Introduction
D-dimer is a byproduct of the blood clotting and breakdown process, serving as a marker of ongoing coagulation and fibrinolysis.[1][2][3] Circulating fibrinogen consists of 3 paired polypeptide chains—Aα, Bβ, and γ.[4] At the site of vascular injury, thrombin cleaves fibrinopeptides from fibrinogen Aα and Bβ that polymerize into fibrin monomers. Factor XIII, activated by thrombin, then binds the interspersed γ units to form a fibrin net, stabilizing the clot.
Under normal physiological conditions, the balance between clot formation and destruction prevents excess bleeding and ensures proper blood flow after blood vessel healing. When a clot is no longer needed, tissue-type plasminogen activator and urokinase plasminogen activator activate plasminogen, a component of the fibrinolytic system. This activation leads to the formation of plasmin, an enzyme that dissolves the clot through lytic action. Clot breakdown produces fibrin degradation products, one of which is D-dimer. Specifically, if 2 D-domains of the original fibrinopeptides link the polymers, D-dimer forms upon degradation. A combination of proteases and the mononuclear phagocytic system, primarily in the liver, clears most fibrin degradation products. However, the kidneys and reticuloendothelial system primarily clear D-dimer, which has a plasma half-life of 6 to 8 hours.[5]
The D-dimer test has high sensitivity but low specificity, resulting in a high negative predictive value, which makes it helpful for excluding diagnoses such as deep vein thrombosis, pulmonary embolism, and disseminated intravascular coagulation in the appropriate clinical setting. Clinicians must take into account that pregnancy, trauma, malignancy, surgery, and liver disease can all cause elevations of the D-dimer.
Interfering Factors
The D-dimer alone is a dubious marker of clotting in the setting of inflammation, ischemia, infarction, and infection.[4][15][16] As an acute-phase reactant, falsely elevated values can occur in the aforementioned clinical situations, making consideration of the entire clinical scenario essential. Measuring C-reactive protein or an erythrocyte sedimentation rate, both indicators of inflammatory activity, helps better delineate these clinical scenarios. If elevated, clinicians may question the utility of the elevated D-dimer. The following is a list of other potential causes of elevated D-dimer levels:
Pregnancy, including the postpartum period
Malignancy
Cigarette smoking
Trauma
Infections such as sepsis and HIV
Older age
Immobilization
Short bursts of strenuous exercise
Oral contraceptive pills
Cirrhosis
Thrombophilias
Hemolysis of the blood sample
Diabetes
Lipemia
Elevated triglyceride levels
HELLP syndrome (Hemolysis, elevated liver enzymes, and low platelets)
Black patients
Congestive heart failure
Autoimmune diseases
Recent surgery
Patients with factor XIII deficiency have a continually low D-dimer level.
Currently, there is no universally accepted international standard or calibrator for the D-dimer test. As a result, different laboratories may use different reporting units, thresholds, and testing methods, which can lead to inconsistent results. Currently, research is underway to achieve harmonization, aligning the D-dimer tests from different laboratories to standardize and enhance the comparability of results.[18] Present testing protocols use enzyme-linked immunosorbent assay, various immunoturbidimetric assays, and VIDAS (bioMérieux) D-dimer exclusion testing.[19]
Emerging research suggests using age-adjusted cutoff values for D-dimer testing, as the D-dimer naturally increases with age. This approach is supported by both American and European medical colleges, although it is not approved by the United States Food and Drug Administration.[20][21][22][23] Using age-adjusted values in older patients can improve test specificity. For patients older than 50, clinicians can calculate the age-adjusted cutoff using the following formula:
Age in years × 10 ng/mL [24]
Clinicians must interpret the results of a D-dimer test while considering the timing of the test. Blood taken after administering an anticoagulant may yield a negative outcome. Additionally, results may be affected if sampling is done too early, such as during the clot formation process.
Clinical Significance
D-Dimer for Pulmonary Embolism
A pulmonary embolism is a blood clot that lodges in the pulmonary vasculature, obstructing blood flow beyond the site of the clot. The severity of symptoms varies depending on the size and location of the clot. Although small pulmonary embolism may cause minimal symptoms, larger emboli can obstruct major pulmonary arteries and lead to life-threatening complications. A saddle embolus, which straddles the bifurcation of the main pulmonary arteries, poses a high risk of cardiopulmonary arrest and death. In patients presenting with symptoms such as chest pain, dyspnea, or hypoxia, a D-dimer test can help guide the differential diagnosis and determine the need for further evaluation.
Clinicians must balance the urgency of diagnosing a pulmonary embolism to prevent morbidity and mortality against the risk of unnecessary testing. Clinical decision tools, such as the Wells criteria and the Geneva or revised Geneva score, assist in stratifying patients into low-, moderate-, or high-risk categories (see Tables. Wells Score for Pulmonary Embolism and Revised Geneva Score for Pulmonary Embolism).
The Wells score assesses risk based on factors such as signs of deep vein thrombosis, clinical suspicion of pulmonary embolism, tachycardia, recent immobilization or surgery, prior pulmonary embolism or deep vein thrombosis, hemoptysis, and active cancer. The Geneva score considers patients older than 65, those with a history of previous pulmonary embolism or deep vein thrombosis, recent surgery or lower limb fracture, active malignancy, hemoptysis, subjective unilateral leg pain, unilateral leg tenderness, and an elevated heart rate. These validated tools help guide diagnostic testing and management decisions in patients with suspected pulmonary embolism.
Each scoring system assigns points to the specified variables, and the total categorizes the patient's pretest probability of a pulmonary embolism. A score of 0 to 3 in the Geneva scoring system corresponds to a low pretest probability, 4 to 10 an intermediate probability, and patients who score 11 or higher have a high pretest probability. Using the Wells criteria, a score of less than 2 corresponds to a low pretest probability, 2 to 6 is considered intermediate, and a score of 6 or higher is considered a high pretest probability.
For nonhospitalized patients with a low pretest probability, the Pulmonary Embolism Rule-out Criteria (PERC) can help determine whether further testing is necessary. If the patient meets all 8 PERC criteria, no additional workup is needed. These criteria include:
Age younger than 50
Heart rate below 100
Oxygen saturation above 95%
No previous history of pulmonary embolism or deep vein thrombosis
No estrogen use
No unilateral leg swelling
No surgery or trauma requiring hospitalization within the preceding 4 weeks
No hemoptysis
Nonhospitalized patients who do not meet all 8 PERC criteria, hospitalized patients, and all other patients categorized as having a low or intermediate pretest probability should undergo a D-dimer test. A D-dimer level of less than 500 ng/mL effectively excludes pulmonary embolism. A D-dimer level of 500 ng/mL or greater warrants further imaging with computed tomography pulmonary angiography (CTPA) or a ventilation-perfusion (V/Q) scan for patients with contraindications to contrast. Previously, a V/Q scan was the test of choice for pregnant patients with a suspected pulmonary embolism. However, CTPA is now an acceptable alternative, given its wider availability, lower radiation dose compared to the past, ability to provide an alternative diagnosis in up to 13% of patients, and better interobserver agreement than nuclear scans.[25][26][27] In patients with a high pretest probability, including those with a high clinical suspicion, D-dimer testing is not recommended; instead, clinicians should proceed directly to diagnostic imaging.
Table 1. Wells Score for Pulmonary Embolism.
*Use clinical judgment (or the PERC) to determine whether ordering a D-dimer is necessary.
Table 2. Revised Geneva Score for Pulmonary Embolism.
D-Dimer for Deep Vein Thrombosis
A deep vein thrombosis is a blood clot located in the deep venous system in the arms or legs. Symptoms of deep vein thrombosis include erythema, pain, swelling, and increased warmth of the affected extremity. The Wells score is a risk-stratification tool for deep vein thrombosis. This scoring system considers recent malignancy; recent immobilization, including recent surgery; asymmetric leg swelling; the presence of collateral veins; tenderness along the location of suspected veins; a history of deep vein thrombosis; and high clinical suspicion for deep vein thrombosis, including subtracting 2 points if an alternative diagnosis is as likely or more likely than deep vein thrombosis. A Wells score of 0 or less indicates low probability, 1 to 2 is moderate probability, and 3 or more indicates high probability. The modified Wells score adds 1 additional point for a previously documented deep vein thrombosis. Using the modified Wells score, a score of 1 or less indicates deep vein thrombosis is unlikely, and a score of 2 or more indicates deep vein thrombosis is likely.
Similar to the evaluation of pulmonary embolism, a D-dimer test is not diagnostic; rather, it serves as a tool to guide further investigation and diagnosis. Patients with a first-suspected deep vein thrombosis and low or moderate pretest probability, 2 or less on the Wells score or less than 2 on the modified Wells score, should undergo D-dimer testing. As with the evaluation of pulmonary embolism, some experts forgo the D-dimer in patients with an intermediate probability and proceed directly to imaging. A high-sensitivity D-dimer value of less than 500 ng/mL in patients with a low or moderate pretest probability successfully rules out deep vein thrombosis, and no further evaluation is necessary. Patients with a positive D-dimer should undergo a whole-leg ultrasound or proximal compression ultrasound. A D-dimer cannot reliably exclude a deep vein thrombosis in patients with a high pretest probability. Therefore, patients with a high pretest probability should undergo ultrasound immediately.
Patients who present with recurrent symptoms in the contralateral leg can undergo the diagnostic process as above. Patients who present with recurrent symptoms in the ipsilateral leg can proceed directly to imaging, given the increased risk of deep vein thrombosis and the lower specificity of the D-dimer test in this patient demographic. However, using the previously discussed risk stratification process is also appropriate.[28]
D-Dimer for Disseminated Intravascular Coagulation
Under normal physiological conditions, hemostasis ensures the controlled formation of a clot, followed by its timely breakdown. Both coagulation and fibrinolysis become excessively activated in disseminated intravascular coagulation, resulting in ongoing clot formation and subsequent clot breakdown. Common triggers for disseminated intravascular coagulation include sepsis, trauma, malignancy, obstetric complications, and hemolysis.[29][30]
Acute disseminated intravascular coagulation can lead to severe bleeding due to the rapid consumption of clotting factors in response to widespread exposure of blood to tissue factors and subsequent thrombin generation. Elevated fibrin degradation products further impair hemostasis by disrupting fibrin polymerization and inhibiting platelet binding to fibrinogen, undermining stable clot formation and platelet aggregation.
Chronic disseminated intravascular coagulation develops when the bloodstream is exposed to lower levels of tissue factors either continuously or intermittently over time. Patients with chronic disseminated intravascular coagulation also have excess consumption of coagulation factors and platelets. However, their production typically keeps pace with demand. The liver also effectively clears fibrin degradation products. As a result, patients with chronic disseminated intravascular coagulation are more prone to thrombotic events rather than bleeding complications.
Clinicians can expect elevated D-dimer levels in both acute and chronic disseminated intravascular coagulation. Other laboratory findings may include low or normal fibrinogen levels, thrombocytopenia, and either normal or prolonged prothrombin time, international normalized ratio, and partial thromboplastin time (aPTT). These values are also helpful in monitoring treatment response. In chronic disseminated intravascular coagulation, clotting times may remain within normal limits, and thrombocytopenia may be mild or even absent.
Disseminated intravascular coagulation is both a clinical and laboratory diagnosis. Thrombocytopenia, consumption of coagulation factors, and fibrinolysis confirmed by a prolonged PT, aPTT, and elevated D-dimer confirm the diagnosis of acute disseminated intravascular coagulation. The presence of bleeding and thrombosis supports the diagnosis but is not required. Clinicians consider the diagnosis of chronic disseminated intravascular coagulation in patients with evidence of fibrinolysis, such as an elevated D-dimer, particularly in the context of underlying conditions, such as advanced malignancy.
D-Dimer and Stroke
D-dimer levels typically rise after a stroke and may be helpful in patients with cryptogenic stroke to evaluate for cancer-related hypercoagulability or hypercoagulability associated with SARS-CoV-2 infection. D-dimer levels in patients with cryptogenic stroke due to cancer-related hypercoagulability tend to be higher than those in patients with cryptogenic stroke without cancer (10,070 ng/mL versus 500 to 700 ng/mL, respectively), and elevated D-dimer levels in patients with cryptogenic stroke should prompt cancer screening for occult malignancy. Likewise, D-dimer levels over 10,000 ng/mL are associated with cryptogenic stroke associated with COVID-19.[18][31][32][33][34] Elevated D-dimer levels also correspond to incomplete recanalization, stroke progression, and recurrence.[9]
In addition to a complete blood count, chemistry panel, PT, and aPTT, a D-dimer test can also help suggest the presence of a central venous thrombosis. However, a negative D-dimer does not exclude the diagnosis.[35]
D-Dimer and Infection
D-dimer levels are also generally elevated in patients with COVID-19. Significantly high levels are associated with a poor prognosis and can assist clinicians in deciding the appropriate level of care and the potential use of investigational therapies. However, management decisions are primarily based on the patient's clinical presentation rather than on changing D-dimer levels.
D-Dimer and Snake Bites
An additional potential use of the D-dimer test is in assessing venom-induced consumption coagulopathy after a snake bite. Patients who experience a bite from a venomous snake and experience collapse, seizures, weakness, paralysis, respiratory failure, shock, coagulopathy, or acute kidney injury should receive antivenom. In many cases, an increase in D-dimer is the first indicator of coagulopathy.
