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DDimer for DVT

Fibrinogen consists of a six peptide molecule with two terminal D domains and a central E domain. Thrombin cleaves fibrinopeptides A and B from the E domain, producing soluble fibrin monomer. These monomers then noncovalently assemble end to end and side to side to form polymers. Factor XIIIa then covalently crosslinks these fibrin polymers to form an insoluble clot. Plasmin degrades insoluble crosslinked fibrin, releasing fibrin degradation proucts (FDP). Among these FDPs is D-dimer, which contains a neo-epitope formed by the crosslinking of adjacent D domains by factor XIIIa. Thus, the presence of D-Dimer in blood corresponds to the in vivo formation and degradation of a fibrin clot.

ddimer for dic

Since 2 to 3% of plasma fibrinogen is physiologically converted to crosslinked fibrin and then degraded, a small quantity of D-Dimer is normally present in the plasma of healthy individuals. D-Dimer has a plasma half-life of approximately 8 hours and clearance primarily occurs by the kidneys and reticuloendothelial system. Continued fibrinolysis that occurs in DVT and PE causes the D-Dimer to remain elevated for about 7 days after the event.

The production of specific antibodies to the unique neo-epitope of D-Dimer permitted the development of immunoassays to quantitate D-Dimer. Today, D-Dimer can be measured in approximately 30 minutes on coagulation or chemistry analyzers using latex agglutination turbidimetric detection. Reportable units vary by manufacturer. Assays that use purified D-dimer as the calibrator report results in D-Dimer units (DDU), while assays that use plasmin proteolysis products of fibrin clots report their results in fibrinogen-equivalent units (FEU). The mass of one unit of FEU is approximately twice the mass of one unit of DDU. Therefore, DDU can be converted to FEU by multiplying D-Dimer concentration by 2. For example, 0.5 ug/mL DDU is equivalent to 1 ug/mL FEU. Currently, there is no established reference method, primary standard or universal calibrator for D-Dimer assays. Consequently, there is no universal threshold for a positive result and results can vary widely from laboratory to laboratory. Each laboratory must establish its own threshold.

D-Dimer results are most commonly used in the evaluation and exclusion of deep vein thrombosis (DVT) and pulmonary embolism (PE). Many studies have indicated that the combination of pretest clinical probability assessment and D-Dimer testing is a safe and effective model for excluding DVT and reducing the number of more expensive imaging studies. In patients that have a low pretest probability score and a negative D-Dimer, a diagnosis of DVT may be excluded without imaging studies. In addition, the use of D-Dimer testing has also been shown to reduce the need for repeated ultrasound testing in patients whose score indicates that DVT is likely. This approach leads to reduced costs per patient and shorter time to diagnostic decision. D-Dimer testing alone should not be used to exclude DVT in patients with high pretest probability scores of. In these cases, imaging studies should be performed.

In hemodynamically stable patients, the diagnosis of PE should follow a sequential diagnostic workup consisting of clinical pretest probability assessment, D-Dimer testing and, if necessary, helical computed tomography pulmonary angiography. D-Dimer is most helpful in assessing patients with a low or intermediate clinical probability of PE, where a normal result avoids unnecessary further investigation. The use of D-Dimer is of limited value in patients with a high clinical probability of PE because they need to undergo imaging regardless of the D-Dimer result.

D-Dimer results should be interpreted cautiously because:

  • D-Dimer is sensitive for detecting proximal, but not distal DVT’s. Distal DVT may have such a small clot burden, that D-Dimer levels remain below the threshold of detection. A negative result does exclude the possibility of a distal DVT.
  • D-Dimer is generally not useful in workup of upper extremity DVT since other risk factors such as central venous catheters and pacemakers cause false positive D-dimer results.
  • Most studies have included only patients with recent (<7 days) symptoms of venous thromboembolism. D-Dimer may be less effective in excluding DVT or PE of longer duration.
  • False negative results may occur. Clinical pretest probability of DVT must be taken into account when evaluating test results.
  • All D-dimer assays have relatively low specificity for diagnosis of venous thromboembolism. Causes of false positive results include infection, malignancy, recent surgery, trauma, critical illness, disseminated intravascular coagulation and pregnancy. Thus while a negative result is useful in ruling out venous thromboembolism, a positive result is not useful in confirming the diagnosis.

D-Dimer is useful in excluding the diagnosis of DVT and PE because a highly sensitive quantitative assay has a negative predictive value (NPV) of nearly 100%. The trade-off for this high sensitivity is relatively low specificity. A positive result is not useful in confirming the diagnosis of DVT or PE. Physicians need to remember that D-Dimer is often elevated in many disorders associated with activation of the coagulation cascade. Common examples include: myocardial infarction, congestive heart failure, stroke, atrial fibrillation, thrombolytic therapy, venous malformations, disseminated intravascular coagulation (DIC), preeclampsia and eclampsia, acute and chronic renal failure, nephrotic syndrome, sickle cell disease, advanced liver disease, surgery, and malignancy. Because of this lack of specificity, D-Dimer testing should not be ordered on most hospitalized inpatients when DVT or PE is suspected.

Some studies suggest that D-dimer levels measured after discontinuation of oral anticoagulant therapy (OAT) may be useful for predicting the likelihood of recurrent VTE (Thromb Haemost 2002; 87:7-12 and Circulation 2003; 108:313-318). One management strategy is to stop anticoagulation in patients with unprovoked VTE after 3 months and measure D-dimer 1 month after cessation of anticoagulation. An elevated D-dimer level is an indication to restart anticoagulation, while a normal result along with the absence of other risk factors for recurrence provides support for discontinuing anticoagulation (Marshall AL, et al. JCOM2015;22:222-240). D-dimer cutoffs of 0.25 or 0.50 ug/mL have been used for this purpose.

D-dimer levels increase with age due to higher fibrinogen concentration, slower urinary excretion of D-Dimer, more frequent fibrin generation due to underlying occult disease and inflammatory disorders. The majority of patients over 70 years of age have elevated D-Dimer levels. D-Dimer should probably not be used in the elderly population to rule out DVT or PE. It should also be remembered that D-Dimer levels are always elevated in the second and third trimesters of normal pregnancies. Routine venipuncture and peripheral intravenous catheters usually do not produce large enough of clots to cause elevation of D-Dimer.

One study demonstrated that the use of an age adjusted d-dimer cutoff for elderly patients ruled out pulmonary embolism in more patients than a fixed cutoff of 500 ug/L without increasing the risk of subsequent venous thromboembolism. Age adjusted cutoff was calculated as the patient’s age multiplied by 10 in patients who were at least 50 years old, expressed as ug/L (Righini M et al. JAMA 2014;311:1117-24).

Reference range for the STA Liatest (Diagnostica Stago) is 0 to 0.4 ug/mL or 0 to 400 ug/L.

Specimen requirement is one 5mL citrate (blue top) tube.

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