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.

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.

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.

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.

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.