The change in plasma D-dimer does not help to guide the timing of reimplantation in two stage exchange for periprosthetic joint infection.

D-dimer has been included in the criteria by the Musculoskeletal Infection Society in 2018 as a novel parameter to diagnose prosthetic joint infection (PJI). However, it is unclear how D-dimer levels change in between stages of a two-stage exchange. We prospectively investigated 30 patients who underwent a two-stage exchange using a spacer for PJI. D-Dimer, CRP and IL-6 were collected before first and second stage surgery and the difference (Δ) in between stages was calculated. The levels of plasma D-Dimer did not change from first to second stage surgery (2770 ng/ml (IQR, 1600-3770 ng/ml) versus 2340 ng/ml (IQR, 1270-4100 ng/ml); p = 0.8) while CRP (4.0 mg/dl (IQR, 1.7-5.5 mg/dl) versus 0.6 mg/dl (IQR, 0.5-0.8 mg/dl); p < 0.001) and IL-6 (21 pg/ml (IQR, 10-29 pg/ml) versus 6 pg/ml (4-9 pg/ml); p < 0.001) decreased. The ΔD-dimer between both stages was 300 ng/ml (range: - 2820 to 4280 ng/ml), the median ΔCRP was - 3.4 mg/dl (IQR, - 1.2 to - 4.8 mg/dl) and ΔIL-6 was - 13 pg/ml (IQR, - 4 to - 20 pg/ml). In 15 of 30 cases (50%) the D-dimer level increased between both stages, whereas the level of CRP (93%; 28/30) and IL-6 (96%; 28/29) decreased in most patients. As the level of serum D-dimers varies greatly, lacks a uniform decrease and does not identify persisting infection, surgeons should be cautious when using it at the timing of reimplantation.

Could Soluble Endothelial Protein C Receptor Levels Recognize SARS-CoV2-Positive Patients Requiring Hospitalization?

INTRODUCTION: The endothelial protein C receptor (EPCR) is a protein that regulates the protein C anticoagulant and anti-inflammatory pathways. A soluble form of EPCR (sEPCR) circulates in plasma and inhibits activated protein C (APC) activities. The clinical impact of sEPCR and its involvement in COVID-19 has not been explored. In this study, we investigated whether sEPCR levels were related to COVID-19 patients' requirement for hospitalization. METHODS: Plasma sEPCR levels were measured on hospital admission in 84 COVID-19 patients, and in 11 non-hospitalized SARS-CoV2-positive patients approximately 6 days after reported manifestation of their symptoms. Multiple logistic regression analysis was performed to identify potential risk factors for hospitalization and receiver operating characteristic (ROC) curves were generated to assess their value. RESULTS: In our cohort, hospitalized patients had considerably higher sEPCR levels upon admission compared with outpatients [107.5 (76.7-156.3) vs. 44.6 (12.1-84.4) ng/mL; P < 0.0001)]. The ROC curve using hospitalization as the classification variable and sEPCR levels as the prognostic variable generated an area under the curve at 0.845 (95% CI = 0.710-0.981, P < 0.001). Additionally, we investigated the predictive value of sEPCR combined with BMI, age, or D-dimers. CONCLUSIONS: In our cohort, sEPCR levels in COVID-19 patients upon hospital admission appear considerably elevated compared with outpatients; this could lead to impaired APC activities and might contribute to the pro-coagulant phenotype reported in such patients. sEPCR measurement might be useful as a point-of-care test in SARS-CoV2-positive patients.

D-Dimer as Predictor of Large Vessel Occlusion in Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: Improving prehospital triage of large vessel occlusion (LVO) would reduce time to reperfusion therapies. We aimed to study early predictors of LVO in acute ischemic stroke to identify candidates for endovascular treatment. METHODS: The Stroke-Chip was a prospective observational study conducted at 6 Stroke Centers in Catalonia. Blood samples were obtained in the first 6 hours from symptom onset of consecutive patients. Stroke severity was evaluated with National Institutes of Health Stroke Scale (NIHSS) and LVO was assessed. Independent association of multiple blood biomarkers with LVO was evaluated using logistic regression models adjusted by covariates. Sensitivity, specificity, and predictive values were assessed for NIHSS and the combination of NIHSS and selected serum biomarkers levels. RESULTS: One thousand three hundred eight suspected strokes were enrolled for a 17-month period. LVO was not assessed in 131 patients. One thousand one hundred seventy-seven patients were selected for analysis (mean age 69.3 years, 56% men, median baseline NIHSS of 6, and median time to blood collection 2.5 hours). LVO was detected in 262 patients. LVO patients were older, had higher baseline NIHSS, history of atrial fibrillation, and lower time from stroke onset to admission. After logistic regression analysis, D-dimer remained an independent predictor of LVO (odds ratio, 1.59 [1.31-1.92]). Specificity and positive predictive value to exclude or detect LVO were higher when using combined D-dimer levels and NIHSS score assessment rather than NIHSS alone. CONCLUSIONS: Early D-dimer levels are an independent predictor of LVO and may be useful to better optimize prehospital patient transport to the appropriate stroke center.

Decreased serum Annexin A1 levels in Kawasaki disease with coronary artery aneurysm.

BACKGROUND: Kawasaki disease (KD) is an acute and systemic vasculitis whose etiology remains unclear. The most crucial complication is the formation of coronary artery aneurysm (CAA). Annexin A1 (ANXA1) is an endogenous anti-inflammatory agent and pro-resolving mediator involved in inflammation-related diseases. This study sought to investigate the serum ANXA1 levels in KD patients and further explore the relationship between ANXA1 and CAA, as well as additional clinical parameters. METHODS: Serum samples were collected from 95 KD patients and 39 healthy controls (HCs). KD patients were further divided into two groups: KD with CAAs (KD-CAAs) and KD non-CAAs (KD-NCAAs). Serum levels of ANXA1 and interleukin-6 (IL-6) were determined using enzyme-linked immunosorbent assays. RESULTS: Serum ANXA1 levels in the KD group were significantly lower than in the HC group. In particular, serum ANXA1 levels were substantially lower in the KD-CAA groups. Moreover, serum ANXA1 levels were positively correlated with N%, C-reactive protein (CRP), and IL-6 but negatively correlated with L% in the KD group. Positive correlations between serum ANXA1 levels and erythrocyte sedimentation rate (ESR), IL-6, and D-dimer (DD) were observed in the KD-CAA group. CONCLUSIONS: ANXA1 may be involved in the development of KD, and downregulation of ANXA1 may lead to the hypercoagulability seen in KD. IMPACT: For the first time, it was demonstrated that serum ANXA1 levels were significantly decreased in Kawasaki disease with coronary artery aneurysms. ANXA1 might be involved in the acute phase of Kawasaki disease. Low serum concentrations of ANXA1 might lead to the hypercoagulability stage in Kawasaki disease. ANXA1 might be a potential therapeutic target for patients with Kawasaki disease.

COVID-19 Infection: Viral Macro- and Micro-Vascular Coagulopathy and Thromboembolism/Prophylactic and Therapeutic Management.

Coronavirus-2019 (COVID-19) predisposes patients to arterial and venous thrombosis commonly complicating the clinical course of hospitalized patients and attributed to the inflammatory state, endothelial dysfunction, platelet activation and blood stasis. This viral coagulopathy may occur despite thromboprophylaxis and raises mortality; the risk appears highest among critically ill inpatients monitored in the intensive care unit. The prevalence of venous thromboembolism in COVID-19 patients has been reported to reach ∼10-35%, while autopsies raise it to nearly 60%. The most common thrombotic complication is pulmonary embolism, which though may occur in the absence of a recognizable deep venous thrombosis and may be due to pulmonary arterial thrombosis rather than embolism, resulting in thrombotic occlusion of small- to mid-sized pulmonary arteries and subsequent infarction of lung parenchyma. This micro-thrombotic pattern seems more specific for COVID-19 and is associated with an intense immuno-inflammatory reaction that results in diffuse occlusive thrombotic micro-angiopathy with alveolar damage and vascular angiogenesis. Furthermore, thrombosis has also been observed in various arterial sites, including coronary, cerebral and peripheral arteries. Biomarkers related to coagulation, platelet activation and inflammation have been suggested as useful diagnostic and prognostic tools for COVID-19-associated coagulopathy; among them, D-dimer remains a key biomarker employed in clinical practice. Various medical societies have issued guidelines or consensus statements regarding thromboprophylaxis and treatment of these thrombotic complications specifically adapted to COVID-19 patients. All these issues are detailed in this review, data from meta-analyses and current guidelines are tabulated, while the relevant mechanisms of this virus-associated coagulopathy are pictorially illustrated.

Probative Value of the D-Dimer Assay for Diagnosis of Deep Venous Thrombosis in the Coronavirus Disease 2019 Syndrome.

OBJECTIVES: To describe the predictive utility of the D-dimer assay among patients with the coronavirus disease 2019 syndrome for unprovoked lower extremity deep venous thrombosis. DESIGN: Prospective observational study with retrospective data analysis. SETTING: Academic medical center surgical ICU. PATIENTS: Seventy-two intubated patients with critical illness from coronavirus disease 2019. INTERVENTIONS: Therapeutic anticoagulation after imaging diagnosis of the first three deep venous thrombosis cases was confirmed; therapeutic anticoagulation as prophylaxis thereafter to all subsequent ICU admissions. MEASUREMENTS AND MAIN RESULTS: Seventy-two patients with severe coronavirus disease 2019 were screened for deep venous thrombosis after ICU admission with 102 duplex ultrasound examinations, with 12 cases (16.7%) of lower extremity deep venous thrombosis identified. There were no differences between groups with respect to age, renal function, or biomarkers except for D-dimer (median, 12,858 ng/mL [interquartile range, 3,176-30,770 ng/mL] for lower extremity deep venous thrombosis vs 2,087 ng/mL [interquartile range, 638-3,735 ng/mL] for no evidence of deep venous thrombosis; p < 0.0001). Clinical screening tools (Wells score and Dutch Primary Care Rule) had no utility. The C-statistic for D-dimer concentration was 0.874 ± 0.065. At the model-predicted cutoff value of 3,000 ng/mL, sensitivity was 100%, specificity was 51.1%, positive predictive value was 21.8%, and negative predictive value was 100%. CONCLUSIONS: Lower extremity deep venous thrombosis is prevalent in coronavirus disease 2019 disease and can be present on ICU admission. Screening has been recommended in the context of the pro-inflammatory, hypercoagulable background milieu. D-dimer concentrations are elevated in nearly all coronavirus disease 2019 patients, and the test appears reliable for screening for lower extremity deep venous thrombosis at or above a concentration of 3,000 ng/mL (more than 13-fold above the normal range). Full anticoagulation is indicated if the diagnosis is confirmed, and therapeutic anticoagulation should be considered for prophylaxis, as all coronavirus disease 2019 patients are at increased risk.

Thrombin generation and cell-dependent hypercoagulability in sickle cell disease.

Essentials Sickle cell disease is increasingly being recognized as a chronic hypercoagulable state. Thrombin generation is elevated in the whole blood, but not the plasma of sickle cell patients. Whole blood thrombin generation inversely correlates to erythrocyte phosphatidylserine exposure. Acquired protein S deficiency is likely explained by binding of protein S to sickle red cells. Click to hear Dr Hillery discuss coagulation and vascular pathologies in mouse models of sickle cell disease. SUMMARY: Introduction Sickle cell disease (SCD) is a hypercoagulable state with chronic activation of coagulation and an increased incidence of thromboembolic events. However, although plasma pre-thrombotic markers such as thrombin-anithrombin complexes and D-dimer are elevated, there is no consensus on whether global assays of thrombin generation in plasma are abnormal in patients with SCD. Based on our recent observation that normal red blood cells (RBCs) contribute to thrombin generation in whole blood, we hypothesized that the cellular components in blood (notably phosphatidylserine-expressing erythrocytes) contribute to enhanced thrombin generation in SCD. Methods Whole blood and plasma thrombin generation assays were performed on blood samples from 25 SCD patients in a non-crisis 'steady state' and 25 healthy race-matched controls. Results Whole blood thrombin generation was significantly elevated in SCD, whereas plasma thrombin generation was paradoxically reduced compared with controls. Surprisingly, whole blood and plasma thrombin generation were both negatively correlated with phosphatidylserine exposure on RBCs. Plasma thrombin generation in the presence of exogenous activated protein C or soluble thrombomodulin revealed deficiencies in the protein C/S anticoagulant pathway in SCD. These global changes were associated with significantly lower plasma protein S activity in SCD that correlated inversely with RBC phosphatidylserine exposure. Conclusion Increased RBC phosphatidylserine exposure in SCD is associated with acquired protein S deficiency. In addition, these data suggest a cellular contribution to thrombin generation in SCD (other than RBC phosphatidylserine exposure) that explains the elevated thrombin generation in whole blood.

Variable Resistance to Plasminogen Activator Initiated Fibrinolysis for Intermediate-Risk Pulmonary Embolism.

BACKGROUND: We examine the clinical significance and biomarkers of tissue plasminogen activator (tPA)-catalyzed clot lysis time (CLT) in patients with intermediate-risk pulmonary embolism (PE). METHODS: Platelet-poor, citrated plasma was obtained from patients with PE. Healthy age- and sex-matched patients served as disease-negative controls. Fibrinogen, α2-antiplasmin, plasminogen, thrombin activatable fibrinolysis inhibitor (TAFI), plasminogen activator Inhibitor 1 (PAI-1), thrombin time and D-dimer were quantified. Clotting was induced using CaCl2, tissue factor, and phospholipid. Lysis was induced using 60 ng/mL tPA. Time to 50% clot lysis (CLT) was assessed by both thromboelastography (TEG) and turbidimetry (A405). RESULTS: Compared with disease-negative controls, patients with PE exhibited significantly longer mean CLT on TEG (+2,580 seconds, 95% CI 1,380 to 3,720 sec). Patients with PE and a short CLT who were treated with tenecteplase had increased risk of bleeding, whereas those with long CLT had significantly worse exercise tolerance and psychometric testing for quality of life at 3 months. A multivariate stepwise removal regression model selected PAI-1 and TAFI as predictive biomarkers of CLT. CONCLUSION: The CLT from TEG predicted increased risk of bleeding and clinical failure with tenecteplase treatment for intermediate-risk PE. Plasmatic PAI-1 and TAFI were independent predictors of CLT.

Preoperative D-dimers as an independent prognostic marker in cervical carcinoma.

Activation of coagulation and fibrinolysis has been observed in many tumors. Our study aimed to investigate the clinical and prognostic significance of various plasma coagulation tests in patients with cervical cancer. A total of 296 patients with cervical cancer were included in the analysis. Patients were followed up for at least 60 months until death. Pretreatment parameters including activated partial thromboplastin time, D-dimer, fibrinogen, prothrombin time, thrombin time, lactate dehydrogenase, and squamous cell carcinoma antigen were evaluated. Prothrombin time (hazard ratio = 1.825; P = 0.006) and plasma D-dimer levels (hazard ratio = 2.179; P = 0.036) were identified as significant independent predictors of overall survival. Patients with elevated D-dimer levels had a significantly shorter overall survival compared with those with low-D-dimer levels (<0.5 µg/ml) in the stage I subgroup (n = 98, P = 0.019) and stage II subgroup (n = 77, P = 0.044). D-dimer levels differed significantly according to mortality (P < 0.001), stage I versus stage II (P = 0.030), and stage I versus stage III/IV (P = 0.038). DD level of patients with chemotherapy and/or radiotherapy was higher than patients with other treatment (P < 0.001). Patients with a low-D-dimer level (<0.5 µg/ml) showed a significantly better 5-year overall survival (OS) compared with patients with an increased D-dimer level for different histological typing of squamous cell carcinoma (SCC) (P = 0.001) and non-SCC (P < 0.043). In conclusion, the pretreatment plasma D-dimer level is a potential prognostic factor for cervical cancer.

Circulating levels of DNA-histone complex and dsDNA are independent prognostic factors of disseminated intravascular coagulation.

INTRODUCTION: Neutrophils can be induced to release DNA combined with histones. The resulting neutrophil extracellular trap (NET) provides a scaffold for growing hemostatic plug. Therefore, the NET formation may be inevitable in clinical conditions that are characterized by formation of vascular thrombi. Thus far, there have been no reports on the clinical significance of NET in disseminated intravascular coagulation (DIC). Therefore, we investigated circulating levels of NET in DIC and analyzed their potential values to assess coagulation severity and predict clinical outcome. METHODS: The plasma levels of DNA-histone complexes and double-stranded DNA (dsDNA), considered to be in vivo markers of NET, were measured in 199 patients suspected of having DIC and 20 healthy controls. RESULT: The circulating levels of DNA-histone complexes and dsDNA were significantly elevated in overt-DIC. The increased levels of these two markers correlated with the severity of coagulopathy including DIC score and D-dimer. Multivariable Cox regression analysis, adjusted for the conventional DIC markers, revealed that elevated DNA-histone complexes and dsDNA are poor independent prognostic markers. CONCLUSION: The circulating levels of NET release reflect the coagulation activation and adverse clinical outcomes in patients with DIC, thereby providing potential clinical relevance for mortality prediction in DIC.

Prognostic role of D-dimer in patients with lung cancer: a meta-analysis.

D-dimer detection in patients suffering from a variety of different types of cancer has become a hot point as an emerging and promising biomarker. In this study, therefore, we evaluated the prognostic role of D-dimer in lung cancer. Initial literature was identified using the PubMed, EMBASE, and CNKI. The primary data was hazard ratio (HR) with 95% confidence interval (CI) of survival outcomes in candidate articles, including overall survival (OS) and disease-free survival (DFS). Finally, 11 eligible studies were included in this meta-analysis, which were published between 1996 and 2013. The estimated pooled HR and 95% CI for OS of all studies was 2.06 (95% CI 1.64-2.58, p < 0.00001) and the HR and 95% CI for DFS in one study was 3.38 (95% CI 1.17-9.75, p = 0.002). The HRs and 95% CIs for OS in Asian and non-Asian patients were 2.48 (95% CI 1.60-3.84, p < 0.0001) and 1.89 (95% CI 1.44-2.47, p < 0.00001), respectively. When we further analyzed the data by various detecting methods, the pooled HR and 95% CI for OS were 3.22 (95% CI 1.99-5.21, p < 0.00001) for ELISA, 1.52 (95% CI 1.25-1.86, p < 0.0001) for Latex assay, and 1.79 (95% CI 1.19-2.69, p = 0.005) for immunoturbidimetry assay. We also did subgroup analysis according to the ratio of histological type and clinical stage. All the above analysis had positive results. This meta-analysis showed that D-dimer had a fine predictive role in lung cancer patients, especially in Asian group. Also, it demonstrated that D-dimer had a stronger predictive value by using the method ELISA.

Characterization of the hypercoagulable state in patients with sickle cell disease.

BACKGROUND: The pathophysiology of sickle cell disease (SCD) is complex, with increasing evidence of a pronounced prothrombotic state. OBJECTIVE: We investigated thrombin generation in SCD utilizing calibrated automated thrombography (CAT) and D-dimer, with subsequent correlation to clinical disease. PATIENT/METHODS: The study included 51 patients homozygous for hemoglobin S, either admitted for vaso-occlusive crisis (VOC) (n=34) or while in steady state and being seen in outpatient clinic (n=37). Twenty patients had blood drawn during both VOC and steady state. Mean values for CAT and D-dimer were compared between groups. Mean values for patients with and without clinical complications such as avascular necrosis and stroke were also compared. Linear regression was used to evaluate correlation to number of hospitalizations and for all pediatric patients, transcranial doppler (TCD) velocities. RESULTS: The mean D-dimer during VOC (2743 ± 3118 ng/ml) was significantly higher than during steady state (1151 ± 802, p<0.0001). Comparison of crisis and steady state by CAT also revealed a significant difference in all phases of thrombin generation, including mean endogenous thrombin potential (1381 ± 295 nM vs 923 ± 316, p<0.0001) and peak thrombin generated (284 ± 9 vs 223 ± 18, p=0.0002). There were no significant differences in mean values for the clinical outcomes examined in adults. In pediatric patients, however, increased TCD velocities correlated with steady state D-dimer (r(2)=0.32, p=0.02) and thrombin-antithrombin complex (r(2)=0.28, p=0.04. CONCLUSION: Hypercoagulable markers distinguish between patients with SCD during and between VOC, but do not correlate with specific clinical phenotypes.

Expression of coagulation factors and their receptors in tumor tissue and coagulation factor upregulation in peripheral blood of patients with cerebral carcinoma metastases.

BACKGROUND: Patients with malignancies often suffer from thrombembolic events that complicate the course of cancer disease and reduce the patients' quality of life or shorten the survival time in severe cases. This phenomenon is also known for patients with primary or secondary brain tumors; but the reasons are not identified. METHODS: We performed a prospective case-controlled study of patients with brain metastases but without any active peripheral tumor site. Blood of patients was collected perioperatively and investigated for coagulation factor activities. Moreover, we analyzed the expression of coagulation factors and their receptors within the tumor material of brain metastases from clear-cell renal cell carcinomas and small-cell carcinomas of the lung. RESULTS: Here, we show that even patients without an active peripheral tumor disease that means without any tumor masses outside the central nervous system after anticancer treatment by surgery, radiation therapy, or chemotherapy but with symptomatic brain metastasis develop an increased systemic activation of multiple coagulation factors. The pro-coagulatory state is expressed preoperatively, but also can be observed in the early postoperative period. Additionally to that, intracerebral metastases of clear-cell renal cell carcinomas and of small-cell carcinomas of the lung express prothrombin, thrombin, factor X, and the protease-activated receptors type 1, 2, 3, and 4. CONCLUSIONS: These observations support the hypothesis of a link between the hemostatic system in the periphery and the malignant tumor disease even when the tumor is an intracerebral metastasis and the affected patient currently is free of a systemically active tumor. The results of this study support the hypothesis that the concerted action of coagulation factors and their receptors within the metastasis tissue itself and the systemic coagulation system could control the malignant behavior of tumor disease and make larger prospective trials mandatory.

The cardioprotective effects of marrubiin, a diterpenoid found in Leonotis leonurus extracts.

ETHNOPHARMACOLOGICAL RELEVANCE: Leonotis leonurus L. (Lamiaceae) is used as a traditional medicine for a variety of ailments in South Africa. The diterpene marrubiin is the major product constituent in specimens of this plant occurring in South Africa. MATERIALS AND METHODS: Marrubiin isolated from South African specimens of L. leonurus in addition to an organic extract of L. leonurus were tested in vivo, ex vivo and in vitro for their anticoagulant, antiplatelet and anti-inflammatory activities. RESULTS: Marrubiin and the organic extract suppressed coagulation, platelet aggregation and inflammatory markers. For the coagulation markers it was found that the organic extract and marrubiin significantly prolonged activated partial thromboplastin time (APTT). Fibrin and D-dimer formation were drastically decreased. These findings were observed in an ex vivo model and an obese rat model. Chemokines enhance leukocyte recruitment to inflammatory sites. TNF-α and RANTES secretion were significantly reduced by the extract and marrubiin when determined in the obese rat model relative to the controls. Calcium mobilization and TXB(2) synthesis were suppressed by the extract and marrubiin. An in vitro model was used to elucidate the antiplatelet mechanism and it was found that the extract and marrubiin inhibited platelet aggregation by inhibiting the binding of fibrinogen to glycoprotein (GP) IIb/IIIa receptor in a concentration dependent manner. CONCLUSION: The findings reflect that marrubiin largely contributes to the extract's anticoagulant, antiplatelet and anti-inflammatory effects observed.

Does the clinical presentation and extent of venous thrombosis predict likelihood and type of recurrence? A patient-level meta-analysis.

AIM: To determine if the mode of presentation of venous thromboembolism (VTE), as deep vein thrombosis (DVT) or pulmonary embolism (PE), predicts the likelihood and type of recurrence. METHODS: We carried out a patient-level meta-analysis of seven prospective studies in patients with a first VTE who were followed after anticoagulation was stopped. We used Kaplan-Meier analysis to determine the cumulative incidence of recurrent VTE according to mode of presentation, and multivariable Cox regression to calculate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for mode of and extent of DVT as potential risk factors for recurrence. RESULTS: The 5-year cumulative rate of recurrent VTE in 2554 patients was 22.6%. In 869 (36.1%) patients with PE, the 5-year rate of any recurrence (DVT or PE) was 22.0%, and recurrence as PE was 10.6%. In 1365 patients with proximal DVT, the 5-year recurrence rate was 26.4%, and recurrence with PE was 3.6%. The risk of recurrence as PE was 3.1-fold greater in patients presenting with symptomatic PE than in patients with proximal DVT (HR, 3.1; 95% CI, 1.9-5.1). Patients with proximal DVT had a 4.8-fold higher cumulative recurrence rate than those with distal DVT (HR, 4.8; 95% CI, 2.1-11.0). CONCLUSION: Whilst DVT and PE are manifestations of the same disease, the phenotypic expression is predetermined. Patients presenting with PE are three times more likely to suffer recurrence as PE than patients presenting with DVT. Patients presenting with calf DVT are at low risk of recurrence and at low risk of recurrence as PE.

Relation between D-dimer level, venous valvular reflux and the development of post-thrombotic syndrome after deep vein thrombosis.

BACKGROUND: The pathophysiology of post-thrombotic syndrome (PTS) is postulated to involve persistent venous obstruction and venous valvular reflux. OBJECTIVE: To study the association between D-dimer level, valvular reflux and the PTS in a well-defined cohort of deep vein thrombosis (DVT) patients. METHODS: Consecutive patients with acute symptomatic DVT were recruited at eight centers and were followed for 24months. D-dimer was measured at 4months. A standardized ultrasound assessment for popliteal valvular reflux was performed at 12months. Using the Villalta scale, patients were assessed for PTS during follow-up by evaluators who were unaware of D-dimer or reflux results. RESULTS: Three hundred and eighty-seven patients were recruited; of these, 305 provided blood samples for D-dimer and 233 had a 12-month reflux assessment. PTS developed in 45.1% of subjects. Mean D-dimer was significantly higher in patients with vs. without PTS (712.0 vs. 444.0µgL(-1) ; P=0.02). In logistic regression analyses adjusted for warfarin use at the time of D-dimer determination and risk factors for PTS, D-dimer level significantly predicted PTS (P=0.03); when stratifying for warfarin use at the time of blood draw, adjusted odds ratio (OR) for developing PTS per unit difference in log D-dimer was 2.33 (95% CI 0.89, 6.10) in those not on warfarin vs. 1.25 (95% CI 0.87, 1.79) in those on warfarin. Ipsilateral reflux was more frequent in patients with moderate-to-severe PTS than in patients with mild PTS (65% vs. 40%, respectively; P=0.01) and was independently associated with moderate-to-severe PTS in logistic regression analyses (P=0.01). CONCLUSION: D-dimer levels, measured 4months after DVT in patients not on warfarin, are associated with subsequent development of PTS. Venous valvular reflux is associated with moderate-to-severe PTS.

Safety of ruling out acute pulmonary embolism by normal computed tomography pulmonary angiography in patients with an indication for computed tomography: systematic review and meta-analysis.

INTRODUCTION: Several outcome studies have ruled out acute pulmonary embolism (PE) by normal computed tomography pulmonary angiography (CTPA). We performed a meta-analysis in order to determine the safety of this strategy in a specific group of patients with a strict indication for CTPA, that is, 'likely' or 'high' clinical probability for PE, an elevated D-dimer concentration, or both. METHODS: Studies that ruled out PE by normal CTPA, with or without subsequent normal bilateral compression ultrasonography (CUS), in patients with a strict indication for CTPA, were searched for in Medline, EMBASE, Web of Science and the Cochrane dataset. The primary endpoint was the occurrence of (fatal) venous thromboembolism (VTE) in a 3-month follow-up period. RESULTS: Three studies were identified that excluded PE by CTPA alone (2020 patients), and three studies that performed additional CUS of the legs after normal CTPA (1069 patients). The pooled incidence of VTE at 3 months was 1.2% [95% confidence interval (CI) 0.8-1.8] based on a normal CTPA result as a sole test, and 1.1% (95% CI 0.6-2.0) based on normal CTPA and negative CUS findings, resulting in negative predictive values of 98.8% (95% CI 98.2-99.2) and 98.9% (95% CI 98.0-99.4), respectively. This compares favorably with the VTE failure rate after normal pulmonary angiography (1.7%, 95% CI 1.0-2.7). The risk of fatal PE did not differ between the diagnostic strategies (0.6% vs. 0.5%). CONCLUSION: A normal CTPA result alone can safely exclude PE in all patients in whom CTPA is required to rule out this disease. There is no need for additional ultrasonography to rule out VTE in these patients.

Different cut-off values of quantitative D-dimer methods to predict the risk of venous thromboembolism recurrence: a post-hoc analysis of the PROLONG study.

BACKGROUND: The PROLONG study showed that patients with venous thromboembolism who had qualitatively abnormal results in a D-dimer assay (Clearview Simplify D-dimer) after discontinuation of vitamin K antagonism benefit from resumption of treatment with vitamin K antagonism. The objective of this study was to evaluate the possible advantage of using quantitative D-dimer assays. DESIGN AND METHODS: VIDAS D-dimer Exclusion (bioMerieux), Innovance D-DIMER (Dade Behring), HemosIL D-dimer HS (Instrumentation Laboratory) and STA Liatest D-dimer (Diagnostica Stago) assays were performed in plasma aliquots sampled 30+/-10 days after cessation of vitamin K antagonism in 321 patients enrolled in the PROLONG study. RESULTS: During the follow-up without vitamin K antagonism, 25 patients had recurrent venous thromboembolism. The cut-off levels of the quantitative assays giving results most comparable with those of the qualitative test were: VIDAS = 800 ng/mL; Innovance = 800 ng/mL; HemosIL HS = 300 ng/mL; STA Liatest = 700 ng/mL. When the effect of the patients' age (< or = 70 vs. >70 years) was analyzed, it was found that only in younger patients was the rate of recurrence of venous thromboembolism significantly higher in patients with abnormal D-dimer levels. However, using the quantitative assays and age-specific cut-off levels it was possible to determine statistically significant hazard ratios also in elderly patients (VIDAS = 600 and 1200 ng/mL, Innovance = 500 and 900 ng/mL, HemosIL HS = 250 and 450 ng/mL, STA Liatest = 700 and 1000 ng/mL, in patients aged < or = 70 and >70 years, respectively). CONCLUSIONS: Quantitative D-dimer assays may provide information useful for evaluating the individual risk of recurrent venous thromboembolism. They seem particularly advantageous since they allow the selection of different cut-off levels according to the age or other characteristics of the patients.