• D-dimer is an antigen that is produced from plasmin-mediated degradation of fibrin-rich thrombi.
• D-dimer assays are a useful tool for the:
  • Exclusion of deep venous thrombosis (DVT) and pulmonary embolism (PE)
  • Diagnosis of disseminated intravascular coagulation (DIC) (1)
• The D-dimer measurement is an adjunct test and should never be used in isolation for diagnosis or exclusion (2).

• In the final steps of the coagulation pathway, thrombin cleaves fibrinogen to produce fibrin monomers. These fibrin monomers polymerize with one another forming protofibrils, thus allowing factor XIII to bind.
• Thrombin also serves to activate factor XIII bound to fibrin polymers (forming factor XIIIa).
• Factor XIIIa catalyzes the formation of covalent bonds between the D-domains (the segment of the fibrin protein containing the D-dimer antigen sequence) in adjacent protofibrils of polymerized fibrin.
• During fibrinolysis, activated plasmin degrades the cross-linked fibrin, which releases fibrin degradation products and exposes the D-dimer antigen, which is typically not present in the body except when the coagulation system has been activated.
• The D-dimer assay
  • The required sample is venous blood in a light blue tube (the same tube used for PT/PTT). The tube must be completely filled.
  • Quantitative values are performed in the laboratory with plasma and have a sensitivity of 95% and specificity of 50%. Quantitative tests rely on either enzyme-linked immunosorbent assays (ELISA) or enzyme-linked fluorescent assays (ELFA) to detect the amount of D-dimer present.
  • Qualitative values can be obtained at the bedside with whole blood and have lower sensitivities (85%) but slightly higher specificities (70%) than quantitative values. Whole blood is mixed with a reagent (a D-dimer monoclonal antibody that is joined to a monoclonal antibody capable of binding to the surface of a red blood cell). When D-dimer is present above a threshold value, agglutination occurs (the conjoined antibodies cause D-dimer and RBCs to clump together). This technique has the advantage of yielding results quickly without advanced laboratory equipment, but it is unable to detect low levels of D-dimer (3).
  • Increased values suggest increased thrombus formation or breakdown in the body.

• DVTs can embolize and travel through the right heart and into the pulmonary vasculature, causing a mechanical obstruction to blood flow (pulmonary embolism) and a secondary immune-inflammatory response. Risk factors include:
  • Previous history
  • Hereditary causes:
    • Antithrombin III deficiency
    • Protein C and S deficiencies
    • Factor V Leiden
    • Prothrombin gene mutations
  • Acquired causes:
    • Reduced mobility
    • Cancer
    • Pregnancy/postpartum
    • Nephrotic syndrome
    • Trauma
    • Spinal cord injury
  • Medications:
    • Hormone replacement therapy
    • Oral contraceptives
    • Chemotherapy
    • Antipsychotics
  • Surgical factors:
    • Major surgery
    • Hip or leg fracture
    • Hip or knee replacement
    • General anesthesia compared to epidural/spinal anesthesia (4)
• Dead space: Pulmonary emboli result in an increase in alveolar dead space with an associated right-to-left shunt and V/Q mismatch. Blood shunted away from the blocked pulmonary arteries can cause edema, loss of surfactant, and alveolar hemorrhage in the overly perfused lung segments (5). Acute blockage can cause right heart strain or acute cor pulmonale.
• DIC causes include infection, malignancy, obstetric disorders, shock, liver disease, extracorporeal circulation, intravascular hemolysis; it is the end result of several disease processes and has a high mortality rate. DIC is characterized by continuous thrombin generation and fibrin formation in the microvasculature which ultimately deplete coagulation factors and their inhibitors, leading to bleeding and/or thrombotic state. The subsequent breakdown of formed fibrin leads to the elevated D-dimer seen in this condition.

• Pulmonary embolism
  • Perioperative PE has an incidence of 1.6% in patients undergoing general surgery. The incidence in patients undergoing orthopedic procedures, especially hip procedures, has been reported as high as 30%.
  • ELISA D-dimer assays have a sensitivity of 95% and specificity of 50% and are therefore helpful in ruling out perioperative PE in patients with low clinical suspicion. In patients with high clinical suspicion, ordering a D-dimer does not change management and should not delay treatment.
  • Values >500 ng/mL are considered positive.
  • False positives may be seen in other conditions unrelated to PE, including infection, cancer, trauma, cardiac disease, rheumatoid arthritis, hyperbilirubinemia, hepatic disease, in the elderly, the surgical procedure itself, hemolysis, or other inflammatory states.
• Disseminated intravascular coagulation
  • In pregnant women with microangiopathic hemolytic anemia, elevated liver enzymes, and low platelets (HELLP) syndrome, 15–38% can progress to DIC.
  • DIC can be diagnosed intraoperatively with thrombocytopenia, elevated PT, aPTT, and D-dimer (6).
  • D-dimer levels >200 ng/mL are considered elevated. Levels correlate with the severity of the disease and can be monitored to assess the effectiveness of therapy.

• Pulmonary Embolism

Mark R. Bombulie , BS