D-Dimer Test: Fibrin Degradation and Clot Detection

D-Dimer Test: Fibrin Degradation and Clot Detection — scientific infographic poster

D-dimer is a fibrin degradation product released when cross-linked fibrin clots are broken down by plasmin. It is widely used to help rule out venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE). The StatPearls chapter on the test describes it as highly sensitive but not specific: a normal result in a person with low or intermediate clinical probability makes a clot unlikely, while a raised result has many possible causes besides a clot.

Table of Contents

  1. Overview — What Is D-Dimer?
  2. Biochemistry — How D-Dimer Is Formed
  3. How the Test Works
  4. Reference Ranges and Units
  5. Wells Score and Clinical Decision Rules
  6. Age-Adjusted D-Dimer Threshold
  7. Causes of Elevated D-Dimer
  8. D-Dimer in DIC and Critical Illness
  9. Pregnancy and Other Special Populations
  10. COVID-19 and D-Dimer
  11. Quantitative vs. Qualitative Assays
  12. Limitations and False Positives
  13. Anticoagulation Duration and the HERDOO2 Rule
  14. Key Research Papers
  15. Connections
  16. Featured Videos

Overview — What Is D-Dimer?

D-dimer is a small protein fragment produced when a blood clot (thrombus) dissolves. The name refers to a specific structural feature of fibrin: after thrombin converts soluble fibrinogen into fibrin monomers, Factor XIIIa (a transglutaminase activated by thrombin) cross-links adjacent fibrin D domains together, forming a stable, reinforced clot. When the fibrinolytic system — driven by plasmin — degrades this cross-linked fibrin network, it releases fragments called D-dimer, named for the two D domains that remain joined after plasmin cleaves the fibrin polymer.

Because D-dimer reflects both clot formation and clot dissolution, it is a marker of clotting activity anywhere in the body, not in one specific blood vessel. A raised D-dimer shows that fibrin has been laid down and is being broken down somewhere; it does not show where. This is the reason for its high sensitivity and low specificity: many processes that activate coagulation produce D-dimer, from wounds and surgery to pulmonary embolism.

Clinically, D-dimer is used as a rule-out test for venous thromboembolism. In the Christopher Study of 3,306 patients with suspected PE, 1,057 (32.0%) had a "PE unlikely" score and a normal D-dimer; of the 1,028 left untreated, 5 (0.5%) had a nonfatal VTE over 3 months (van Belle 2006). In a randomized trial in suspected DVT, 39% of patients in the D-dimer group needed no ultrasound, and 0.4% of those in whom DVT had been ruled out had a VTE over 3 months (Wells 2003). Ruling a clot out this way spares people CT pulmonary angiography (with its radiation and contrast) or compression ultrasound.

The coagulation cascade responsible for D-dimer production has two pathways: the intrinsic pathway (contact activation via Factor XII, XI, IX, VIII) and the extrinsic pathway (tissue factor plus Factor VII). Both converge on a common pathway involving Factor X, Factor V, prothrombin (Factor II), thrombin, and finally fibrinogen. D-dimer appears at the very end of this process — after the clot has formed and after plasmin has acted. The StatPearls chapter notes that results can be affected if blood is sampled too early, during clot formation, and that blood taken after an anticoagulant has been given may test negative; it gives D-dimer a plasma half-life of 6 to 8 hours.

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Biochemistry — How D-Dimer Is Formed

D-dimer is the end product of a two-stage sequence: a clot must first be built and chemically reinforced, and then it must be enzymatically taken apart. Neither step alone produces D-dimer. This is why the molecule is a marker of completed clot turnover rather than of coagulation activity in the abstract.

Step 1: Cross-Linked Fibrin Clot Formation

When coagulation is triggered — by tissue factor exposure, endothelial injury, or contact activation — thrombin cleaves fibrinopeptides A and B from circulating fibrinogen, converting it into fibrin monomers. These monomers polymerize into fibrin protofibrils, which associate laterally into fibers. Thrombin also activates Factor XIII into Factor XIIIa, a transglutaminase that forms covalent bonds between the gamma chains of adjacent fibrin monomers and, more slowly, between their alpha chains. The resulting cross-linked polymer is mechanically stronger and more resistant to enzymatic digestion than uncross-linked fibrin.

Step 2: Plasmin-Mediated Fibrinolysis

Tissue plasminogen activator (t-PA) and urokinase plasminogen activator convert plasminogen into plasmin, the principal fibrinolytic enzyme. Plasmin cleaves fibrin at lysine and arginine residues throughout the clot. Because Factor XIIIa has already joined the gamma chains, plasmin cannot fully disassemble the polymer into its original subunits; instead it liberates a characteristic set of fragments. One of them is D-dimer — two D domains from neighboring fibrin monomers still joined through their cross-link. StatPearls notes that most fibrin degradation products are cleared mainly by the liver, while D-dimer itself is cleared primarily by the kidneys and the reticuloendothelial system.

Why the Cross-Link Matters Analytically

D-dimer is not generated from fibrinogen or from uncross-linked fibrin. That biochemical constraint is what allows monoclonal antibody assays to distinguish D-dimer from circulating fibrinogen and from other fibrin(ogen) degradation products. It also explains how the result is read: a raised D-dimer means a clot was built and is being dismantled — whether that clot is a deep vein thrombus, a pulmonary embolus, a surgical wound, a resolving hematoma, or the diffuse microthrombi of disseminated intravascular coagulation. StatPearls adds that people with Factor XIII deficiency have continually low D-dimer levels.

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How the Test Works

D-dimer is measured from a plasma sample; StatPearls describes collection into a tube containing 3.2% sodium citrate, which binds calcium so that the sample does not clot in the tube. The plasma is separated by centrifugation and analyzed by immunoassay. Modern D-dimer assays use monoclonal antibodies that recognize an epitope present on cross-linked fibrin degradation products and not on fibrinogen.

Three main assay formats are in common use:

D-dimer assays differ in the antibody used, the capture method, the instrument and the calibration standard, and these differences change how the assays perform, so evidence for one assay cannot simply be extrapolated to another (Linkins 2017). StatPearls lists hemolysis of the sample, lipemia and heterophile antibodies among the causes of falsely raised results.

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Reference Ranges and Units

StatPearls gives a typical normal D-dimer of less than 500 ng/mL (0.50 µg/mL), with 500 ng/mL or more counted as positive, and notes that no critical level has been established. MedlinePlus does not give a numeric range; it explains that a low or normal result means a clotting disorder is probably absent, that blood thinners can cause a false-negative result, and that a high result needs further tests to find where a clot is or what kind of clotting disorder is present.

Units are a common source of confusion. There is no universally accepted international standard or calibrator for the test, so laboratories use different reporting units, thresholds and methods (StatPearls):

The cut-offs quoted on this page are given in the units the cited studies used (ng/mL or µg/L). A cut-off validated for one assay and unit does not automatically transfer to another (Linkins 2017), and laboratory reports give the value together with the unit and the laboratory's own threshold.

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Wells Score and Clinical Decision Rules

D-dimer is validated as a rule-out test when combined with a structured clinical pre-test probability assessment. The 2019 ESC guideline notes that the negative predictive value of D-dimer testing is high and the positive predictive value of a raised result is low (Konstantinides 2019). StatPearls describes clinical decision tools such as the Wells and revised Geneva scores as the first step, and states that D-dimer testing is not recommended for patients with a high pre-test probability, who go directly to imaging. The main validated algorithms are:

Wells PE Score (Pulmonary Embolism)

The Wells PE score was derived from 40 clinical variables in a prospective cohort and assigns points to seven items (Wells 2000):

In the two-level version, a score of 4 or less means "PE unlikely" and more than 4 means "PE likely". In the derivation study, 7.8% of patients scoring 4 or less had PE, but when their D-dimer was also negative the rate was 2.2% in the derivation set and 1.7% in the validation set (Wells 2000). In the Christopher Study's algorithm, "PE unlikely" patients had D-dimer testing and PE was excluded if the result was normal, while all others went to CT; the 3-month VTE rate after a normal D-dimer was 0.5% (van Belle 2006).

Wells DVT Score (Deep Vein Thrombosis)

The Wells DVT score uses a leg-focused set of items. StatPearls describes it as considering recent malignancy; recent immobilization, including recent surgery; asymmetric leg swelling; collateral veins; tenderness along the deep veins; and a history of DVT — and as subtracting 2 points if an alternative diagnosis is as likely as, or more likely than, DVT. The modified Wells score adds 1 point for a previously documented DVT; a score of 1 or less means DVT is unlikely and 2 or more means DVT is likely.

In a randomized trial of outpatients with suspected DVT (530 assigned to ultrasound alone, 566 to D-dimer testing), patients judged clinically unlikely to have DVT who had a negative D-dimer did not have ultrasound. Over 3 months, 0.4% of those in whom DVT had been ruled out in the D-dimer group had a VTE, compared with 1.4% in the ultrasound-only group (P=0.16); ultrasound use fell from 1.34 to 0.78 tests per patient, and 39% of the D-dimer group needed no ultrasound at all (Wells 2003). StatPearls states that a high-sensitivity D-dimer below 500 ng/mL in a patient with low or moderate pre-test probability rules out DVT, and that D-dimer cannot reliably exclude DVT at high pre-test probability.

YEARS Algorithm

The YEARS algorithm (van der Hulle 2017) uses three clinical items plus a D-dimer threshold that depends on them:

If no YEARS items are present and D-dimer is below 1000 ng/mL, PE is considered excluded. If one or more YEARS items are present and D-dimer is below 500 ng/mL, PE is considered excluded. All other patients have CT pulmonary angiography. In the prospective YEARS study of 3,465 patients at 12 hospitals in the Netherlands, 18 of the 2,946 patients in whom PE was ruled out and who were left untreated were diagnosed with VTE over 3 months (0.61%). CT pulmonary angiography was not indicated in 1,651 patients (48%) with YEARS, compared with 1,174 (34%) had the Wells rule with a fixed 500 ng/mL threshold been applied — an absolute difference of 14% (van der Hulle 2017). The 2019 ESC guideline describes the YEARS approach as one way to adapt the D-dimer cut-off to clinical probability (Konstantinides 2019).

PERC Rule (Pulmonary Embolism Rule-Out Criteria)

The PERC rule is a block of eight criteria; if all are met, the rule is used to stop the work-up without a D-dimer: age under 50, pulse under 100, oxygen saturation of 95% or more, no unilateral leg swelling, no hemoptysis, no surgery or trauma requiring hospitalization within 4 weeks, no prior DVT or PE, and no estrogen use (Kline 2008). The rule is meant to prevent ordering a D-dimer in a very-low-probability patient whose slightly raised non-specific result would then lead to imaging. The 2019 ESC guideline describes PERC as selecting patients whose likelihood of PE is so low that a diagnostic work-up need not be started, and notes the low overall prevalence of PE in the studies (Konstantinides 2019).

The criteria were derived by Kline et al. (J Thromb Haemost 2004, PMID 15304025) from 3,148 emergency department patients at 10 US hospitals. The authors estimated a test threshold of 1.8% — the probability below which a D-dimer is not worth ordering. In the two validation groups, 1.4% of rule-negative patients in the low-risk group and 0% in the very-low-risk group had PE. In a 2008 prospective study of 8,138 patients in 13 emergency departments, low clinician suspicion (a gestalt estimate below 15%) together with a negative PERC was present in 1,666 patients (20%), with a false-negative rate of 1.0% for VTE or death within 45 days (Kline 2008).

The PROPER trial, a crossover cluster-randomized noninferiority trial in 14 emergency departments in France, enrolled 1,916 patients with a low gestalt clinical probability of PE. During the PERC period, one PE (0.1%) was diagnosed during the 3-month follow-up, compared with none in the control period, which met the noninferiority test; CT pulmonary angiography was used in 13% versus 23% of patients (Freund 2018).

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Age-Adjusted D-Dimer Threshold

D-dimer rises with age, so a fixed cut-off rules out fewer older patients. In a meta-analysis of 13 cohorts including 12,497 patients with a non-high clinical probability, the specificity of the conventional 500 µg/L cut-off fell from 57.6% in patients aged 51–60 to 39.4% at 61–70, 24.5% at 71–80 and 14.7% over 80. The age-adjusted cut-off (age × 10 µg/L) gave higher specificity in every age group — 62.3%, 49.5%, 44.2% and 35.2% — while sensitivity stayed above 97% (Schouten 2013). A lower specificity means more people without a clot are sent to imaging.

The age-adjusted D-dimer threshold was prospectively validated in the ADJUST-PE study (Righini et al., JAMA 2014, PMID 24643601):

A threshold plot of the D-dimer exclusion cut-off against age: the fixed cut-off stays flat at 500 µg/L at every age, while the age-adjusted cut-off stays at 500 until age 50 and then rises as age times 10 µg/L, opening a shaded wedge of results above 500 but below the patient's own cut-off. A meta-analysis found the specificity of the fixed cut-off fell from 57.6% at ages 51 to 60 to 14.7% over 80, and in the ADJUST-PE study the wedge carried a 3-month failure rate of 0.3%. THE CUT-OFF RISES WITH AGE D-dimer exclusion cut-off, µg/L · non-high or unlikely clinical probability only 500 cut-off, µg/L → 50 60 70 80 patient age, years → fixed cut-off: 500 at every age from age 50: age × 10 µg/L above 500, below age × 10: PE excluded with no scan under the age-adjusted rule WHAT THE WEDGE BUYS specificity of the fixed 500 falls with age 57.6% at ages 51–60, 14.7% over 80 age-adjusted: 62.3% and 35.2%, sensitivity above 97% meta-analysis of 13 cohorts (Schouten 2013) the wedge proved safe in ADJUST-PE 1 of 331 failed at 3 months — 0.3% (95% CI 0.1–1.7%) 75 and over: PE excluded on D-dimer 6.4% with the fixed cut-off → 29.7% age-adjusted studied in emergency outpatients with a non-high or unlikely clinical probability, using highly sensitive D-dimer assays (Righini 2014) units matter: FEU and DDU results differ about two-fold for the same sample (Favaloro 2020)

The 2019 ESC guideline states that age-adjusted cut-offs (age × 10 µg/L for patients aged over 50) may improve the performance of D-dimer testing in older people (Konstantinides 2019). StatPearls notes that the approach is supported by both American and European medical colleges, although it is not approved by the United States Food and Drug Administration.

The age-adjusted threshold is part of a rule-out strategy for people with a low or intermediate (non-high) pre-test probability. In people with a high pre-test probability, StatPearls describes going directly to imaging rather than D-dimer testing. Combining the two strategies was tested in a post hoc analysis of the YEARS cohort: fully integrating the age-adjusted cut-off into YEARS would have spared CT in 1,627 patients (47%) instead of 1,651 (48%), at the cost of four additional missed PE diagnoses, and the authors found no added value (van der Pol 2017).

Groups in Which the Age-Adjusted Threshold Has Not Been Established

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Causes of Elevated D-Dimer

Because D-dimer reflects clot formation and dissolution anywhere in the body, any condition that activates coagulation or triggers inflammation with fibrin deposition can raise it. The list is long, which is why D-dimer is a poor rule-in test despite being a useful rule-out test: in the 2004 systematic review, positive likelihood ratios were in the general range of 1.5 to 2.5, which does not greatly increase the certainty of a diagnosis (Stein 2004).

Thrombotic Conditions (Primary Indications)

Physiological Elevation

Inflammatory and Infectious Conditions

Malignancy

Post-Procedural and Traumatic

Cardiovascular

Hematologic

Organ Dysfunction

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D-Dimer in DIC and Critical Illness

Disseminated intravascular coagulation is the condition in which D-dimer reaches its most extreme values, and it is also the condition in which the test has a formal, scored diagnostic role rather than a rule-out role. DIC is simultaneous, widespread coagulation activation and fibrinolysis: microthrombi form throughout the circulation while platelets and clotting factors are consumed, so the patient can be clotting and bleeding at the same time.

The ISTH DIC Score

The International Society on Thrombosis and Haemostasis scoring system (Taylor et al., Thromb Haemost 2001, PMID 11816725) gives D-dimer — or another fibrin-related marker — a central weighting. As tabulated in a 2024 scoping review of DIC criteria (Matsuoka 2024):

Three other items complete the score: platelet count, prolongation of the prothrombin time, and fibrinogen level. A total of 5 or more is compatible with overt DIC (Matsuoka 2024). In a prospective validation in 217 intensive care patients, the 0–8-point score had a sensitivity of 91% and a specificity of 97% against an expert-opinion standard, and each 1-point increase carried an odds ratio of 1.25 for 28-day mortality (Bakhtiari 2004). StatPearls describes acute DIC as thrombocytopenia and consumption of coagulation factors with a prolonged PT and aPTT and an elevated D-dimer — a pattern that separates it from the isolated D-dimer rise of ordinary VTE.

DIC Always Has a Trigger

DIC is a downstream consequence of another illness, and StatPearls describes treatment as centering on the underlying disorder. Triggers it lists include:

Because both DIC and a large pulmonary embolism can produce a very high D-dimer, the number alone does not separate them. The ISTH score combines D-dimer with platelet count, PT and fibrinogen, and imaging remains the way to find a PE. MedlinePlus notes that D-dimer may also be used to monitor how well DIC treatment is working.

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Pregnancy and Other Special Populations

Some groups have a physiologically higher D-dimer baseline, which lowers the share of people in whom the standard cut-off rules a clot out. In several of these groups the baseline is highest in the people at greatest thrombotic risk, so the test is least discriminating where it would be most useful.

Pregnancy: Physiology

Pregnancy is a hypercoagulable state. Fibrinogen and several clotting factors (including Factors VII, VIII and X) rise, Protein S falls, and fibrinolytic activity decreases. The net effect is more fibrin turnover and therefore more D-dimer, with no thrombus anywhere. StatPearls lists pregnancy, including the postpartum period, among the causes of a raised D-dimer.

Pregnancy: How Much the Test Helps by Trimester

The usefulness of D-dimer falls as pregnancy advances. In the Pregnancy-Adapted YEARS study, CT pulmonary angiography was avoided in 65% of women who entered the study in the first trimester and in 32% of those who entered in the third trimester (van der Pol 2019).

Pregnancy: Diagnostic Algorithms That Have Been Studied

The Pregnancy-Adapted YEARS algorithm (van der Pol 2019) assessed the three YEARS items with a D-dimer: PE was ruled out if no item was present and D-dimer was below 1000 ng/mL, or if one or more items were present and D-dimer was below 500 ng/mL. Women with symptoms of DVT had compression ultrasonography first, and if it showed a clot, CT pulmonary angiography was not performed. Of 510 women screened, 12 were excluded, and PE was diagnosed in 20 (4.0%) at baseline; during the 3-month follow-up one woman (0.21%) was diagnosed with a popliteal DVT and none with PE. CT pulmonary angiography was avoided in 195 women (39%). The 2019 ESC guideline also presents a dedicated diagnostic algorithm for suspected PE in pregnancy and notes that D-dimer is more frequently elevated during pregnancy (Konstantinides 2019). There are no universally adopted trimester-specific reference ranges, and the age-adjusted formula has not been established in pregnancy. StatPearls notes that CT pulmonary angiography is now an accepted alternative to ventilation-perfusion scanning in pregnancy.

Active Malignancy

People with active cancer often carry a raised D-dimer (StatPearls), so a positive result adds less information in this group than in the general population. A result below the cut-off keeps its rule-out value only within the algorithms and populations in which it was studied.

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COVID-19 and D-Dimer

The COVID-19 pandemic brought D-dimer into wide public awareness, as SARS-CoV-2 infection was recognized to cause a hypercoagulable state often called COVID-19-associated coagulopathy (CAC), typically described as a raised D-dimer and fibrinogen with relatively preserved platelet counts. In one early series of 183 patients in Wuhan, however, 71.4% of non-survivors (and 0.6% of survivors) met the criteria for DIC during their hospital stay (Tang, J Thromb Haemost 2020, PMID 32073213).

Proposed Mechanisms of COVID-19 Hypercoagulability

D-Dimer as a COVID-19 Severity and Mortality Predictor

Observational cohorts during the pandemic found that a raised D-dimer on hospital admission was associated with worse outcomes. StatPearls notes that a D-dimer of 1000 ng/mL in a patient with COVID-19 corresponds to severe disease, and that management decisions are based mainly on the clinical picture rather than on changing D-dimer levels.

COVID-Associated Pulmonary Embolism

Early pandemic series reported a high rate of thrombosis in hospitalized COVID-19 patients:

Long COVID and D-Dimer

In some people with Long COVID (post-acute sequelae of SARS-CoV-2 infection), persistent symptoms including fatigue, shortness of breath and brain fog have been linked to ongoing microclot formation. Fibrin amyloid microclots — identified by fluorescence microscopy — have been reported in blood samples from Long COVID patients, and some studies have found modestly raised D-dimer months after acute infection; this remains an area of active research rather than established clinical practice.

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Quantitative vs. Qualitative Assays

The distinction between quantitative and qualitative D-dimer assays determines which clinical algorithms can be applied and how results are interpreted.

Quantitative Assays

Quantitative assays give a numeric result (in FEU or DDU). They:

Qualitative Assays

Qualitative assays give a positive or negative result against a fixed cut-off. The 2019 ESC guideline describes point-of-care D-dimer assays as less sensitive than laboratory-based tests and limits their use to patients with a low pre-test probability (Konstantinides 2019). Because they give no number, they cannot be combined with age-adjusted or YEARS thresholds.

High-Sensitivity vs. Standard Assays

Not all quantitative assays are equivalent. D-dimer assays vary in antibody, capture method, instrument and calibration standard, and the evidence available for one assay cannot simply be extrapolated to another (Linkins 2017). The major outcome studies — the Christopher Study, ADJUST-PE and YEARS — each used their own assays, and ADJUST-PE specified highly sensitive D-dimer measurement (Righini 2014). The 2019 ESC guideline gives quantitative ELISA or ELISA-derived assays a sensitivity of 95% or more (Konstantinides 2019). Whether a given laboratory's assay matches those used in the studies is a property of that assay, documented by its manufacturer and the laboratory.

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Limitations and False Positives

The limitations of D-dimer testing matter as much as its strengths. Where specificity is low, a raised result leads to imaging in many people who have no clot, with the contrast and radiation that imaging brings.

Low Specificity

The fundamental limitation of D-dimer is that it is raised by many conditions other than VTE. Positive likelihood ratios of the assays were in the general range of 1.5 to 2.5 in a 2004 systematic review (Stein 2004). Specificity falls with age: with the conventional 500 µg/L cut-off it was 14.7% in patients over 80 (Schouten 2013). Pregnancy, malignancy and recent surgery are other causes with frequent non-specific elevations (StatPearls). Used without a clinical probability assessment, D-dimer leads to a great deal of extra testing.

Cannot Localize the Clot

A raised D-dimer shows that a clot has formed and is being dissolved somewhere in the body. It cannot show whether the source is a leg vein, pulmonary artery, portal vein, cerebral sinus or coronary artery. Imaging is needed to confirm and locate a clot (MedlinePlus).

Cannot Distinguish Old from New Clot Activity

D-dimer can stay raised for a time after an acute VTE event, even during treatment. This makes it less reliable for diagnosing a recurrence soon after a prior VTE, because a new elevation cannot be told apart from persistent elevation from the earlier event. StatPearls notes that patients with recurrent symptoms in the same leg can go directly to imaging, because of their higher risk and the lower specificity of D-dimer in this group.

Not a Treatment-Monitoring Test for VTE

D-dimer is not a routine marker of anticoagulation response: levels often fall during treatment, but the pace varies and depends on the underlying condition, and MedlinePlus notes that blood thinners can cause a false-negative result. One narrowly validated use is in deciding the length of treatment after a first unprovoked VTE in women (see the HERDOO2 rule below).

Post-Surgical and Post-Trauma Populations

Surgery and trauma reliably raise D-dimer for some time, due to wound healing and fibrinolysis at the injured sites. In these groups a raised result says little about whether a VTE is present.

Analytical Interference

StatPearls lists heterophile antibodies, hemolysis of the sample and lipemia among causes of falsely raised results, and a case report describes heterophile-antibody interference in a D-dimer assay (Lippi 2014). Because assays differ in their antibodies (Linkins 2017), an interference that affects one platform may not affect another.

Subsegmental PE Controversy

Some subsegmental PEs (small clots in peripheral pulmonary arteries) may not raise D-dimer above the usual cut-off, particularly in ambulatory patients. The clinical significance of small subsegmental PEs — increasingly detected on high-resolution CT — is debated, and their management remains controversial.

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Anticoagulation Duration and the HERDOO2 Rule

D-dimer is not used to titrate day-to-day anticoagulation. There is one narrowly validated use in deciding treatment length, and it is easy to over-generalize.

After a first unprovoked venous thromboembolism, the question is how long to continue anticoagulation: stopping carries a risk of recurrence, and continuing carries a risk of bleeding. The HERDOO2 rule (Rodger et al., BMJ 2017, PMID 28314711) was developed to identify women at low risk of recurrence. The acronym enumerates four risk markers, each worth one point:

In the validation study (2,785 participants at 44 centres in seven countries, after 5 to 12 months of initial treatment), women with 0 or 1 of these markers were classified as low risk and stopped anticoagulation. Their recurrence rate was 3.0% per patient-year (95% CI 1.8% to 4.8%), and the authors concluded that such women can safely discontinue anticoagulants after short-term treatment. Among high-risk women and men who stopped, the rate was 8.1% per patient-year. The rule does not apply to men: the study report states that no subgroup of men could be identified as low risk.

Two constraints limit the rule. First, HERDOO2 applies only to unprovoked events; a VTE that followed surgery, immobilization, or another transient trigger is a different question. Second, the D-dimer in this rule is drawn on treatment, was measured with one specific assay in the study, and is interpreted against a 250 µg/L threshold, not the 500 µg/L diagnostic cut-off — the two numbers answer different questions and are not interchangeable.

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Key Research Papers

  1. Righini M et al. (2014). Age-adjusted D-dimer cutoff levels to rule out pulmonary embolism: the ADJUST-PE study. JAMA 311(11):1117–1124. — PubMed PMID: 24643601
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  3. van Belle A et al. (2006). Effectiveness of managing suspected pulmonary embolism using an algorithm combining clinical probability, D-dimer testing, and computed tomography. JAMA 295(2):172–179. — PubMed PMID: 16403929
  4. Tang N et al. (2020). Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost 18(5):1094–1099. — PubMed PMID: 32220112
  5. Klok FA et al. (2020). Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res 191:145–147. — PubMed PMID: 32291094
  6. Schouten HJ et al. (2013). Diagnostic accuracy of conventional or age adjusted D-dimer cut-off values in older patients with suspected venous thromboembolism: systematic review and meta-analysis. BMJ 346:f2492. — Search PubMed
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  13. Kline JA et al. (2004). Clinical criteria to prevent unnecessary diagnostic testing in emergency department patients with suspected pulmonary embolism. J Thromb Haemost 2(8):1247–1255. — PubMed PMID: 15304025 (Derivation and validation of the PERC rule.)
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  16. Tang N et al. (2020). Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost 18(4):844–847. — PubMed PMID: 32073213
  17. Linkins LA, Takach Lapner S (2017). Review of D-dimer testing: good, bad, and ugly. Int J Lab Hematol 39(Suppl 1):98–103. — PubMed PMID: 28447414
  18. Rodger MA et al. (2017). Validating the HERDOO2 rule to guide treatment duration for women with unprovoked venous thrombosis: multinational prospective cohort management study. BMJ 356:j1065. — PubMed PMID: 28314711
  19. Wells PS et al. (2000). Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: increasing the models utility with the SimpliRED D-dimer. Thromb Haemost 83(3):416–420. — PubMed PMID: 10744147
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External Authoritative Resources

  1. MedlinePlus — D-Dimer Test
  2. StatPearls / NCBI Bookshelf — D-Dimer Test
  3. StatPearls / NCBI Bookshelf — Disseminated Intravascular Coagulation
  4. StatPearls / NCBI Bookshelf — Interpretation of Blood Clotting Studies and Values (PT, PTT, aPTT, INR, Anti-Factor Xa, D-Dimer)

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