D-dimer testing: A narrative review.

D-dimer containing species are soluble fibrin degradation products derived from plasmin-mediated degradation of cross-linked fibrin, i.e., 'D-dimer'. D-dimer can hence be considered a biomarker of in vivo activation of both coagulation and fibrinolysis, the leading clinical application in daily practice of which is ruling out venous thromboembolism (VTE). D-dimer has been further evaluated for assessing the risk of VTE recurrence and helping define optimal duration of anticoagulation treatment in VTE, for diagnosing disseminated intravascular coagulation (DIC), and for screening those at enhanced risk of VTE. D-dimer assays should however be performed as intended by regulatory agencies, as their use outside these indications might make them a laboratory-developed test (LDT). This narrative review is aimed at: (1) reviewing the definition of D-dimer, (2) discussing preanalytical variables affecting D-dimer measurement, (3) reviewing and comparing the assays performance and some postanalytical variables (e.g., different units and age-adjusted cutoffs), and (4) discussing the interest of D-dimer measurement across different clinical settings, including pregnancy, cancer, and coronavirus disease 2019 (COVID-19).

COVID-19 associated coagulopathy and thrombosis in cancer.

Cancer patients are at risk for a more severe COVID-19 infection as well as an adverse outcome of such infection. This may be caused by the cancer itself (e.g haematological malignancies and lung cancer) or due to immune suppression caused by anti-cancer treatment. Severe COVID-19 infections are often complicated by a coagulopathy that clinically results in a high incidence of venous thromboembolic disease. Cancer itself is associated with a hypercoagulable state and a markedly increased incidence of thromboembolic complications, hence the combination of cancer and COVID-19 may amplify this risk. COVID-19 vaccination seems safe and effective in most cancer patients although adapted and bespoke vaccination schemes may increase the seroconversion rate and immune response in selected patients. Specific management strategies to improve outcomes of cancer patients in COVID-19 (e.g. higher intensity antithrombotic prophylaxis) are lacking and should be evaluated in clinical studies simultaneously focusing on efficacy and safety.

Venous thromboembolism in COVID-19: A meta-summary of cases.

OBJECTIVES: To summarize cases of venous thromboembolism (VTE), including pulmonary embolism (PE) and deep vein thrombosis (DVT) among coronavirus disease (COVID-19) patients and discuss their symptoms, diagnostic method, clinical features, and prognosis. METHODS: All major databases were searched for relevant studies published between December 1, 2019 and May 5, 2021. RESULTS: A total of 233 articles were identified, 22 describing 48 patients were included. A total of 79.1% had PE and 20.9% had DVT. Most patients were men, with a mean age of 56 years. Comorbidities were present in 70.8%, and 85.4% had at least one risk factor of VTE. 56.3% had received anticoagulation therapy. Most patients were treated in the general ward. Complications occurred in 27.1% of the patients, and recovery was achieved in 80.4%. CONCLUSION: Venous thromboembolism must be suspected even in patients who had received prior anticoagulant regimens or in stable cases, especially in males, the elderly, and patients with comorbidities and high D-dimer levels.

Methodological Issues and Controversies in COVID-19 Coagulopathy: A Tale of Two Storms.

Venous thromboembolism, occlusion of dialysis catheters, circuit thrombosis in ECMO devices, all in the face of prophylactic and sometimes even therapeutic anti-coagulation, are frequent features of COVID-19 coagulopathy. The trials available to guide clinicians are methodologically limited. There are several unresolved controversies including 1) Should all hospitalized patients with COVID-19 receive prophylactic anti-coagulation? 2) Which patients should have their dosage escalated to intermediate dose? 3) Which patients should be considered for full-dose anti-coagulation even without a measurable thromboembolic event and how should that anti-coagulation be monitored? 4) Should patients receive post-discharge anti-coagulation? 5) What thrombotic issues are related to the various medications being used to treat this coagulopathy? 6) Is anti-phospholipid anti-body part of this syndrome? 7) How do the different treatments for this disease impact the coagulation issues? The aims of this article are to explore these questions and interpret the available data based on the current evidence.

Binding to carboxypeptidase M mediates protective effects of fibrinopeptide Bß15-42.

During fibrinolysis a 28-amino-acid peptide is generated besides other degradation products of fibrin. This peptide, called Bß15-42, which is cleaved by plasmin from the end of the fibrin Bß-chain, is protective in myocardial and renal ischemia/reperfusion injury and improves the outcome in experimental sepsis. Bß15-42 has been shown to mediate different beneficial effects in endothelial cells through binding to vascular endothelial-cadherin. Here, we provide in vitro and in vivo evidence that Bß15-42 has additional cell protective activity in tubular cells, which is caused by a distinct mechanism. As vascular endothelial-cadherin is not expressed by tubular cells we used ligand-receptor capture technology LRC-TriCEPS to search for tubular cell surface receptors and identified carboxypeptidase M (CBPM) as a novel binding partner of Bß15-42. Silencing CBPM with siRNA reduced the protective potential of Bß15-42 against tubular cell stress. Bß15-42 inhibited the enzymatic activity of CBPM and modified the impact of CBPM on bradykinin signaling. We conclude that beneficial properties of Bß15-42 are not restricted to endothelial cells but are also active in epithelial cells where cytoprotection depends on CBPM binding.

General practitioner use of D-dimer in suspected venous thromboembolism: historical cohort study in one geographical region in the Netherlands.

OBJECTIVES: To investigate how many general practitioner (GP)-referred venous thromboembolic events (VTEs) are diagnosed during 1 year in one geographical region and to investigate the (urgent) referral pathway of VTE diagnoses, including the role of laboratory D-dimer testing. DESIGN: Historical cohort study. SETTING: GP patients of 47 general practices in a demarcated geographical region of 161 503 inhabitants in the Netherlands. PARTICIPANTS: We analysed all 895 primary care patients in whom either the GP determined a D-dimer value or who had a diagnostic work-up for suspected VTE in a non-academic hospital during 2015. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcomes of this study were the total number of VTEs per year and the diagnostic pathways-including the role of GP determined D-dimer testing-of patients urgently referred to secondary care for suspected VTE. Additionally, we explored the use of an age-adjusted D-dimer cut-off. RESULTS: The annual VTE incidence was 0.9 per 1000 inhabitants. GPs annually ordered 5.1 D-dimer tests per 1000 inhabitants. Of 470 urgently GP-referred patients, 31.3% had a VTE. Of those urgently referred based on clinical assessment only (without D-dimer testing), 73.8% (96/130) had a VTE; based on clinical assessment and laboratory D-dimer testing yielded 15.0% (51/340) VTE. Applying age-adjusted D-dimer cut-offs to all patients aged 50 years or older resulted in a reduction of positive D-dimer results from 97.9% to 79.4%, without missing any VTE. CONCLUSIONS: Although D-dimer testing contributes to the diagnostic work-up of VTE, GPs have a high detection rate for VTE in patients who they urgently refer to secondary care based on clinical assessment only.

Chemotherapy in Patients with Hereditary Angioedema.

BACKGROUND: Hereditary angioedema (HAE) is an autosomal dominant hereditary disorder characterized by episodic swelling of many body regions (especially throat and abdomen), potentially triggered by medication. No data are available for HAE in patients with cancer assigned to standard chemotherapy. The aim of our study was to identify circulating mediators potentially predictive of acute HAE attacks during chemotherapy. PATIENT AND METHODS: Repeated blood testing (approximately every week) for complement system members (C3, C4, CH50, C1 inhibitor, C1-inhibitor functional C1Q), D-dimers and for routine haematochemistry were performed in a 42-year-old male affected by type 2 HAE during standard adjuvant oxaliplatin/fluorouracil-based chemotherapy administered for stage III radically resected rectal cancer. Pre-medication with 1,000 U Berinert inhibitor C1 was administered every week throughout treatment. Mann-Whitney U-test was used to determine statistical differences in measures between the first 30 days of therapy and beyond day 30 of therapy. RESULTS: Pre-chemotherapy values of tested variables (day 0) were: C3: 101 mg/dl, C4: 5.71 mg/dl, CH50: 74%, C1 inhibitor: 43.4 mg/dl, C1-inhibitor functional: 18%, C1Q: 150 mg/dl, and D-dimers: 113 g/ml. A significant change in circulating values was observed for C3, D-dimers and C1-inhibitor functional. Four HAE attacks were observed, they started from the forth cycle of treatment and all were manageable. Changes in C3, D-dimers and C1-inhibitor functional preceded the attacks. CONCLUSION: The stress induced by chemotherapy such a standard oxaliplatin/fluorouracil increases the risk of attacks in patients with HAE. However, circulating biomarkers such as D-dimers, C3 and C1-inhibitor functional may serve as early predictors of acute HAE crisis.

Usefulness of Fibrinogen/Fibrin Degradation Products Value in Differential Diagnosis Between Acute Ischemic Stroke and Acute Aortic Dissection.

A post-marketing surveillance study reported fatalities following tissue plasminogen activator administration in acute aortic dissection (AAD) with the symptoms of acute ischemic stroke (AIS) patients. Therefore, it is important to discriminate AAD from AIS. The present study aimed to investigate whether fibrinogen/fibrin degradation products (FDP) value can be useful in differential diagnosis between AAD and AIS. The study group comprised 20 AAD patients (10 men and 10 women; age 63.9 ± 13.6 years) and 159 AIS patients (91 men and 68 women; age 74.2 ± 10.6 years) who were transported to our hospital from 2007 to 2012. The AAD cases were further divided into patent-type AAD and thrombosed-type AAD. FDP values were significantly higher in the AAD group than in the AIS group (18.15 [5.2 - 249.9] µg/ml vs. 2.3 [1.5 - 4.45] µg/ml ; P < 0.001). In AAD groups, FDP values were significantly higher in the patent-type AAD group (n = 9) than in the thrombosed type AAD group (n = 11) (293.2 µg/ml [63.1 - 419.6 µg/ml ] vs. 5.6 µg/ml [3.8 - 7.9 µg/ml ]. FDP values were significantly higher in patients with AAD than in those with AIS, especially those with patent-type AAD compared with AIS patients. High FDP values may be a useful marker for differential diagnosis between patent-type AAD and AIS.

Automated Pulmonary Embolism Risk Classification and Guideline Adherence for Computed Tomography Pulmonary Angiography Ordering.

BACKGROUND: The assessment of clinical guideline adherence for the evaluation of pulmonary embolism (PE) via computed tomography pulmonary angiography (CTPA) currently requires either labor-intensive, retrospective chart review or prospective collection of PE risk scores at the time of CTPA order. The recording of clinical data in a structured manner in the electronic health record (EHR) may make it possible to automate the calculation of a patient's PE risk classification and determine whether the CTPA order was guideline concordant. OBJECTIVES: The objective of this study was to measure the performance of automated, structured data-only versions of the Wells and revised Geneva risk scores in emergency department (ED) encounters during which a CTPA was ordered. The hypothesis was that such an automated method would classify a patient's PE risk with high accuracy compared to manual chart review. METHODS: We developed automated, structured data-only versions of the Wells and revised Geneva risk scores to classify 212 ED encounters during which a CTPA was performed as "PE likely" or "PE unlikely." We then combined these classifications with D-dimer ordering data to assess each encounter as guideline concordant or discordant. The accuracy of these automated classifications and assessments of guideline concordance were determined by comparing them to classifications and concordance based on the complete Wells and revised Geneva scores derived via abstractor manual chart review. RESULTS: The automatically derived Wells and revised Geneva risk classifications were 91.5 and 92% accurate compared to the manually determined classifications, respectively. There was no statistically significant difference between guideline adherence calculated by the automated scores compared to manual chart review (Wells, 70.8% vs. 75%, p = 0.33; revised Geneva, 65.6% vs. 66%, p = 0.92). CONCLUSION: The Wells and revised Geneva score risk classifications can be approximated with high accuracy using automated extraction of structured EHR data elements in patients who received a CTPA. Combining these automated scores with D-dimer ordering data allows for the automated assessment of clinical guideline adherence for CTPA ordering in the ED, without the burden of manual chart review.

Imaging Trends in Acute Venous Thromboembolic Disease: 2000 to 2015.

PURPOSE: To measure diffusion of new knowledge and correlate imaging utilization for suspected acute venous thromboembolism (VTE) with d-dimer utilization, landmark publications, and institutional guidelines. MATERIALS: Between 2000 and 2015, the number of CT pulmonary angiograms (CTPAs), CTPA combined with indirect CT venography (CTV), ventilation-perfusion (VQ) scans, and lower extremity venous Doppler ultrasound (US) examinations were obtained for inpatients and emergency department (ED) patients and correlated with d-dimer utilization, landmark publications regarding radiation and VTE imaging, and an institutional inpatient best-practice alert requiring VTE prophylaxis assessment (2008). Volume data were normalized per 1,000 patients. RESULTS: CTPA and d-dimer utilization were correlated (ED: r = 0.94, inpatient: r = 0.87; P < .001). VQ volume peaked in 2004 to 2005 (20 of 1,000 ED patients; 14 of 1,000 inpatients) and decreased since to a low of 1 of 1,000 and 3 of 1,000, respectively. US volume increased since 2002 and was higher than CT volume for inpatients (annual mean 149 of 1,000 patients [US], 46 of 1,000 patients [CT]), but not ED patients (annual mean 18 of 1,000 patients [US], 35 of 1,000 patients [CT]). For ED patients, CTPA volume peaked in 2008 at 57 of 1,000 patients, declined through 2012 to 30 of 1,000 patients, and rose annually since to 37 of 1,000 patients (2015). For inpatients, CTPA volume also peaked in 2008 at 70 of 1,000, but continued to decline through 2015 to 27 of 1,000 patients. CONCLUSION: After the Prospective Investigation of Pulmonary Embolism II and Brenner and Hall publications, there was a transient 4-year decline in ED CTPA utilization. The decline was sustained in inpatients, where a best-practice VTE prophylaxis alert was implemented. Best-practice alerts may sustain the impact of new knowledge.

FDP/fibrinogen ratio reflects the requirement of packed red blood cell transfusion in patients with blunt trauma.

PURPOSE: To find factors that predict the requirement of packed red blood cells (pRBC) transfusion in patients with blunt trauma on arrival at the hospital. METHODS: We conducted blood tests in trauma patients whose trauma severity was suspected as being 3 and over in the Abbreviated Injury Scale. Patients were divided into the blood transfusion (BT) and control groups according to the requirement of pRBC transfusion within 24h after arrival. RESULTS: We analyzed 347 patients (BT group, n=14; control group, n=333). On univariate analysis, there were significant differences in Glasgow Coma Scale (GCS), rate of positive FAST (focused assessment with sonography for trauma) finding, hematocrit, international normalized ratio of prothrombin time, activated partial thromboplastin time, fibrinogen (Fib), and level of fibrin degradation products (FDP). On multivariable analysis, positive FAST finding, GCS, Fib, and FDP influenced the requirement of pRBC transfusion. In the area under the receiver operating characteristic curve analysis, Fib and FDP were markers that predicted the requirement of pRBC transfusion. The FDP/Fib ratio had a better correlation with the requirement of pRBC transfusion than FDP or Fib. CONCLUSIONS: The FDP/Fib ratio can be easily measured and may be a predictor of the need for pRBC transfusion.

D-Dimer Plasma Levels Parallel the Clinical Response to Omalizumab in Patients with Severe Chronic Spontaneous Urticaria.

Omalizumab is very effective in the majority of patients with severe chronic spontaneous urticaria (CSU), but its mechanism of action is still unclear. In CSU the coagulation cascade is activated with an intensity that parallels the disease severity, and elevated plasma D-dimer levels are associated with a poor response to both antihistamines and cyclosporin. We measured D-dimer plasma levels before and after the first administration of omalizumab in 32 patients with severe CSU. A number of clinical and laboratory parameters were recorded, including the urticaria activity score, presence of angioedema, disease duration, C-reactive protein, anti-nuclear, and anti-thyroid antibodies. Baseline D-dimer levels were elevated in 19 (59%) cases. Omalizumab induced a complete response in 25 patients (78%), in most cases already after the first administration. At baseline, 14/25 responders had increased D-dimer plasma levels versus 5/7 non-responders. All responders showed a dramatic decrease of D-dimer plasma levels after the first administration of the drug (from 1,024 ± 248 [mean ± SE] to 251 ± 30 ng/mL; p = 0.003). In contrast, non-responders did not show any reduction in D-dimer levels after omalizumab administration (from 787 ± 206 to 1,230 ± 429 ng/mL; p = ns). In conclusion, plasma levels of D-dimer are frequently elevated in patients with severe CSU before omalizumab administration and decrease according to the clinical response of the disease to the drug, suggesting a possible effect of omalizumab on coagulation activation and fibrin degradation in a subset of CSU patients.

d-Dimer as a Screening Marker for Venous Thromboembolism After Surgery Among Patients Younger Than 50 With Lower Limb Fractures.

OBJECTIVE: For the present study, the authors hypothesized that the d-dimer levels would be systematically raised in a postoperative population of patients younger than 50 with lower limb fractures and to define a feasible cutoff value for identification of venous thromboembolism (VTE). METHODS: Doppler ultrasonography of lower limbs was performed pre- and postoperatively to evaluate for deep vein thrombosis in 150 patients who underwent open reduction and internal fixation (ORIF). Plasma d-dimer levels were assessed 2 days before surgery and on the 3rd, 7th, and 10th days after surgery. Statistical analysis was carried out to define a feasible threshold for the d-dimer levels. RESULTS: Plasma d-dimer levels were found to be systematically raised postoperatively, and they differed between patients with and without VTE significantly. On the third day after surgery, d-dimer levels of more than 3 mg/L indicated VTE with a sensitivity of 88.37% and a specificity of 96.96%, allowing for the definition of a feasible cutoff value. Duration of surgery, duration of tourniquet, ventilation time, and time of postoperative immobility of lower limbs were identified as highly significant risk factors for the development of VTE. CONCLUSION: Using a threshold of 3 mg/L, the d-dimer levels will screen out VTE with a high degree of sensitivity and specificity in younger patients who have undergone ORIF for lower limb fractures.

Fibrin/fibrinogen degradation products (FDP) at hospital admission predict neurological outcomes in out-of-hospital cardiac arrest patients.

OBJECTIVE: This study aimed to test the hypothesis that coagulation, fibrinolytic markers and disseminated intravascular coagulation (DIC) score (International Society on Thrombosis and Haemostasis) at hospital admission of out-of-hospital cardiac arrest (OHCA) patients can predict neurological outcomes 1 month after cardiac arrest. METHODS: In this retrospective, observational analysis, data were collected from the Sapporo Utstein Registry and medical records at Hokkaido University Hospital. We included patients who experienced OHCA with successful return of spontaneous circulation (ROSC) between 2006 and 2012 and were transferred to Hokkaido University Hospital. From medical records, we collected information about the following coagulation and fibrinolytic factors at hospital admission: platelet count; prothrombin time; activated partial thromboplastin time; plasma levels of fibrinogen, D-dimer, fibrin/fibrinogen degradation products (FDP), and antithrombin; and calculated DIC score. Favorable neurological outcomes were defined as a cerebral performance category 1-2. RESULTS: We analyzed data for 315 patients. Except for fibrinogen level, all coagulation variables, fibrinolytic variables, and DIC score were associated with favorable neurological outcomes. In the receiver operating characteristic curve analysis, FDP level had the largest area under the curve (AUC; 0.795). In addition, the AUC of FDP level was larger than that of lactate level. CONCLUSIONS: All of the coagulation and fibrinolytic markers, except for fibrinogen level, and DIC score at hospital admission, were associated with favorable neurological outcomes. Of all of the variables, FDP level was most closely associated with favorable neurological outcomes in OHCA patients who successfully achieved ROSC.