D-dimer concentration may be determined by ablood test to help diagnosethrombosis.[2] Since its introduction in the 1990s, it has become an important test performed in people with suspected thrombotic disorders, such asvenous thromboembolism.[2][3] While a negative result practically rules out thrombosis, a positive result can indicate thrombosis but does not exclude other potential causes.[3] Its main use, therefore, is to excludethromboembolic disease where the probability is low.[1][2]
D-dimer formation. Shown arefibrinogen, with its oneE domain and twoD domains, acted upon in cascade, by the followingenzymes:Thrombin, to create amesh of fibrin protofibrils;Factor XIII tocrosslink the fibrin mesh (linking protofibril D domains), the scaffold forclot formation;Plasmin, whose action infibrinolysis producesfibrin degradation products (FDPs), the smallest of which areD-dimers, protein fragments with one E and two crosslinked D domains.[1][5]
Coagulation, the formation of a blood clot orthrombus, occurs when the proteins of thecoagulation cascade are activated, either by contact with a damaged blood vessel wall and exposure to collagen in the tissue space (intrinsic pathway) or by activation offactor VII bytissue activating factors (extrinsic pathway). Both pathways lead to the generation ofthrombin, an enzyme that turns the soluble blood proteinfibrinogen into fibrin, which aggregates into protofibrils. Another thrombin-generated enzyme,factor XIII, then crosslinks the fibrin protofibrils at the D fragment site, leading to the formation of an insoluble gel that serves as a scaffold for blood clot formation.[1]
The circulating enzymeplasmin, the main enzyme offibrinolysis, cleaves the fibrin gel in a number of places. The resultant fragments, "high molecular weight polymers", are digested several times more by plasmin to lead to intermediate and then to small polymers (fibrin degradation products or FDPs). The cross-link between two D fragments remains intact, however, and these are exposed on the surface when the fibrin fragments are sufficiently digested. The structure of D-dimer is either a 180 kDa[6] or 195 kDa[7] molecule of two D domains, or a 340 kDa[7] molecule of two D domains and one E domain.[1] Thehalf-life of D-dimer in blood is approximately 6 to 8 hours.[8]
D-dimers are not normally present in human blood plasma, except when the coagulation system has been activated, for instance, because of the presence ofthrombosis ordisseminated intravascular coagulation. The D-dimer assay depends on the binding of amonoclonal antibody to a particularepitope on the D-dimer fragment. Several detection kits are commercially available; all of them rely on a different monoclonal antibody against D-dimer. For some of these, the area of the D-dimer to which the antibody binds is known. The binding of the antibody is then measured quantitatively by one of various laboratory methods.[1]
For DVT and PE, there are possible various scoring systems that are used to determine thea priori clinical probability of these diseases; the best-known is theWells score.[5]
For a high score, or pretest probability, a D-dimer will make little difference andanticoagulant therapy will be initiated regardless of test results, and additional testing for DVT or pulmonary embolism may be performed.
For a moderate or low score, or pretest probability:[citation needed]
A negative D-dimer test will virtually rule out thromboembolism:[5] the degree to which the D-dimer reduces the probability of thrombotic disease is dependent on the test properties of the specific test used in the clinical setting: most available D-dimer tests with a negative result will reduce the probability of thromboembolic disease to less than 1% if the pretest probability is less than 15-20%. Chest computed tomography (CT angiography) should not be used to evaluatepulmonary embolism for persons with negative results of a D-dimer assay.[9] A low pretest probability is also valuable in ruling out PE.[10]
If the D-dimer reads high, then further testing (ultrasound of the leg veins or lungscintigraphy orCT scanning) is required to confirm the presence ofthrombus.Anticoagulant therapy may be started at this point or withheld until further tests confirm the diagnosis, depending on the clinical situation.
In some hospitals, they are measured by laboratories after a form is completed showing the probability score and only if the probability score is low or intermediate. This reduces the need for unnecessary tests in those who are high-probability.[11] Performing the D-dimer test first can avoid a significant proportion of imaging tests and is less invasive. Since the D-dimer can exclude the need for imaging,specialtyprofessional organizations recommend that physicians use D-dimer testing as an initial diagnostic.[12][13][14][15]
D-dimer increases with age. It has therefore been suggested to use a cutoff equal to patient's age in years × 10 μg/L (or x 0.056 nmol/L) for patients aged over 50 years for the suspicion of venous thromboembolism (VTE), as it decreases thefalse positive rate without substantially increasing thefalse negative rate.[17][18]
An alternative measurement of D-dimer is in fibrinogen equivalent units (FEU). The molecular weight of the fibrinogen molecule is about twice the size of the D-dimer molecule, and therefore 1.0 mcg/mL FEU is equivalent to 0.5 mcg/mL of d-dimer.[19]
Various kits have a 93 to 95%sensitivity (true positive rate). For hospitalized patients, one study found thespecificity to be about 50% (related to false positive rate) in the diagnosis of thrombotic disease.[20]
False negative readings can occur if the sample is taken either too early after thrombus formation or if testing is delayed for several days. Additionally, the presence of anti-coagulation can render the test negative because it prevents thrombus extension. The anti-coagulation medicationsdabigatran andrivaroxaban decrease D-dimer levels but do not interfere with the D-dimer assay.[22]
False values may be obtained if the specimen collection tube is not sufficiently filled (false low value if underfilled and false high value if overfilled). This is due to the dilutional effect of the anticoagulant (the blood must be collected in a 9:1 blood to anticoagulant ratio).
Likelihood ratios are derived from sensitivity and specificity to adjust pretest probability.
In interpretation of the D-dimer, for patients over age 50, a value of (patient's age) × 10 μg/L may be abnormal.[23][24]
D-dimer was originally identified, described and named in the 1970s (Fibrinolysis, Dr P J Gaffney) and found its diagnostic application in the 1990s.[1][5]
^Lippi G, Cervellin G, Franchini M, Favaloro EJ (November 2010). "Biochemical markers for the diagnosis of venous thromboembolism: the past, present and future".J Thromb Thrombolysis.30 (4):459–71.doi:10.1007/s11239-010-0460-x.PMID20213258.S2CID23806848.
^van Es J, Mos I, Douma R, Erkens P, Durian M, Nizet T, et al. (January 2012). "The combination of four different clinical decision rules and an age-adjusted D-dimer cut-off increases the number of patients in whom acute pulmonary embolism can safely be excluded".Thrombosis and Haemostasis.107 (1):167–71.doi:10.1160/TH11-08-0587.hdl:1765/74645.PMID22072293.S2CID4832019.
