The Bone Cement Hypercoagulation Syndrome: Pathophysiology, Mortality, and Prevention.

Since Charnley introduced acrylic cement to seal metallic hip prostheses in the 1950s, reports of perioperative fatal cardiorespiratory and vascular dysfunctions have been published. Studies on humans and animals have shown neurogenic stimulation and substantial local and systemic activation of coagulation are caused by surgical bone marrow damage and chemical cell destruction by toxic monomeric methyl methacrylate from the implanted cement and other tissue-released substances. Venous blood-borne cell fragments and conjugates of activated cells from the surgical site are sequestered and trapped in the pulmonary microcirculation. A substantial hypercoagulation occurs in the lung circulation. Hypercoagulable blood is passed over to the arterial side and may cause vessel obliteration and organ damage. This process may affect the brain, heart, and kidneys and, through the release of vasoactive substances, introduce hemodynamic imbalances that can lead to fatal outcomes in susceptible populations such as elderly patients with hip fractures. The main underlying pathophysiologic processes leading to these occasionally devastating outcomes are a substantial activation of coagulation and cell destruction caused by the toxic substance released by curing bone cement and several vasoactive substances.

Does the Risk of Death Within 48 Hours of Hip Hemiarthroplasty Differ Between Patients Treated with Cemented and Cementless Implants? A Meta-analysis of Large, National Registries.

BACKGROUND: Although current recommendations suggest that hip hemiarthroplasties performed for femoral neck fractures be implanted with bone cement, it is known to cause cardiorespiratory and hemodynamic reactions that in some patients can be fatal. Older patients may be at particular risk of this complication, but because of its relative infrequency, large studies-perhaps even larger than can be achieved in the context of single-country national registries-are needed to get reasonably precise estimates as to its frequency. Pooling results from national registries reporting on death within 48 hours of cement exposure in this setting may therefore be helpful. QUESTION/PURPOSE: In a systematic review of studies based on large national registries, we asked: Does the risk of death within 48 hours of hip hemiarthroplasty differ between patients treated with cemented and cementless implants? METHODS: MEDLINE and Embase data sources were searched for cohort studies on patients with hip fractures treated with cement or cementless hip hemiprostheses based on results from national registries that tracked perioperative deaths within 48 hours of surgery, from 2010 or later (to include only studies that used contemporary cement techniques). We excluded registry research on elective THAs for other indications (such as degenerative joint disease), mixed populations (registries that combined patients having arthroplasty for fracture and for other diagnoses like osteoarthritis, such that we could not separate them), and overlapping data from the same registers (to avoid double and triple publications of similar data). Five studies met our inclusion criteria. The cohorts ranged from about 11,000 to about 25,000 patients. About 31% of the patients were in the cementless group. Two studies reported the age ranges of participating patients, and three studies communicated mean ages (which were 82 years for both sexes). Twice as many females as males were present in both the cemented and cementless group. When reported, more than 50% in both groups were in the American Society of Anesthesiologists physical status classification 3 or 4. Study quality was deemed good according to the Newcastle-Ottawa Scale. Publication bias was assessed using a funnel plot and the Egger test, and study heterogeneity was evaluated using the I2 heterogeneity statistic and Cochran Q heterogeneity test. There was some heterogeneity between the studies, with a Cochran Q statistics of 8.13 (degrees of freedom = 4; p = 0.08) and an I2 statistic of 50.8%. There was evidence for a small amount of publication bias (Egger test; p = 0.02). The pooled risk ratio (RR) from a random-effects model is presented with 95% confidence intervals. The primary endpoint was the occurrence of any fatalities within 48 hours of hip fracture treatment with cementless compared with cemented prostheses. We performed a sensitivity analysis to assess the needed association of a potential unmeasured or uncontrolled confounding, and we made an estimate of the amount of unmeasured confounding that would need to be present in order to change the direction of the result. We summarized this using a parameter known as the "E-value." Based on that sensitivity analysis, we found it unlikely that an unmeasured hypothetical confounder could explain the significant association between cemented and cementless implants and risk of death within 48 hours of hip hemiarthroplasty. RESULTS: Compared with the cementless group, mortality was increased in the cemented group (RR 1.63 [95% CI 1.31 to 2.02]; p < 0.001). The number needed to harm from the pooled data was 1 of 183 operated patients; that is, for every 183 patients treated with cemented implants, one death would be expected. CONCLUSION: Bone cement is associated with a higher risk of fatalities within 48 hours of surgery compared with cementless prostheses. However, numerous prior studies have found a higher risk of serious complications resulting in additional surgical procedures associated with cementless devices in this population; those complications, as well, may result in death. Based on our study alone, we cannot recommend cementless implants in this setting. Large, national registries should evaluate fixation choice in older patients with hip fractures, and those studies should consider both early death and the potential for later harms. LEVEL OF EVIDENCE: Level III, therapeutic study.

Correction to: Do direct oral anticoagulants (DOACs) cause delayed surgery, longer length of hospital stay, and poorer outcome for hip fracture patients?

The original version of this article unfortunately contained a mistake.

Do direct oral anticoagulants (DOACs) cause delayed surgery, longer length of hospital stay, and poorer outcome for hip fracture patients?

PURPOSE: The perioperative consequences of direct oral anticoagulants (DOACs) in hip fracture patients are not sufficiently investigated. The primary aim of this study was to determine whether DOAC-users have delayed surgery compared to non-users. Secondarily, we studied whether length of hospital stay, mortality, reoperations and bleeding complications were influenced by the use of DOAC. METHODS: The medical records of 314 patients operated for a hip fracture between 2016 and 2017 in a single trauma center were assessed. Patients aged < 60 and patients using other forms of anticoagulation than DOACs were excluded. Patients were followed from admission to 6 months postoperatively. Surgical delay was defined as time from admission to surgery. Secondary outcomes included length of hospital stay, transfusion rates, perioperative bleeding loss, postoperative wound ooze, mortality and risk of reoperation. The use of general versus neuraxial anaesthesia was registered. Continuous outcomes were analysed using Students t test, while categorical outcomes were expressed by Odds ratios. RESULTS: 47 hip fracture patients (15%) were using DOACs. No difference in surgical delay (29 vs 26 h, p = 0.26) or length of hospital stay (6.6 vs 6.1 days, p = 0.34) were found between DOAC-users and non-users. DOAC-users operated with neuraxial anaesthesia had longer surgical delay compared to DOAC-users operated with general anaesthesia (35 h vs 22 h, p < 0.001). Perioperative blood loss, transfusion rate, risk of bleeding complications and mortality were similar between groups. CONCLUSION: Hip fracture patients using DOAC did not have increased surgical delay, length of stay or risk of reported bleeding complications than patients without anticoagulation prior to surgery. The increased surgical delay found for DOAC-users operated with neuraxial anaesthesia should be interpreted with caution.

Low-molecular-weight heparin for hip fracture patients treated with osteosynthesis: should thromboprophylaxis start before or after surgery? An observational study of 45,913 hip fractures reported to the Norwegian Hip Fracture Register.

Background and purpose - Controversies exist regarding thromboprophylaxis in orthopedic surgery. We studied whether the thromboprophylaxis in hip fracture patients treated with osteosynthesis should start preoperatively or postoperatively. Data were extracted from the nationwide Norwegian Hip Fracture Register (NHFR). The risks of postoperative deaths, reoperations, and intraoperative bleeding were studied within 6 months after surgery. Patients and methods - After each operation for hip fracture in Norway the surgeon reports information on the patient, the fracture, and the operation to the NHFR. Cox regression analyses were performed with adjustments for age group, ASA score, sex, duration of surgery, and year of surgery. During the period 2005-2016, 96,599 hip fractures were reported to the register. Only osteosyntheses where low-molecular-weight heparin (LMWH) were given and with known information on preoperative start of the prophylaxis were included in the analyses. Dalteparin and enoxaparin were used in 58% and 42% of the operations respectively (n = 45,913). Results - Mortality (RR =1.01, 95% CI 0.97-1.06) and risk of reoperation (RR =0.99, CI 0.90-1.08) were similar comparing preoperative and postoperative start of LMWH. Postoperative start reduced the risk of intraoperative bleeding complications compared with preoperative start (RR =0.67, CI 0.51-0.90). Interpretation - The initiation of LMWH did not influence the mortality or the risk of reoperation in hip fracture patients treated with osteosynthesis. Postoperative start of LMWH could possibly decrease the risk of intraoperative bleeding.

Similar Clinical Outcomes with Preoperative and Postoperative Start of Thromboprophylaxis in THA: A Register-based Study.

BACKGROUND: Elective THA is associated with a high risk of thromboembolic events. Although these events may be less common now than they were in the past, they can be serious, and most patients undergoing the procedure therefore still receive thromboprophylaxis. However, controversy remains regarding whether to begin thromboprophylaxis before THA or after to best balance the risks of clotting and bleeding. QUESTIONS/PURPOSES: We asked the following questions: (1) Is there a difference in bleeding events with pre- versus postoperative thromboprophylaxis? (2) Is there a difference in thromboembolic episodes after THA between the two regimens? (3) How do the two approaches of thromboprophylaxis influence mortality, readmissions, and other complications? METHODS: We used a population-based followup design with predefined data based on international health codification to assess clinical effects of LMWH prophylaxis initiated before or after THA. We took data limited to primary THAs done in Norway between January 1, 2008, and December 31, 2011, from the Norwegian Arthroplasty Register and the National Patient Register to have necessary data elements to complete the study. The two registers were merged after identifying patients with their 11-digit personal identification number (Social Security number). We obtained data regarding demographics, administrative and surgical details, and episode histories for prophylaxis-related events within 180 days of surgery. A total of 25,163 patients undergoing THA were included for analysis, and 9977(40%) versus 15,186 (60%) patients received pre- and postoperative LMWH, respectively. We performed statistical adjustment for differences in baseline characteristics using multivariate logistic regression. RESULTS: After adjustment for age, sex, operation time, year of surgery, and American Society of Anesthesiologists class, we could not show major differences in bleeding events; (odds ratio [OR], 1.04; 95% CI, 0.88-1.22; p = 0.660), thromboembolic episodes; (OR, 1.03; 95% CI, 0.84-1.27; p = 0.786), or other postoperative clinical complications; (OR, 0.86; 95% CI, 0.76-0.99; p = 0.034), with the two regimens. Six-month mortality was similar, (OR, 0.76; 95% CI, 0.56-1.05; p = 0.093), and the readmission rate was higher in the preoperative group; (OR, 0.92; 95% CI, 0.85-0.97; p = 0.016). CONCLUSIONS: The risk for postoperative complications seems to be comparable whether LMWH prophylaxis is initiated before or after THA. The postoperative approach reduces costs, decreases risks related to neuraxial anesthesia, and facilitates same-day admissions. Methods for individual risk assessment including laboratory tests would be feasible. LEVEL OF EVIDENCE: Level III, therapeutic study.

Thrombin Generation in Patients With Suspected Venous Thromboembolism.

Increasing number of patients with clinically suspected venous thromboembolism is referred to radiological departments for definitive diagnosis. A simple assay to exclude the diagnosis and avoid radiological examinations is needed. We have reported correlations between D-dimer and prothrombin fragment 1 + 2 measured in plasma and urine. To further develop an analysis based on urine, more understanding of thrombin generation in these patients is needed. The aim of this study was to compare ex vivo thrombin generation with in vivo markers in plasma and urine in patients with and without venous thromboembolism. Urine and blood samples were collected from patients with suspected venous thromboembolism. Commercially available enzyme-linked immunosorbent assay (ELISA) kits were used to analyze the samples for in vivo thrombin generation. The ex vivo thrombogram parameters were measured by the calibrated automated thrombogram assay. Venous thromboembolism was verified with compression ultrasound of the lower extremity deep veins or with computer tomography of the pulmonary arteries. Venous thromboembolism was diagnosed in 117 of 591 patients, and they had significantly higher levels of urine and plasma prothromin fragment 1 + 2, D-dimer, lag time, time to peak, and endogenous thrombin potential when adjusted for covariates. The pattern of ex vivo and in vivo thrombin generation in patients with suspected venous thromboembolism was comparable when adjusted for covariates. Prothrombin fragment 1 + 2 in plasma and urine reflects thrombin generation ex vivo in the same manner. This indicates that urine may be an alternative substrate to quantify a procoagulant state.

Postoperative start compared to preoperative start of low-molecular-weight heparin increases mortality in patients with femoral neck fractures.

Background and purpose - Controversies exist regarding thromboprophylaxis in orthopedic surgery. Using data in the nationwide Norwegian Hip Fracture Register (NHFR) with postoperative death and reoperation in the first 6 months after surgery as endpoints in the analyses, we determined whether the thromboprophylaxis in patients who undergo hemiarthroplasty for femoral neck fracture should start preoperatively or postoperatively. Patients and methods - After each operation for hip fracture in Norway, the surgeon reports information on the patient, the fracture, and the operation to the NHFR. Cox regression analyses were performed with adjustments for age, ASA score, gender, type of implant, length of surgery, and year of surgery. Results - During the period 2005-2014, 25,019 hemiarthroplasties as treatment for femoral neck fractures were reported to the registry. Antithrombotic medication was given to 99% of the patients. Low-molecular-weight heparin predominated with dalteparin in 57% of the operations and enoxaparin in 41%. Only operations with these 2 drugs and with known information on preoperative or postoperative start of the prophylaxis were included in the analyses (n = 20,241). Compared to preoperative start of thromboprophylaxis, postoperative start of thromboprophylaxis gave a higher risk of death (risk ratio (RR) = 1.13, 95% CI: 1.06-1.21; p < 0.001) and a higher risk of reoperation for any reason (RR =1.19, 95% CI: 1.01-1.40; p = 0.04), whereas we found no effect on reported intraoperative bleeding complication or on the risk of postoperative reoperation due to hematoma. The results did not depend on whether the initial dose of prophylaxis was the full dosage or half of the standard dosage. Interpretation - Postoperative start of thromboprophylaxis increased the mortality and risk of reoperation compared to preoperative start in femoral neck fracture patients operated with hemiprosthesis. The risks of bleeding and of reoperation due to hematoma were similar in patients who received low-molecular-weight heparin preoperatively and in those who received it postoperatively.

D-Dimer and prothrombin fragment 1 + 2 in urine and plasma in patients with clinically suspected venous thromboembolism.

Increased levels of urine prothrombin fragment 1 + 2 was recently reported to be associated with imaging-verified venous thromboembolism. In this study we evaluated the relationship between plasma D-dimer and plasma and urine prothrombin fragment 1 + 2 in patients with suspected venous thromboembolism. Urine and blood samples were collected from patients with suspected pulmonary embolism or deep vein thrombosis. The samples were analysed with commercially available ELISA kits. The diagnosis of venous thromboembolism was verified with contrast-enhanced computer tomography of the pulmonary arteries or lower extremity deep vein compression ultrasound and venography as appropriate. Venous thromboembolism was diagnosed in 150 of 720 patients. Significantly higher levels of plasma D-dimer and prothrombin fragment 1 + 2 in plasma and urine were found in those with imaging-confirmed venous thromboembolism versus those without (P < 0.001). The correlation between the three biomarkers was statistically significant (range of rs values 0.45-0.65, P < 0.001). Plasma D-dimer had the highest diagnostic accuracy followed by prothrombin fragment 1 + 2 in plasma. Further development of ELISA analyses for urine testing of prothrombin fragment 1 + 2 may improve its diagnostic accuracy.

Oral dabigatran etexilate versus enoxaparin for venous thromboembolism prevention after total hip arthroplasty: pooled analysis of two phase 3 randomized trials.

BACKGROUND: Two phase 3 trials compared 28-35 days of treatment with oral dabigatran 220 mg or 150 mg (RE-NOVATE) or 220 mg (RE-NOVATE II) once daily with subcutaneous enoxaparin 40 mg once daily for prevention of venous thromboembolism (VTE) after elective total hip arthroplasty. METHODS: This prespecified pooled analysis compared the outcomes for the dabigatran 220 mg dose with enoxaparin, which included 4,374 patients. Total VTE (venographic and symptomatic) plus all-cause mortality (primary efficacy), major VTE (proximal deep vein thrombosis [DVT] or non-fatal pulmonary embolism) plus VTE-related death, and bleeding events were evaluated. Efficacy analysis was based on the modified intention-to-treat (ITT) population and safety analysis was based on all treated patients. The common risk difference (RD) for dabigatran versus enoxaparin was estimated using a fixed effects model. RESULTS: Total VTE and all-cause mortality occurred in 6.8 % (114/1,672) and 7.7 % (129/1,682) (RD:-0.8 %, 95 % confidence interval [CI] -2.6 to 0.9) for dabigatran and enoxaparin, respectively. Major VTE plus VTE-related mortality occurred in 2.7 % (46/1,714) and 4.0 % (69/1,711) (RD: -1.4 %, 95 % CI -2.6 to -0.2) of patients receiving dabigatran 220 mg and enoxaparin, respectively. Major bleeding occurred in 1.7 % (37/2,156) and 1.3 % (27/2,157) (RD: 0.5 %, 95 % CI -0.2 to 1.2), for dabigatran and enoxaparin respectively. CONCLUSIONS: Extended prophylaxis with oral dabigatran 220 mg once daily was as effective as enoxaparin 40 mg once daily in reducing the risk of total VTE and all-cause mortality after total hip arthroplasty, with a similar bleeding profile. The clinically relevant outcome of major VTE and VTE-related death was significantly reduced with dabigatran versus enoxaparin. TRIAL REGISTRATION: NCT00657150 and NCT00168818.

The population attributable risk of nutrition and lifestyle on hip fractures.

INTRODUCTION: Norway is among the countries with the highest incidence of hip fractures, and how to reduce this incidence is a major public health concern. MATERIALS AND METHODS: The population attributable risk (PAR), which measures the portion of hip fracture incidences in the population that can be attributed to an exposure if there is a causal relationship, was assessed for the exposure to excessive alcohol consumption, being underweight, low calcium from dairy products, low physical activity and current tobacco smoking. The risk ratio (RR) of the exposures summarized from systematic reviews and meta-analyses, as well as their prevalence from national statistics or Norwegian population-based studies, were used to estimate PARs. RESULTS: Low physical activity and current tobacco smoking had the highest RR for hip fractures, with 1.65 (95% CI 1.50-1.81) and 1.52 (95% CI 1.41-1.63). Low physical activity had the highest prevalence in the population (27.4%) and the highest PAR (0.151), followed by tobacco smoking (PAR = 0.081) and excessive alcohol consumption (PAR = 0.01). By comparison, being underweight and low calcium from dairy products had negligible PAR estimates. CONCLUSIONS: From a public health perspective, increased daily physical activity is the most promising intervention to reduce the incidence of hip fractures. Reduced smoking and alcohol consumption are of relevance, but other health risks related to these exposures are of greater public health concern. Low body weight and nutritional calcium from dairy products seem to be of less importance.

Arterial and venous thrombosis following trauma and major orthopedic surgery: molecular mechanisms and strategies for intervention.

A variety of harmful effects can be triggered by trauma and major orthopedic surgery. One of the key players involved in this process is thrombin. The clinical consequence of this process has, for several decades, been considered to be formation of deep vein thrombosis and pulmonary embolism. Controlling thrombin generation and activation has therefore been the goal of thromboprophylaxis regimens administered to patients suffering from trauma or undergoing major surgery. Protecting patients from venous thromboembolism has, for many years, been the main goal of preventive strategies. However, our knowledge of cell destruction and release of substances that may cause organ damage has expanded in recent years. Release of molecules such as RNA and histones from destroyed tissues may cause cell destruction and organ damage at distal sites if released in huge amounts and disseminated systemically. This new knowledge points toward an unmet need for therapies that prevent both vascular events and organ deterioration. This article briefly reviews molecular mechanisms associated with the occurrence of vascular events and cellular destruction in patients with major bone damage caused by trauma.

Prothrombin fragment 1+2 in urine as a marker on coagulation activity in patients with suspected pulmonary embolism.

INTRODUCTION: We have recently reported that increased levels of urine prothrombin fragment 1+2 reflected radiologically verified deep vein thrombosis. In this study we evaluated whether urine prothrombin fragment 1+2 was associated with pulmonary embolism in non-selected patients. MATERIALS AND METHODS: Patients with clinical suspected pulmonary embolism were interviewed on comorbidities and medications. Urine was collected from each patient before radiological examination and snap frozen until analysed on urine prothrombin fragment 1+2 with an ELISA kit. Imaging of the pulmonary arteries were conducted with contrast enhanced computer tomography. RESULTS: Pulmonary embolism was diagnosed in 44/197 patients. Non-significantly higher urine prothrombin fragment 1+2 levels were found in non-selected patients with pulmonary embolism vs. those without (p=0.324). Significantly higher urine prothrombin fragment 1+2 levels were found in the pulmonary embolism positive patients without comorbidities (n=13) compared to the control group (n=28) (p=0.009). The calculated sensitivity, specificity and negative predictive value using the lowest detectable urine prothrombin fragment 1+2 level was 82%, 34% and 87%, respectively. CONCLUSIONS: There was no significant urine prothrombin fragment 1+2 level difference in patients with and without pulmonary embolism. In non-comorbide pulmonary embolism positive patients the urine prothrombin fragment 1+2 levels were significantly higher compared to the control group. The negative predictive value found in this study indicates that uF1+2 has the potential to identify patients with a low risk of PE.

The proportion of perioperative mortalities attributed to cemented implantation in hip fracture patients treated by hemiarthroplasty.

INTRODUCTION: Bone cement for fixation of prostheses, comorbidity and age have been previously shown to be associated with increased relative risk of mortality within the first day of surgery. However, the proportion of mortalities associated to each of these exposures is not adequately expressed by relative risk estimates. MATERIALS AND METHODS: The attributable fraction (AF), i.e., the fraction of diseased individuals attributed to a given risk factor, was estimated for cemented fixation of hip prostheses in the elderly (>65 years) with a hip fracture. Dementia, symptomatic comorbidity (American Society of Anesthesiologists (ASA)≥ 3), old age (≥85 years), male gender, and a delay of 24 hours or more from fracture to operation were considered as additional risk factors for a fatal outcome in close proximity to surgery. RESULTS: In the entire study population (n = 11210), the unadjusted and adjusted population AFs of cemented fixation on mortalities within the first day after surgery were 0.58 (95% CI 0.28-0.76) and 0.59 (95% CI 0.29-0.76), respectively. Symptomatic comorbidity and old age as risk factors had population AFs of 0.71 (95% CI 0.51-0.83) and 0.55 (95% CI 0.39-0.67), respectively. Male gender, dementia and time from fracture to operation all had considerably lower population AFs. CONCLUSIONS: The estimated AFs on perioperative mortality in hip fracture patients treated by hemiarthroplasty showed that about half of the mortalities within the first day of surgery could be associated with the use of bone cement.

Clinical venous thromboembolism following joint surgery: effect of extended thromboprophylaxis on its annual frequency and postoperative pattern over 22 years.

We describe annual incidences and 6-month postoperative patterns of clinical venous thromboembolism (VTE) in 9078 patients undergoing major joint surgery in a Scandinavian hospital. In cohort I (1989-1999), low-molecular-weight heparin thromboprophylaxis for 7 to 10 days was uniformly introduced, 5-week thromboprophylaxis becoming routine after total hip replacement (THR), partially applied after hip fracture surgery (HFS), but not used after total knee replacement (TKR) thereafter (2003-2011; cohort II). Mean annual VTE incidence was lower in cohort II than in cohort I after THR and HFS but not after TKR. In cohort I, the cumulative VTE incidence increased sharply during the first 5 postoperative weeks in all groups, subsequently plateauing up to 6 months postsurgery. In cohort II, this incidence remained low and stable during 5 weeks post-THR, rising gradually up to 6 months, with a comparable but less pronounced pattern following HFS but not TKR. In conclusion, the VTE risk after major joint surgery seems to persist after 5- and 1-week prophylaxis in patients undergoing hip surgery and TKR, respectively.

Thrombin split products (prothrombin fragment 1 + 2) in urine in patients with suspected deep vein thrombosis admitted for radiological verification.

INTRODUCTION: The appearance of prothrombin fragment 1 + 2 (F1 + 2) in urine has been associated with postoperative hypercoagulability and thromboembolism. We wanted to assess if F1 + 2 was released in urine (uF1 + 2) in patients with procoagulant disorders, and if higher levels were found in patients with radiological verified deep vein thrombosis (DVT). MATERIALS AND METHODS: Consecutive patients were interviewed on comorbidities and medications. An unselected total cohort (n = 534) and a control cohort (n = 177) were analysed. A urine sample (10 ml) was collected and snap frozen before levels of uF1 + 2 were measured with an ELISA kit. Visualisation of DVT was done with compression ultrasound, supplied with venography when feasible. All patients were followed up for 3-6 months. RESULTS: DVT was diagnosed in 108/534 patients. Statistical significant higher uF1 + 2 levels were found in patients with DVT (p < 0.001), in DVT positive patients with ongoing malignancy (p = 0.034) and in pregnant women compared to the control cohort (p < 0.001). Non-significant increased urine concentrations were found in DVT positive vs. DVT negative patients with infections and traumas. CONCLUSIONS: Levels of uF1 + 2 was associated with DVT both in the total cohort and in the control cohort as well as in most patients with coexisting conditions.