indirect marker of thromboticactivity.

D-DIMER ASSAYS

D-dimer in whole blood or plasma is detected withmonoclonal antibodies that recognize an epitope on

cross-linked D-dimer that is absent in the D domain offibrinogen and non–cross-linked fibrin monomers.Although there are numerous commercial D-dimerassays, they are of 3 general types: whole-bloodagglutination assays, enzyme-linked immunosorbentor immunofluorescent assays (ELISA and ELFA,respectively), and latex agglutination assays (7).

Whole-blood agglutination assays use a bispecificantibody conjugate with binding sites for bothD-dimer and a red blood cell membrane antigen suchthat red blood cell agglutination occurs when D-dimerlevels are elevated (Central Illustration, A). Whole-blood agglutination assays are semiquantitative andyield positive or negative results. By contrast, plasmaD-dimer levels can be quantified using ELISA, ELFA, orlatex agglutination assays. ELISA and ELFA rely on theuse of 2 monoclonal antibodies—one that captures theD-dimer in the sample, and a second labeled antibodythat is used to tag and quantify the captured D-dimer(Central Illustration, B). Contemporary latex aggluti-nation assays use immunoturbidometric techniquesto detect D-dimer conjugated to antibody-coated latexbeads. Latex agglutination assays are popular becausethey can be performed using automated coagulationanalyzers (Central Illustration, C). Therefore, modernassays provide rapid quantification of plasma D-dimerlevels.

D-dimer results are not comparable among thevarious assays, even among those using similarformats (8). Reasons for this divergence includeemployment of monoclonal antibodies with varyingspecificities for D-dimer, differences in assaymethodology or instrumentation, and variations inthe values used to discriminate between positiveand negative test results. Because of the multiplereasons for divergent results, standardization of thetests is difficult. As an additional confounder, levelsare reported either as D-dimer concentration inassays that use purified D-dimer as the calibrator,or as fibrinogen equivalent units in those that useD-dimer–containing fragments that are generatedby clotting fibrinogen in the presence of factor XIIIaand then exposing it to limited plasmin digestion.Fibrinogen equivalent units can be converted toD-dimer concentration by dividing the level in half.Therefore, clinicians need to be aware of the per-formance characteristics of the specific D-dimerassay used at their institution.

D-DIMER FOR DIAGNOSIS OF VTE

D-dimer testing is an integral part of validatedalgorithms for the diagnosis of deep-vein thrombosis(DVT) and pulmonary embolism (PE) (9). A common

FIGURE 1 D-Dimer Formation

Fibrinogen is clotted by thrombin, and the fibrin monomers that are produced polymerize spontaneously in a half-staggered format into protofibrils.

The tensile strength of the fibrin network is enhanced by factor XIIIa, which crosslinks adjacent monomers. Plasminogen activation is enhanced with fibrin

formation, and the resultant plasmin digests the individual fibers. Plasmin cleavage between the D and E domains yields (DD)E, the noncovalent complex of

D-dimer (DD) and fragment E. Further proteolysis liberates fragment E from DD.

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CENTRAL ILLUSTRATION Diagnostic Assays for D-Dimer Quantification

Weitz, J.I. et al. J Am Coll Cardiol. 2017;70(19):2411–20.

(A)Whole blood agglutination assays utilize a bi-specific antibody directed against an epitope on D-dimer (DD) and an epitope on red blood cells (RBC). In the presence

of D-dimer, RBC agglutination is monitored by turbidity. (B) Enzyme-linked immunosorbent assays (ELISA) or enzyme-linked immunofluorescent assays (ELFA) involve

capture of D-dimer with an immobilized antibody specific for D-dimer. A second antibody tagged with horseradish peroxidase or a fluorescent marker binds D-dimer

and is used to generate a chromophore or fluorophore that is detected with a spectrophotometer or fluorimeter. (C) The latex agglutination assay uses latex beads

coated with D-dimer specific antibodies. In the presence of D-dimer, latex bead agglutination is detected by turbidity.

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disorder, VTE is diagnosed in about 1.5 per 1,000persons each year (10). For every person diagnosedwith VTE, the diagnosis is excluded in about 9others. About two-thirds of these patients presentwith suspected DVT, whereas the remainder presentwith suspected PE, with or without associated DVT.Therefore, efficient diagnostic pathways are neededto avoid performing expensive radiological tests inall of these patients.

Diagnosis of VTE in outpatients usually starts withassessment of clinical pre-test probability using vali-dated scoring systems such as the Wells score for DVTand the Wells or Geneva score for PE (Figure 2) (11–13).The pre-test probability is higher if there are riskfactors for VTE, such as active cancer or recentsurgery or immobilization, and if the symptomsand signs are typical, particularly if they are severe.Using such scores, clinical pre-test probability is

categorized as likely or unlikely, or as high, inter-mediate, or low.

The clinical pre-test probability is used to guidefurther testing. If VTE is unlikely, D-dimer testing isthe next step (Figure 2). For this purpose, clinicallyuseful D-dimer assays can be divided into 2 maincategories (Table 1)—those with high sensitivity(95% or greater), but lower specificity (about 40%),and those with moderate sensitivity (80% to 94%),but with higher specificity (up to 70%). In ameta-analysis of over 300 studies, ELISA, ELFA,and quantitative latex agglutination assays weremore sensitive than whole-blood agglutinationassays (14). Therefore, unless other assays areunavailable, the whole-blood D-dimer assay shouldnot be used.

D-dimer levels are elevated in most patients withacute thrombosis, but the levels also are increased

TABLE 1 Performance Characteristics of Commercially Available D-Dimer

Assays for Detection of VTE

AssaySensitivity, %,

(95% CI)Specificity, %,

(95% CI)Negative Predictive Value, %

(95% CI)

Whole blood

SimplyRed 75 (63–87) 83 (77–89) 89 (82–97)

ELISA

Asserachrome 95 (83–98) 45 (29–65) 97 (95–100)

Instant IA 87 (59–96) 65 (43–81) 91 (84–93)

ELFA

Vidas 96 (88–99) 57 (54–61) 99 (98–100)

Latex

Tina-quant 95 (78–100) 61 (55–67) 99 (97–100)

STA-Liatest 95 (78–100) 48 (42–55) 99 (96–100)

Adapted from Di Nisio et al. (14) and manufacturers’ data. Sensitivity, specificity, and negativepredictive value can vary depending on the prevalence of VTE in the study’s population.

CI ¼ confidence interval; ELFA ¼ enzyme-linked immunofluorescence assay; ELISA ¼ enzyme-linked immunosorbent assay; VTE ¼ venous thromboembolism.

FIGURE 2 Algorithm for Diagnosis of DVT or PE Using D-Dimer

Clinical pre-test probability

Low or intermediate High

D-dimer

Normal Elevated

PositiveNegative

Compression ultrasound orCT pulmonary angiogram

Diagnosisexcluded

Diagnosisexcluded

Diagnosisestablished

Suspected DVT or PE

D-dimer quantification aids clinical decision making for patients with low or intermediate

pre-test probability of DVT or PE. CT ¼ computed tomography; DVT ¼ deep-vein

thrombosis; PE ¼ pulmonary embolism.

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with advanced age, after surgery, during pregnancyand the puerperium, with cancer and chronicinflammatory conditions, and with many otherdisorders (Table 2). Therefore, D-dimer is a sensitivemarker for detection of thrombosis, but it lacksspecificity. Exploiting these test characteristics, anormal high-sensitivity D-dimer level in thesesettings helps to exclude the diagnosis of VTE.Because of the low specificity of high-sensitivityD-dimer tests, however, some patients withsuspected VTE may have negative results.

D-dimer testing is of limited value in patientswith a high pre-test probability because even if theD-dimer level is normal, the negative predictive valueof the test is reduced by the high prevalence of VTEin such patients. Therefore, if the pre-test probabilityis high, patients should go directly to diagnostictesting with compression ultrasonography for DVTand computed tomography pulmonary angiographyfor PE (Figure 2).

Two maneuvers show promise for increasing thediagnostic yield of D-dimer testing in patients whereVTE is unlikely. Both options involve adjustment ofthe cutoff used to define a negative D-dimer test,which traditionally has been a level below 500 mg/l.Because D-dimer levels increase with age, onemaneuver uses an age-adjusted cutoff. The othermaneuver adjusts the cutoff on the basis of thepre-test clinical probability because the prevalenceof VTE is lower in patients with a low pre-test prob-ability than in those with a moderate pre-testprobability.

In the age-adjusted approach, the cutoff of<500 mg/l is retained for patients #50 years of age,whereas a threshold of 10 times the patient ageis used for those >50 years of age (15–17). Thus, for a75-year-old patient, the D-dimer cutoff would be750 mg/l. This approach increases the specificity ofD-dimer testing without compromising its sensitivity,and has been prospectively validated in patients withsuspected PE (18–20). For adjustment by pre-testclinical probability, the cutoff of <500 mg/l isretained for patients with a moderate pre-test prob-ability, whereas a cutoff <1,000 mg/l is used for thosewith a low pre-test probability (21–23). This approachhas been prospectively validated in patients withsuspected DVT (24). Therefore, cutoff adjustmentsby age or by clinical pre-test probability have thepotential to increase the diagnostic efficacy ofD-dimer testing.

There are other limitations of D-dimer testing fordiagnosis of VTE. The specificity of the test decreaseswith pregnancy, cancer, recent surgery, or trauma,and with being an inpatient (25). D-dimer levels

increase with gestational age and with complicatedpregnancies (26). Therefore, by the third trimester,only a minority of patients will have D-dimerlevels <500 mg/l. Although the specificity of D-dimertesting may be improved by using a higher cutoff (27),

TABLE 2 Patient Characteristics and Disorders Associated

With Increased D-Dimer Levels

Venous or arterial thrombosis

Disseminated intravascular coagulation

Advanced age

Recent surgery or trauma

Cancer

Pregnancy or puerperium

Infection

Chronic inflammation

Liver disease

Renal disease

Thrombolytic therapy

TABLE 3 Incorporat

Predicting the Risk of

Age, yrs

Sex

Elevated D-dimer level

Post-thromboticsyndrome

Site of VTE

Other factors

BMI ¼ body mass index;HERDOO2 ¼ hyperpigmenmass index $30; or older

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such an approach has yet to be validated in prospec-tive management studies. Consequently, with thecurrent cutoff, D-dimer testing is likely to be ofgreater value in the first and second trimesterof pregnancy than in the third.

The specificity of the D-dimer test in patients withcancer is reduced by the high prevalence of VTE andthe higher frequency of elevated D-dimer values inthis patient population. Although studies have yieldedconflicting results about the negative predictive valueof D-dimer assays in cancer patients, a pooled analysissuggests that a negative D-dimer together with alow or unlikely pre-test probability excludes VTE incancer patients like it does in those without cancer(28). However, only about 15% of cancer patientshave this combination of results. Therefore, mostcancer patients with suspected VTE should undergodiagnostic imaging rather than D-dimer testing.

D-dimer testing for diagnosis of VTE shouldbe avoided in situations where it is expected to bepositive, such as after major surgery or trauma or inhospitalized medical patients, particularly those

ion of D-Dimer Levels Into Various Scoring Systems for

Recurrent VTE

Vienna (34) DASH (35) HERDOO 2 (36)

Not assessed #50 $65

Male Male Males continue

After stoppinganticoagulation(>500 mg/l)

After stoppinganticoagulation(>500 mg/l)

On anticoagulation(>250 mg/l)

Not assessed Not assessed HyperpigmentationErythremaRedness

PE versus DVT;proximal versus

distal DVT

Not assessed Not assessed

Not assessed Hormone therapy BMI $30 kg/m2

DASH ¼ D-dimer, age, sex, and hormonal therapy; DVT ¼ deep-vein thrombosis;tation, edema, or redness in either leg; D-dimer level $250 mg/l; obesity with bodyage, $65 years; PE ¼ pulmonary embolism; VTE ¼ venous thromboembolism.

in the intensive care unit. Because of the highfrequency of false-positive results in these settings,using D-dimer to screen for VTE increases the needfor additional testing. However, an elevated D-dimerin hospitalized medically ill patients may helpidentify patients at risk for VTE who may benefit fromthromboprophylaxis.

D-DIMER FOR DETERMINING THE OPTIMAL

DURATION OF ANTICOAGULATION THERAPY

IN VTE PATIENTS

The optimal duration of anticoagulant therapy inpatients with a first unprovoked DVT or PE isuncertain. Such patients require at least 3 months ofanticoagulant therapy, and current guidelines sug-gest extending anticoagulation treatment, providedthat the risk of bleeding is not high (29). A D-dimerlevel measured on anticoagulant therapy or 1 monthafter stopping therapy and the sex of the patient mayhelp to stratify patients according to their risk ofrecurrent VTE, thereby providing an individualizedapproach to management (30–32). Thus, D-dimerlevels have been incorporated into risk predictionmodels, including the Males Continue and HERDOO2(hyperpigmentation, edema, or redness in either leg;D-dimer level $250 mg/l; obesity with body massindex $30; or older age, $65 years) rule and the DASH(D-dimer, age, sex, and hormonal therapy) andVienna scores (Table 3) (33–36).

Patients with a positive D-dimer test have abouttwice the risk of recurrence as those with a negativetest, and the risk of recurrence in men is about 2-foldhigher than that in women. Furthermore, the risk ofrecurrence with these 2 factors appears to be additive.Thus, for men, the risk of recurrence with a positiveD-dimer test 1 month after stopping anticoagulanttherapy is in the range of 15% to 18% at 1 year,whereas the risk of recurrence is about 8% to 10% at1 year if the test is negative (37,38). In either case,the risk of recurrence is sufficiently high to justifycontinued anticoagulant therapy, particularly withthe favorable benefit–risk profiles of reduced dosesof apixaban or rivaroxaban for extended VTE treat-ment (39,40). Therefore, D-dimer testing in men is oflimited value for making decisions about the optimalduration of anticoagulant therapy for a first episodeof unprovoked VTE.

D-dimer testing may be of value in women wherethe risk of recurrence with a positive D-dimer test1 month after stopping anticoagulant therapy is about10% at 1 year, whereas the risk is only about 5% at 1year if the test is negative (37,38). Therefore, it maybe reasonable to stop anticoagulant therapy in

TABLE 4 Disorders Associated With DIC

Sepsis

Extensive trauma or burns

Cancer

Obstetrical complications Amniotic fluid embolism, placentalabruption, placenta previa, retainedproducts of conception

Vascular disorders Cavernous hemangioma, aorticaneurysm

Toxins Snake bites, drugs

Immunological disorders Transfusion reactions, organ rejection

DIC ¼ disseminated intravascular coagulation.

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women with a normal D-dimer level, and to continuetreatment if the level is elevated.

In patients with proximal DVT, an elevated D-dimerlevel 1 month after stopping anticoagulation togetherwith residual vein occlusion on compression ultra-sound was reported to double the risk of recurrencein one study (41). However, this finding was notconfirmed in another study (42), and meta-analysessuggest that residual vein thrombosis in patients withDVT is a weak risk factor for recurrent VTE (43,44).

D-DIMER IN CANCER PATIENTS

Patients with cancer are at increased risk of throm-bosis, and VTE is the second leading cause of death incancer patients (45,46). Furthermore, VTE in cancerpatients increases hospitalization and health carecosts by 3-fold (47) and may delay cancer treatments.Thromboprophylaxis has the potential to reduce theburden of VTE in cancer patients, but needs to betargeted to those at highest risk. A validated riskassessment tool that includes the site of the cancer,platelet count, white blood cell count, and hemoglo-bin level before chemotherapy, use of erythropoiesisstimulating agent, and body mass index has beenused to assess the risk of VTE in cancer patients(48,49). Adding measurement of D-dimer levels tothis scoring system may improve VTE risk prediction(50). Therefore, prospective management studies areneeded to determine the benefit–risk of primarythromboprophylaxis in cancer patients identifiedusing these risk assessment models.

D-DIMER IN MEDICALLY ILL PATIENTS

Hospitalized medically ill patients are at risk of VTEwhile in hospital and for up to 3 months afterdischarge (51,52). To reduce this risk, current guide-lines recommend thromboprophylaxis for suchpatients while in hospital, but recommend againstextended prophylaxis after hospital discharge (53).The recommendation for in-hospital treatmentis based on randomized placebo-controlled trialsrevealing a benefit of short-term thromboprophylaxisin hospitalized patients (54–56). By contrast, therecommendation against extended thromboprophy-laxis is based on randomized trials that failed to showa favorable benefit–risk profile for longer periods ofthromboprophylaxis (57–59). Elevated D-dimer levelsover twice the upper limit of normal identifymedically ill patients at increased risk of VTE whomay benefit from extended prophylaxis (60–62)and incorporating D-dimer determination into vali-dated risk assessment models such as the IMPROVE(International Medical Prevention Registry on Venous

Thromboembolism) score, enhances their capacity toidentify those at risk (63). Using elevated D-dimerlevels to identify medically ill patients at risk for VTE,a recent study demonstrated that compared with a10-day course of enoxaparin, a 35- to 42-day course ofbetrixaban, an oral factor Xa inhibitor, reduced therisk of VTE by 24% without increasing the rate ofmajor bleeding (64). Betrixaban also reduced the rateof new ischemic stroke from 0.9% to 0.5% (65).Betrixaban has been licensed for extended thrombo-prophylaxis in medically ill patients, and D-dimerlevels may help to identify those who will benefitmost from such treatment.

D-DIMER AND DIC

DIC is characterized by a consumptive coagulopathyas a result of increased thrombin generation andenhanced fibrinolysis (66). DIC can complicate anarray of disorders (Table 4), and patients with DICmay present with thrombosis, bleeding, or bothdepending on the cause and the extent of thecoagulopathy.

D-dimer levels are helpful for the diagnosis of DIC.Because of its sensitivity, a normal D-dimer levelexcludes the diagnosis of DIC (7). However, on its own,an elevated D-dimer level is insufficient to establishthe diagnosis of DIC. Instead, scoring systems havebeen developed that include determination of theplatelet count, fibrinogen level, and the prothrombintime in addition to the D-dimer level (67). Such scoringsystems are helpful, not only for the diagnosis of DIC,but also for monitoring its progression.

D-DIMER AND OTHER DISORDERS

D-dimer levels are elevated in a variety of conditionsincluding atrial fibrillation, coronary artery disease,acute aortic dissection, and HIV infection. The valueof D-dimer measurement in each of these disordersis briefly discussed.

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ATRIAL FIBRILLATION. Patients with atrial fibrillationhave higher levels of D-dimer than those without, andthe levels of D-dimer in atrial fibrillation patientsdecrease with anticoagulant treatment or after success-ful cardioversion (68–70). D-dimer levels are higher inatrial fibrillation patients with additional risk factors forstroke, such as hypertension, diabetes, or heart failure,than in those without risk factors. Consequently,D-dimer has been proposed as a biomarker for predict-ing the risk of stroke in patients with atrial fibrillation.However, its utility for this indication is limited becauseother biomarkers such as troponin, N-terminal pro-B-type natriuretic peptide, and growth differentiationfactor-15 are better predictors of stroke than D-dimerlevels, and incorporating D-dimer into risk predictionmodels does not appear to increase their predictivevalue. Therefore, measurement of D-dimer levels is oflimited value for predicting the risk of stroke in atrialfibrillation patients.

ACUTE AORTIC DISSECTION. Rapid diagnosis of acuteaortic dissection is essential to limit mortality andmorbidity. D-dimer levels are elevated with acuteaortic dissection and low in its absence (71,72).Consequently, a normal D-dimer level may help toexclude the diagnosis of aortic dissection. In patientsat low risk for acute aortic dissection, a pooled analysisof data from 4 studies that included 1,557 patientsconcluded that a D-dimer level below 500 mg/l had asensitivity of 98% and a negative predictive value of95% for ruling out the diagnosis. For those not at lowrisk, however, the test lacks sufficient sensitivity to beof value (73). The American Heart Association riskscore used to assess pre-test probability of acute aorticdissection designates patients as low risk if there areno high-risk findings, such as sudden onset of severechest, back, or abdominal pain, Marfan syndrome, or anew aortic insufficiency murmur (74). The prevalenceof acute aortic dissection in low-risk patients is <6%,and without any of these features, the diagnosis isunlikely to be considered. Therefore, at present,D-dimer is of limited utility in patients with suspectedacute aortic dissection.

CORONARY ARTERY DISEASE. Longitudinal studiesevaluating the utility of D-dimer levels to predictmyocardial infarction and cardiovascular death haveyielded conflicting results. Some prospective studiessuggest an association between elevated D-dimerlevels at baseline and the subsequent risk of cardio-vascular events, whereas others do not (75–77). Like-wise, in patients with established coronary arterydisease, D-dimer levels are of uncertain value inpredicting future cardiovascular events (78). Finally,in patients presenting with chest pain, D-dimer

appear to be of no value for identifying those withacute coronary syndrome or for determining prog-nosis (79). Therefore, there is no role for routinemeasurement of D-dimer levels in patients with cor-onary artery disease.

HUMAN IMMUNODEFICIENCY VIRUS. With effectiveantiretroviral therapy, HIV-infected individuals livelonger and succumb to non–HIV-related disorders,particularly cardiovascular disease. The rate of car-diovascular disease is higher with HIV infection thanwithout (80). In addition to usual risk factors such asdyslipidemia, diabetes, smoking, and hypertension,immune dysfunction characterized by elevated levelsof D-dimer, C-reactive protein, and interleukin-6 alsomay contribute (81). These biomarkers are betterpredictors of cardiovascular disease in HIV-infectedindividuals than in those without HIV infection, andthe levels decrease with antiretroviral therapy andincrease when treatment is stopped (81,82). Themechanism responsible for the immune dysfunctionis uncertain and studies evaluating the effect of in-terventions such as intensified HIV therapy andintravenous immunoglobulin have yielded mixed re-sults (83,84). Therefore, until more data are available,measurement of D-dimer and other inflammatorymarkers in HIV-infected individuals remains aresearch tool.

CONCLUSIONS

As a marker of activation of coagulation and fibrino-lysis, D-dimer levels provide a rapid assessment ofthrombotic activity. The test has an established rolein the diagnosis of VTE where it reduces the need forexpensive imaging studies in the majority of patientswith suspected DVT or PE. D-dimer also is usedroutinely for the diagnosis of DIC, and it may help toidentify cancer and medically ill patients at high riskfor VTE who would benefit from extended thrombo-prophylaxis. D-dimer is of limited value in deter-mining the optimal duration of anticoagulation inVTE patients and in ruling out acute aortic dissection.

Standardization of D-dimer assays and furtherinvestigation of cutoff adjustment by age or pre-testclinical probability would increase the effectivenessof the test for the diagnosis of VTE. Although D-dimermay be useful for risk assessment in other disorders,additional studies are needed to establish its role.

ADDRESS FOR CORRESPONDENCE: Dr. Jeffrey I.Weitz, Thrombosis and Atherosclerosis ResearchInstitute, McMaster University, 237 Barton Street East,Hamilton, Ontario L8L 2X2, Canada. E-mail: weitzj@taari.ca.

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KEY WORDS D-dimer, deep-veinthrombosis, disseminated intravascularcoagulation, pulmonary embolism, venousthromboembolism