The D-Dimer Assay

Eric D. Johnson1 MD, John C. Schell2 PhD, and George M. Rodgers1 MD, PhD

1. Division of Hematology and Hematologic Malignancies

University of Utah Health Sciences Center

Salt Lake City, Utah 84132, USA

2. University of Utah School of Medicine

Salt Lake City, Utah UT 84112, USA

Key words: D-dimer, fibrinolysis, coagulation, disseminated intravascular coagulation (DIC),

venous thromboembolism (VTE).

Running Title: The D-dimer Assay

Abstract Word Count: 158

Text Word Count: 1577
Summary Word Count: 678

This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process which may lead to
differences between this version and the Version of Record. Please cite this article as doi:
10.1002/ajh.25482

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Figures: 2
Tables: 4
References: 53
*
Correspondence to:
Eric D. Johnson, MD, Division of Hematology and Hematologic Malignancies

Huntsman Cancer Institute, University of Utah

Salt Lake City, Utah 84132, USA

Tel: 1-801-584-7000. Email: Eric.Johnson@hci.utah.edu

Author disclosures for conflicts of interest: Authors have no conflicts of interest to disclose.

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Abstract:

The D-dimer is an indirect marker of fibrinolysis and fibrin turnover; this molecule exhibits

unique properties as a biological marker of hemostatic abnormalities as well as an indicator of

intravascular thrombosis. D-dimer is a soluble fibrin degradation product which results from the

systematic degradation of vascular thrombi through the fibrinolytic mechanism. Because of this,

the D-dimer serves as a valuable marker of activation of coagulation and fibrinolysis in a number

of clinical scenarios. Most commonly, the D-dimer has been extensively investigated for

excluding 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

anticoagulation in VTE patients, for diagnosing and monitoring disseminated intravascular

coagulation, and for monitoring in other conditions in which the patient is at high risk for

bleeding or thrombosis. Limitations of the assay include D-dimer elevation in a constellation of

clinical scenarios (age, pregnancy, cancer), and lack of clinical standardization.

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Background:

D-dimer molecules are generated through the degradation of crosslinked fibrin during

fibrinolysis. D-dimer generation requires the activity of 3 enzymes: thrombin, activated factor

XIII (factor XIIIa), and plasmin. The process starts when thrombin generated by the coagulation

system converts soluble fibrinogen to fibrin monomers. These monomers then form fibrin

polymers through non-covalent interactions based on allosteric changes within the protein as a

result of thrombin cleavage of fibrinopeptides from the N-terminal domain (Figure 1). Fibrin is

strengthened through interactions with factor XIII, which after activation by thrombin, cross-

links the D domains of adjacent fibrin monomers. Plasmin digestion of the fibrin clot results in

the D-dimer molecule1.

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 D-dimer measurements are done usually by central laboratory assays as well as by point of

care assays with various cut offs designed for both quantitative and qualitative measurement2.

The presence of D-dimer molecules is suggestive of intravascular coagulation because it can

only be generated after thrombin formation and subsequent degradation of cross-linked fibrin.

Because of this, D-dimer measurements serve as a global marker of activation of the coagulation

and fibrinolytic systems, and function as an indirect marker of thrombotic and subsequent

thrombolytic activity2.

There are a variety of uses for the presence or absence of D-dimer molecules in a number of

different pathologic conditions. The analysis of D-dimer is critical for the modern triage and

diagnosis of deep vein thrombosis3-5, pulmonary embolism6-8, aortic dissection9, and

disseminated intravascular coagulation10-13. Measuring D-dimer is most useful in situations

where the likelihood of thromboembolism is low with a negative test effectively excluding

thrombosis, and a positive test being suggestive, but not conclusive of thrombosis3-5. Additional

complexity results from pretest probability that influences accuracy of diagnosis of

thromboembolism3-6.

There has been extensive work on assessing the usefulness of the D-dimer test in diagnosis of

coagulation disorders with the number of PubMed articles on this subject rising steadily since the

1980s. This work includes testing D-dimer in conjunction with clinical information as part of a

diagnostic model/paradigm for example, in exclusion of venous thromboembolism and in

determining duration of anticoagulation14,15. Despite this volume of data, its clinical value and

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significance for many indications remains controversial16. Many attempts have been made to

increase clinical utility of the D-dimer test in a variety of other medical conditions, including

combining D-dimer with other laboratory tests and clinical algorithms17-20.

Assay Methods and Technical Aspects:

D-dimer is detected and quantified in whole blood, plasma, or serum using monoclonal

antibodies that recognize a specific epitope on cross-linked D-dimer molecules that are otherwise

absent on the D-domain of fibrinogen and fibrin monomers which are non–cross-linked2. At least

thirty commercial D-dimer assays are available21, but there are three general types: enzyme-

linked immunosorbent assays (ELISA), immunofluorescent assays, and latex agglutination

assays2,22-24. Each of these test methods have their own specific considerations and limitations,

which have been thoroughly reviewed elsewhere2,22-24. A widely used method, the Vidas D-

dimer assay reportedly shows no interference from heparin, bilirubin, hemoglobin, fibrin

degradation products, or plasma turbidity25.Tables 1 and 2 provide a summary of specific D-

dimer assays that have been frequently used in clinical trials for VTE exclusion, including their

respective cutoff values, sensitivity, and specificity. A summary table is included for additional

details regarding the D-dimer test.

Lack of a Reference Standard:

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 As most laboratory assays are validated against a reference standard, the lack of such a

standard for D-dimer assays makes direct comparison of different assays impossible21. Despite

its use as a biomarker, the development of a reference standard has been difficult, and studies

comparing different D-dimer assays confirm that they are not interchangable26. The use of

proprietary antibodies that recognize different epitopes with varying kinetics makes development

of a universal reference for calibration and standardization unlikely.

Another standardization issue with the D-dimer assay is the definition of the reported result.

There are two such definitions of D-dimer units: fibrin equivalent units (FEU); this relates the

mass of D-dimer to the mass of fibrinogen; and D-dimer units (DDU) that relates to the mass of

D-dimer alone2. The calibrator used for FEU assays compares D-dimer mass to a related

molecular weight of 340 kDa, while the calibrator for DDU assays compares D-dimer mass to

195 kDa. Therefore, testing a sample for D-dimer with both FEU and DDU assays would lead to

a 1.75-fold difference in the result2. In addition, different assay manufacturers use different

magnitude of units (eg. ng/mL, mcg/mL, etc). Each assay manufacturer recommends a unit

definition for their assays; however, laboratory proficiency testing data suggest that ~33% of

laboratories report results in different units than recommended by the assay manufacturer2. Such

reporting could result in inaccurate classification of normal vs abnormal results.

Common Uses of D-dimer Assays:

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VTE Exclusion:

The original clinical scoring system using a D-dimer assay was reported in 2000, with

numerous subsequent trials confirming the utility of this approach3-5. The most commonly used

D-dimer assays in these trials were Asserachrom D-dimer, VIDAS D-Dimer, STA-Liatest D-

Dimer (Stago), Hemosil HS 500 D-dimer, and Innovance D-Dimer assays. Figure 2 illustrates a

clinical algorithm utilizing D-dimer testing to diagnose VTE. Not all commercially available

assays have sufficient sensitivity to be used to exclude VTE27. According to the Clinical and

Laboratory Standards Institute (CLSI), assays should have ≥ 98% negative predictive value

(NPV) and ≥ 97% sensitivity to be used for VTE exclusion27. For some assays, the cut-off

between normal and abnormal is the same as the cut-off for VTE exclusion. However, it is

important to note that for other D-dimer assays, the cut-off between normal and abnormal is

different than the cut-off for VTE exclusion. Clinicians and laboratory professionals must be

aware of the specific cut-offs assigned for the assay that they are using.

D-dimer in assessing duration of anticoagulation:

Assessing the length of oral anticoagulation in a patient with unprovoked VTE is

controversial. Longer durations of anticoagulation carry the risk of bleeding, while shorter

durations of anticoagulation may increase the risk of recurrent VTE. Palareti et al reported that

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measuring D-dimer in patients with unprovoked VTE one month after completion of oral

anticoagulation therapy predicted recurrent VTE28. These results were confirmed in a larger

study14, and an additional trial reported that serial D-dimer testing of patients with an initial

normal result after stopping anticoagulation could identify patients at higher risk of late recurrent

VTE29. These investigators used the Vidas D-dimer ELISA and Clearview Simplify D-dimer

assay. In contrast to the results of the above three European trials, another trial found that

negative D-dimer results in female patients could justify discontinuing anticoagulation, but not in

male patients15. These latter investigators used the Clearview Simplify assay.

D-dimer utility in DIC

D-dimer testing is particularly useful in evaluating patients for possible disseminated

intravascular coagulation (DIC), those with an unknown coagulopathy (prolonged PT and PTT

values), or patients with thrombocytopenia. One concern with using D-dimer assays in

evaluating DIC is identifying a D-dimer level that is consistent with a diagnosis of DIC. For

example, while a D-dimer level of 1.1 mcg/mL FEU is above the normal reference interval, such

levels are frequently seen in patients without DIC, including outpatients and inpatients without

serious illness16. One study used a quantitative D-dimer assay and receiver operating

characteristic curve (ROC) analysis in a cohort of patients thought to have DIC. A D-dimer

cutoff of 8.2 mcg/mL FEU provided excellent sensitivity and negative predictive value for the

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diagnosis of DIC13. Serial monitoring of D-dimer in DIC patients also provides clinical evidence

as to whether the underlying disease process is being successfully treated13.

The utility of D-dimer testing in diagnosing DIC has been addressed by the Scientific and

Standardization Committee on DIC of the International Society of Thrombosis and Haemostasis

(ISTH). Their recommendation is to use a scoring system to diagnose DIC that includes fibrin-

related markers such as D-dimer30. Other parameters in the scoring system include: a relevant

clinical diagnosis, and other laboratory tests – prothrombin time, platelet count, and fibrinogen30

(Table 4). Cutoff values for D-dimer have been evaluated in this model; ROC analysis indicated

that cutoff values for diagnosing DIC varied depending on the D-dimer assay used31. The data

did suggest that D-dimer levels of 3-7 mcg/mL might be sensitive for diagnosing DIC with all D-

dimer assays evaluated (FEU or DDU not specified)31.

Clinical Aspects and Limitations:

Circulating D-dimer is also elevated in patients with liver disease18, coronary artery

disease20,32 and other cardiovascular diseases9, cancer33, trauma17, pregnancy23, infections19,

inflammatory diseases34, severe renal disease35, recent surgical procedures36, and advanced

age23,37 as summarized in Table 3. However, the D-dimer elevation in these conditions is less

specific than for DVT/PE. Although reporting age-adjusted values has been proposed to account

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for a relative increase in circulating D-dimer with aging38, there currently is insufficient evidence

to recommend widespread use of age-adjusted reference intervals39.

D-dimer has been falsely positive/elevated in certain assays, in which rheumatoid factor

causes cross reactivity with human anti-mouse antibodies (HAMA)40. Because the preparation of

antibodies used in D-dimer testing is routinely done in mice, those patients who have received

mouse monoclonal antibody therapy may also have falsely elevated values. This limitation can

be overcome by using alternative assays such as fibrin monomer if an unexpected positive result

occurs, but concerns remain for underlying active thrombosis/fibrinolysis remains low.

Conclusion:

The D-dimer test is clinically useful as a biological marker of hemostasis and hemostatic

abnormalities, especially as an indicator of intravascular thrombosis. Despite limitations,

including lack of standardization, D-dimer is used routinely to exclude VTE, diagnosing and

monitoring DIC; the test may also be useful in determining duration of anticoagulation.

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43. Geersing GJ, Toll DB, Janssen KJ, et al. Diagnostic Accuracy and User-Friendliness of 5 Point-

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45. STA-LIATEST Manufacturer Package Insert:

https://www.stago.com/fileadmin/user_upload/notices/Notices_Reactifs/0051512201701/EN_ST

A-LIATEST%23D-DI%23US_20170131.pdf

46. Clearview Simplify D–dimer Manufacturer Package Insert:

https://www.cliawaived.com/web/items/pdf/Simplify_D_dimer_Test_Insert~1211file1.pdf

47. VIDAS-D -dimer Manufacturer Package Insert:

http://www.ilexmedical.com/files/PDF/DDimerexclusionII30455.pdf

48. INNOVANCE D-dimer FDA Memorandum:

https://www.accessdata.fda.gov/cdrh_docs/reviews/K091916.pdf

49. Hemosil D-dimer HS 500 FDA Memorandum:

https://www.accessdata.fda.gov/cdrh_docs/pdf9/K090264.pdf

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50. TinaQuant D-dimer Manufacturer Package Insert:

https://www.fda.gov.tw/MLMS/ShowFile.aspx?LicId=06022014&Seq=002&Type=9

51. SimpliRED D-Dimer Manufacturer Package Insert:

https://www.sekisuidiagnostics.com/writable/product_documents/files/800sr_ifu_rev_d_copy1.p

df

52. Triage D-Dimer Manufacturer Package Insert:

https://sdmctrlprod.biosite.com/mc/main/mastercontrol/vault/view_pdf.cfm?ui=021419102427&

infocardID=1180193D031130457A

53. PATHFAST D-Dimer FDA Memorandum:

https://www.accessdata.fda.gov/cdrh_docs/reviews/K072288.pdf

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Figure Legends:

Figure 1: Generation of D-dimer following thrombin generation and fibrinolysis. A.) Thrombin cleaves

fibrinopeptides from the E-domain of fibrinogen, producing fibrin monomers. B.) Fibrin monomers

aggregate, and C.) are crosslinked by the action of factor XIIIa to form a fibrin clot. The degradation of

cross-linked polymers by plasmin leads to the liberation of fibrin degradation products, including D-

dimer (D).

Figure 2: Algorithmic approach to evaluate thromboembolism and utility of the D-dimer assay3.

Beginning with a case of possible thromboembolism, it is necessary to quantify the clinical probability of

such an event using a tool such as the Wells score. Following this, patients with high probability scores

are evaluated with imaging and treated accordingly. Those patients with low to intermediate probability

are assessed via D-dimer assay and those below threshold are effectively ruled out, while those above the

threshold are subjected to imaging and treated appropriately.

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Figure 1:

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Figure 2:

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Table 1: Central laboratory D-dimer assays frequently used in VTE clinical trials:

Manufacturer
Assay Cut-Off for DVT Sensitivity DVT Specificity
Detection
Asserachrom D-dimer 500 ng/mL FEU 98% (91% - 100%) 47% (29% - 65%)
Clearview Simplify D-dimer 500 ng/mL DDU 100% (92% - 100%) 48% (43% - 53%)
Hemosil D-dimer HS 500 500 ng/mL DDU 100% (85% - 99%) 45% (41% - 49%)
INNOVANCE D-dimer 500 ng/mL FEU 99% (97% - 99%) 40% (38% - 40%)
MiniQuant D-dimer 200 ng/mL DDU 96% (95% - 98%) 44% (40% - 47%)
STA-Liatest D-dimer 500 ng/mL FEU 96% (90% - 100%) 47% (33% - 76%)
TinaQuant D-dimer 500 ng/mL FEU 99% (90% - 100%) 46% (39% - 72%)
Vidas D-dimer 500 ng/mL FEU 100% (82% - 100%) 42% (37% - 46%)
FEU = Fibrinogen Equivalent Units, DDU = D-Dimer Units

*Values per Manufacturer Package Insert, FDA Memorandum, and Independent expert
comparison. References: 41-53. Other studies might report other sensitivities/specificities.
Reported ranges represent 95% CI.

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Table 2: Point of care D-dimer assays frequently used in VTE clinical trials:

Manufacturer Cut-
Assays DVT Sensitivity DVT Specificity
Off for Detection
LABGEO 450 ng/mL FEU 99% (93% - 100%) 53% (38% - 68%)
Roche Cardiac D-Dimer 500 ng/mL FEU 95% (88% - 99%) 62% (58% - 67%)
PATHFAST D-Dimer 570 ng/mL FEU 98% (94% - 100%) 40% (35% - 44%)
SimpliRED D-Dimer 400 ng/mL FEU 94% (84% – 95%) 67% (56% – 84%)
TRIAGE 200 ng/mL DDU 97% (93% - 100%) 48% (44% – 53%)
FEU = Fibrinogen Equivalent Units, DDU = D-Dimer Units

*Values per Manufacturer Package Insert, FDA Memorandum, and Independent expert
comparison. References: 41-53. Other studies might report other sensitivities/specificities.
Reported ranges represent 95% CI.

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Table 3: Clinical disorders associated with elevated measurement / positive D-dimer result.

Venous/arterial thrombosis3-8
Inflammation34
DIC10-13
Age37,38
Surgery36
Trauma/Burns17
Aortic Dissection9
Cancer/Malignancy2,33
Infection/Sepsis19
Pregnancy2
Liver Disease18
Thrombolytic Therapy2
Renal Disease35
Cardiovascular Disease20,32

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Table 4: ISTH DIC Scoring System:

Test Score
Platelet Count > 100,000 = 0
50,000 - 100,000 = 1
< 50,000 = 2
D-Dimer No Increase = 0
Moderate Increase = 1
Strong Increase = 2
Prolongation of < 3 seconds = 0
Prothrombin Time
> 3 but < 6 seconds = 1
> 6 seconds = 2
Fibrinogen mg/dL > 100 mg/dL = 0
< 100 mg/dL = 1

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 Score ≥ 5 = Overt DIC
*Information in this table is taken from Reference #30.

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