Prophylactic P-selectin inhibition with PSI-421 promotes resolution of venous thrombosis without anticoagulation.

P-selectin inhibition has been evaluated as a therapeutic for prevention and treatment of venous thrombosis. In this study, a novel oral small-molecule inhibitor of P-selectin, PSI-421, was evaluated in a baboon model of stasis induced deep vein thrombosis (DVT). Experimental groups included i) primates receiving a single oral dose of 1 mg/kg PSI-421 two days prior and continued six days after thrombosis (n = 3); ii) primates receiving a single daily subcutaneous dose of 0.57 mg/kg enoxaparin sodium two days prior and continued six days post thrombosis (n = 3); and iii) primates receiving no treatment (n = 3). PSI-421 treated primates had greater percent vein reopening and less vein wall inflammation than the enoxaparin and controls at day 6. Microparticle tissue factor activity (MPTFA) was significantly lower in the animals receiving PSI-421 immediately after thrombosis (T+6 hours day 0) suggesting lower potential for thrombogenesis in these animals. PSI-421 also reduced soluble P-selectin levels versus controls at T+6 hours day 0, day 2 and 6. Experimental animals in any group showed no adverse effects on coagulation. This study is the first to demonstrate a reduction in MPTFA associated with vein reopening and reduced vein inflammation due to oral P-selectin inhibition in a baboon model of DVT.

Resolution of venous thrombosis using a novel oral small-molecule inhibitor of P-selectin (PSI-697) without anticoagulation.

P-selectin inhibition has been shown to decrease thrombogenesis in multiple animal species. In this study, we show that a novel oral small-molecule inhibitor of P-selectin, PSI-697, promotes thrombus resolution and decreases inflammation in a baboon model of venous thrombosis. Experimental groups consisted of the following: 1) primates receiving a single oral dose of PSI-697 (30 mg/kg) daily starting three days pre-iliac vein balloon occlusion, and continued for six days; 2) primates receiving a single treatment dose of a low-molecular-weight-heparin (LMWH) (1.5 mg/kg) daily starting one day pre-iliac balloon occlusion, and continued for six days; and 3) primates receiving a single oral dose of a vehicle control daily starting three days pre-iliac vein balloon occlusion, and continued for six days. Animals receiving PSI-697, although thrombosed after balloon deflation, demonstrated greater than 80% vein lumen opening over time, with no opening (0%) for vehicle control (p < 0.01). LMWH opening evident after balloon deflation slightly deteriorated over time compared to PSI-697. PSI-697 therapy also significantly decreased vein wall inflammation determined by magnetic resonance venography (MRV). Importantly, this beneficial opening occurred without measured anticoagulation. Animals receiving PSI-697 demonstrated significantly increased plasma D-dimer levels versus LMWH and control animals six hours post thrombus induction (p < 0.01). This study is the first to demonstrate the effectiveness of oral P-selectin inhibition to modify venous thrombogenesis, increase vein lumen opening, and decrease inflammation in a large animal model.

Normal D-dimer levels do not exclude thrombotic complications in trauma patients.

BACKGROUND: Deep venous thrombosis (DVT) and pulmonary embolism (PE) are common complications in trauma patients. These diagnoses can be difficult and expensive to make. Recent studies report that a negative D-dimer test excludes thrombotic complications. We questioned the predictive value of a D-dimer test to exclude DVT and PE. METHODS: Adult trauma patients admitted March 1999 to March 2001, with an Injury Severity Score > or =9 and expected length of stay >3 days, were approached for enrollment. Bilateral lower extremity duplex ultrasounds and d-dimer levels were performed within 36 hours of admission, day 3-4, day 7, and weekly until discharge. RESULTS: Twenty-three patients were diagnosed with DVTs, with 18 DVTs detected within the first week of admission. Five DVT patients had normal D-dimer levels. One of three PE patients tested had a normal D-dimer level. The false negative rate for DVT by d-dimer assay was 24%, and the sensitivity was 76%. The negative predictive value for D-dimers was 92%. All false negative d-dimer tests occurred in patients diagnosed with DVT or PE within the 4 days after admission. CONCLUSION: In the early postinjury phase, a negative d-dimer test does not exclude DVT or PE. However, the negative predictive value of a D-dimer test after the first 4 days from admission rose to 100%. Patients with clinical signs and symptoms of DVT or PE in the immediate postinjury phase should undergo further screening to exclude thromboembolic complications.

Compression stockings and venous function.

HYPOTHESIS: Surgical compression stockings measurably improve venous physiologic mechanisms, and stocking brands do not differ from one another. METHODS: Eleven patients, (8 men and 3 women [mean age, 53 years]), were included. Six patients had primary venous insufficiency and 5 patients had secondary venous insufficiency; 5 patients were in CEAP class 4 and 6 were in CEAP class 5. Patients were randomly assigned to a sequence of 4 brands of knee-high, open-toe, 30- to 40-mm Hg stockings. Each patient wore a stocking for a 1-month equilibration period, then a different stocking monthly for 4 months in a row. Air plethysmography examinations were performed with and without stockings before and after each month of wear. Patients filled out a daily stocking record log and a monthly satisfaction survey. Stockings underwent compression testing after use. RESULTS: Stockings controlled reflux better than they improved calf muscle pump function. With stockings on, patients in CEAP 4 benefited more than those in CEAP 5 in decreasing reflux, while patients in CEAP 5 benefited more than those in CEAP 4 in improving calf muscle pump function. Changes in residual volume fraction were improved in patients in CEAP 5 wearing stockings but not in patients in CEAP 4. Patients with primary disease had greater volumes of reflux and calf ejection than with secondary disease. There were no hemodynamic differences between stocking brands but there were differences in patient compliance and acceptance. CONCLUSIONS: Surgical support stockings seem to be more effective in controlling reflux than in improving calf muscle pump function. All stocking brands function equally as measured by air plethysmography.

Tissue loss, early primary graft occlusion, female gender, and a prohibitive failure rate of secondary infrainguinal arterial reconstruction.

PURPOSE: This study tested the hypothesis that a subset of secondary infrainguinal arterial reconstructions show prohibitive failure rates. METHODS: Records of 79 consecutive patients, 44 men and 35 women, with a mean age of 60 years, who underwent secondary infrainguinal bypass from 1992 to 2000 at the University of Michigan Hospital, were reviewed. Data were analyzed with life-table analysis, logistic regression, and descriptive statistics. RESULTS: Secondary infrainguinal reconstructions were performed in patients who had undergone earlier ipsilateral bypasses once (n = 35) or twice (n = 44). Among the prior procedures, 68% (n = 54) were done at an institution other than the authors'. Comorbidities included coronary artery disease (72%), tobacco use (77%), and diabetes mellitus (34%), but no patient had hemodialysis-dependent renal failure. Disabling claudication, with average ankle brachial index of 0.48, had been the indication for the primary operation in 77% of cases. Femoral-popliteal bypass was the primary procedure in 67%, with a prosthetic graft used in 62%. The mean patency duration of these earlier bypasses was 25 months. The indication for the final bypass was rest pain or tissue loss in 51% of patients, with an average ankle brachial index of 0.37. The most common procedure was a femoral-distal bypass with autologous vein (63%). Mean patency duration of the secondary bypasses was 30 months. Graft failure within 30 days of operation occurred in 22 patients (28%), and amputation was necessitated in 86% of these patients. The presence of rest pain or tissue loss, when accompanied with a history of early prior graft thrombosis in female patients, correlated with worse mean patency rates, recurrent graft failure (P