Disseminated Intravascular Coagulation and Advances in D-Dimer Testing: Progress in Harmonization of Clinical Assays and Innovative Detection Methods.

D-dimer for Suspected Pulmonary Embolism: Whom Should We Test?

The Clinical Utility of D-dimer Testing in Diagnosing Venous Thromboembolic Disease

Harmonisation of D-dimer — A call for action

D-dimer testing after anticoagulant discontinuation to predict recurrent venous thromboembolism

To the Editor: Venous thromboembolism (VTE), including both deep venous thrombosis (DVT) and pulmonary embolism (PE), is an important cause of morbidity and mortality in children. Although there is heightened awareness of this disease and its risk factors in children, there has been minimal evaluation of diagnostic tests (clinical prediction models, imaging modalities, and D-dimer assays) in children compared to adults.(1) ELISA based D-dimer assays have excellent sensitivity for the diagnosis of VTE in adults and this may permit the exclusion of VTE.(2) However, the utility of D-dimer assays for VTE in children has not been evaluated. We performed a retrospective chart review of patients ≤21 years of age at Johns Hopkins Hospital with suspected VTE, imaging studies, and quantitative D-dimer. We used a discharge and billing database to identify patients and extracted information on potential risk factors, clinical findings, laboratory and imaging studies, and treatment. D-dimer was measured with an immunoturbidimetric assay on a Blood Coagulation System (BCS) analyzer (Advanced D-dimer; Dade-Behring) per the manufacturer's specifications. We identified 33 patients (20 male and 13 female) with diagnostic imaging studies and measurement of D-dimer within 72 hours. Twenty-six had acute VTE (15 DVT, 3 PE and 8 both], 6 with unchanged chronic VTE (5 DVT and 1 PE), and 1 without VTE (suspected PE). Most patients had multiple acquired risk factors for VTE with central venous catheters (54%), infections (40%), and immobility (42%) most frequent. D-dimer was significantly elevated in children with VTE (median 5.0, IQR 2.05-16.44) compared to children with negative evaluations for acute VTE (median 1.58, IQR 1.46-3.11, P 40 years old, 0.43-2.24 mg/L) and children (2-12 years old, 0.4-2.27 mg/L). Figure 1 D-dimer (log-scale) by diagnosis and the normal range for children 2 – 12 years of age We found that the D-dimer test was sensitive but only moderately specific for the diagnosis of VTE in children, and that the performance varied with the chosen cut-off. This assay is approved for the diagnosis of VTE in adults; the cut-off is 1.6 mg/L as the normal range is significantly higher than many D-dimer assays.(3) A D-dimer 1.75 mg/L was 92% sensitive (95% CI 75 – 99) and 57% specific (95% CI 18 – 90). Raising the threshold of the D-dimer to >2 mg/dl decreased the sensitivity to 77% (95% CI 56 – 91) while increasing the specificity to 71% (95% CI 29 – 96) for the diagnosis of VTE (Table 1). In a previous study of hospitalized adults from our institution,(4) the sensitivity of this test at a threshold of 2 mg/L was comparable (70% in adults versus 77% in children), however the specificity was considerably lower (42% in adults versus 71% in children). We calculated the area under the ROC [0.86 (95% CI 0.72-1.0)] to assess the performance of the D-dimer test to diagnose VTE. The greater the area under the curve, the better the performance of the diagnostic test with an area of 0.5 corresponding to a test that performs no better than flipping a coin. Table 1 Diagnostic Test Characteristics by Cut-Off (95% CI) While the utility of the D-dimer testing has been studied extensively in adults, its performance for the diagnosis of VTE in pediatric patients has not been evaluated. A report of children with PE from a single institution described elevated levels of D-dimer in 6 of 10, but the normal range was not described.(5) In children with acute thrombotic events, elevated D-dimer was found to be predictive of poor outcome (persistent thrombosis, VTE recurrence, or post-thrombotic syndrome); however, measurement of D-dimer was semi-quantitative and its predictive value for the diagnosis of VTE was not reported.(6) In both adults and children, an elevated D-dimer after treatment of VTE appears to be a risk factor for recurrent thrombus.(6-8) To our knowledge, this is the first report that describes the sensitivity of D-dimer measurements for the diagnosis of VTE in children. The incidence of VTE is significantly lower in children than adults, but perhaps even more challenging to diagnose. Compression ultrasonography of the lower extremities (sensitivity 91% and specificity 99%)(9) and MR venography (sensitivity 92% and specificity 95%)(10) have only been validated against the gold standard (contrast venography) in adults. D-dimer assays, in particular automated assays with rapid turn around times like the immunoturbidimetric assay used in this study, offer several advantages over other diagnostic modalities for VTE. They are relatively inexpensive and readily available in the outpatient and inpatient setting. A normal level in adults may potentially exclude VTE and avoid the need for expensive and time consuming imaging studies. Further prospective trials are necessary to validate our findings in children, as well as to address the utility of the D-dimer in selected subsets of pediatric patients.

Patients with suspected deep vein thrombosis (DVT) or pulmonary embolism (PE) are frequently admitted to an Emergency Department (ED) for initial evaluation. However, management of patients with suspicion of acute venous thromboembolism (VTE) in this clinical setting can be difficult; in fact symptoms and signs of DVT are non-specific and can be found in a broad spectrum of non-thrombotic disorders. An accurate and timely objective diagnosis is necessary for immediate and correct identification of patients with acute VTE, while avoiding the bleeding risk associated with unnecessary anticoagulant therapy in patients where DVT or PE have been ruled out. The diagnostic approach to patients with suspected VTE includes clinical evaluation, diagnostic imaging and D-dimer testing [1, 2]. In a recent issue of Internal and Emergency Medicine, Siragusa [3] exhaustively discussed the currently used assays, clinical indications and limitations of D-dimer testing for managing acute VTE in emergency medicine. Measurement of D-dimer values, a degradation product of cross-linked fibrin, is a simple laboratory test, and has been extensively studied in numerous prospective cohort studies in cases of suspected DVT or PE, showing a high negative predictive value. The author [3] shows that D-dimer testing has sufficient diagnostic accuracy for ruling out acute VTE if used in combination with standardised clinical judgement. The review is important for at least three reasons. First, many physiological and pathological conditions can increase plasma D-dimer levels (pregnancy, age, trauma, cancer, inflammation and several other clinical conditions); on the other hand D-dimer levels may fail to increase in patients with acute VTE for multiple reasons (impaired fibrinolytic activity, use of heparin or oral anticoagulants, onset of symptoms more than two weeks before blood sampling). For these reasons, D-dimer testing has a high sensitivity but a low specificity in the diagnosis of acute VTE; in clinical practice it may be associated with frequent “false positive” results, but also more rarely with “false negative” findings. However, its use should always be associated with a careful clinical assessment to rule out the presence of acute VTE only in symptomatic patients. Overuse or misuse of the D-dimer screen for VTE may have negative consequences, in terms of a burden both for patients and for healthcare costs; in fact, despite clinical guidelines, inappropriate and unnecessary measurement of D-dimer is a significant clinical problem [4]. Second, commercially available assays are very differ

D-dimer, the final degradation product of cross-linked fibrin, is typically elevated in patients with acute venous thromboembolism. With its high sensitivity and negative predictive value, D-dimer testing may have a role for ruling-out the diagnosis in patients with suspected deep vein thrombosis or pulmonary embolism. For this purpose, D-dimer testing has been integrated in sequential diagnostic strategies including those using pretest clinical probability assessment and imaging techniques. A large variety of assays are now available for D-dimer measurement, with different sensitivities and specificities for the diagnosis of venous thromboembolism. Attempts to standardize the various D-dimer assays have been made but without any definitive answers as yet. The diagnostic yield of D-dimer testing is affected not only by the choice of the appropriate assay but also by patient characteristics. As a consequence, the clinical usefulness of D-dimer testing for the exclusion of suspected venous thromboembolism should be carefully evaluated in special clinical settings.

Letter to the Editor on “Combined Measurement of D-Dimer and C-Reactive Protein Levels: Highly Accurate for Diagnosing Chronic Periprosthetic Joint Infection”

PURPOSE: To validate the Canadian clinical probability tool and utility of bedside rapid D-dimer testing using SimpliRed® among patients with suspected acute deep-vein thrombosis (DVT) in an emergency room setting. METHODS: Consecutive patients with clinically suspected DVT in a leg and no past history of symptomatic DVT were evaluated in the UC Davis emergency room by emergency room staff using the clinical probability tool developed by Wells and colleagues [Lancet,1997; 350:1795], which was provided on a one page form. After completing the form, each patient underwent venous ultrasound (US) imaging, whole blood D-dimer testing using SimpliRed®, and D-dimer measurement using a sensitive ELISA technique. All patients were followed for 3 months. Diagnosis of thromboembolism required objective confirmation of DVT using US or venography, or confirmation of pulmonary embolism using a high-probability lung scan or pulmonary arteriography. RESULTS: Of 102 patients who were evaluated, 17 (17%) were diagnosed as having DVT initially; none of the 85 in whom DVT was excluded developed thromboembolism within 3 months. Ten of 17 (59%, CI 36%–82%) who met criteria for ‘high-probability’, 6 of 44 (13%, CI 5%–21%) with ‘intermediate probability’ and 1 of 41 (2.4%, CI 0.5%–7%) with ‘low probability’ had objectively confirmed DVT. This compares to published values of 49%, 14% and 3%, respectively, from two Canadian emergency rooms. Forty-one of the 102 (40%) patients had an ‘alternate diagnosis as likely or greater than DVT’, which lowered the probability of DVT by one or more levels in 35 (85%) cases. Thirty-eight of the 41 (93%) patients with an ‘alternate diagnosis’ did not have DVT; the 3 who did have DVT were thought to have cellulitis (n = 2) or knee hyperextension (n = 1). The negative predictive value of the SimpliRed rapid D-dimer test was 100%, 100% and 71% (5 of 7) in the low, intermediate and high probability groups. Both ‘false negative’ SimpliRed® tests had normal levels of D-dimer using a sensitive ELISA method, and careful re-review of the US studies revealed findings consistent with subacute or chronic DVT. CONCLUSION: The Canadian probability tool for DVT appears to be a valid instrument in our emergency department. Similarly, we documented the high negative predictive value of bedside D-dimer (SimpliRed®) testing among patients classified as ‘low’ or ‘intermediate’ probability for having DVT, as reported in the literature. Radiographic misinterpretation of subacute or chronic DVT as acute DVT may partially explain the lower negative predictive value of SimpliRed® testing in patients with high clinical probability of having DVT.

Distinct reactivity of the commercially available monoclonal antibodies of D-dimer and plasma FDP testing to the molecular variants of fibrin degradation products

Measurement of D-dimer (fibrin degradation product) is important for determining not only the activation of fibrinolysis but also the severity of a hypercoagulable state. However, fibrin degradation products are in variable, and the reactivity to cross-linked fibrin degradation products produced during fibrin degradation differs depending on the kind of antibody used against D-dimer. In patients with disseminated intravascular coagulation or earthquake-induced mental and physical stress and in patients after percutaneous transluminal coronary angioplasty, all of which are associated with acute fibrin formation and degradation, some discrepancies between two methods of D-dimer detection, automated latex agglutination assay (LPIA) and enzyme-linked immunosorbent assay (Stago), were found. No discrepancies in persistent fibrin formation and degradation were found among the healthy elderly, patients with lacunar stroke, and patients with coronary artery disease, almost all of whom had levels under 5.0 microg/mL, as determined by both methods. Evidence of persistently increased intravascular coagulation and fibrin turnover in patients with atherosclerotic disease was found. The cleavage of cross-linked fibrin by plasmin results in a production of fibrin degradation products, mostly contained D-dimer domains. Although the clinical utility of D-dimer can be achieved by their detection with specific antibodies, measurement of D-dimer as high-molecular-weight fragments may be useful to determine whether patients will undergo further fibrin degradation. When intermediate products of the degradation process need to be assessed, D-dimer level measurement by LPIA may serve as a suitable marker for ongoing fibrinolysis.

New quantitative enzyme immunoassays for degradation products of fibrin and fibrinogen in plasma: A comparison with other laboratory methods

The usefulness of five d-dimer assays in the exclusion of deep venous thrombosis

Clinical Utility of D-dimer in Patients With Suspected Pulmonary Embolism and Nondiagnostic Lung Scans or Negative CT Findings

Nowadays D-dimer testing is frequently applied in the diagnosis of venous thromboembolism. However, the test results of different quantitative D-dimer tests can differ significantly. The background of this variability, which is mainly caused by the variety of fibrin degradation products in plasma, the specificity of D-dimer assays, and the calibrators used in the test, is summarized here. Because D-dimer is not a single entity in plasma but a mixture of heterogeneous fibrin degradation products, method standardization is in principle impossible. Efforts undertaken in the past to standardize D-dimer methods are summarized. All these projects failed and it was concluded that only harmonization of D-dimer test results seems to be feasible. The results of a large field study on which a new approach to the harmonization of quantitative D-dimer methods will be based is summarized in this article. This approach seems to be an adequate solution for overcoming the practical problem of variation of test outcome in different D-dimer assays.