Paul J. Zajkowski

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.

Venous thrombosis incidence in burn patients: Preliminary results of a prospective study

There are few prospective data on the incidence of deep venous thrombosis (DVT) in burn patients. In an on-going prospective study, hospitalized burn patients 18 years or older with an expected hospital length of stay more than 72 hours were imaged with baseline venous duplex ultrasound of all extremities within the first 48 hours after admission and weekly until discharge. Patient demographics and clinical risk factors for DVT were assessed. At the time of submission, 40 patients met screening criteria, and 30 were enrolled. Ultrasound diagnosed seven patients with 11 acute DVT for an incidence of 23%. One pulmonary embolism was documented. DVT patients had a mean age of 49 +/- 23 years with an average TBSA burn of 15 +/- 4% compared with those without thrombosis with a mean age of 44 +/- 17 years (P = NS) and TBSA burn of 18 +/- 25% (P = NS). There were no statistically significant differences for DVT patients in terms of age, number of central line days, hospital length of stay, or TBSA burned. Given the preliminary findings of this small study, we believe that all hospitalized burn patients are at risk for DVT. On-going investigation will be helpful in defining level of risk and improved prevention strategies for thromboembolic complications in burn patients.

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.

Exercise with compression stockings improves reflux in patients with mild chronic venous insufficiency

Purpose: This study evaluates the effectiveness of calf muscle strengthening with compression stockings on the haemodynamics in patients with venous disease. Method: Patients were assigned to a protocol of aggressive management of their chronic venous insufficiency (CVI) including compression stockings (Jobst knee high, 30–40 mmHg ankle), intermittent leg elevation, and a supervised calf muscle strengthening programme. Patients underwent baseline air plethysmography (APG) with and without stockings (T1) and SF-12, Aberdeen varicose vein questionnaire and venous severity score. Exercise sessions included a total of 18, 1 h supervised sessions, 2–3 times per week, consisting of 15 min on treadmill, 10 min on a Stairmaster, 10 min on a Nustep, and 5 min on an airdyne bicycle and lower body strength training. The sessions were supervised by an exercise physiologist. At completion, patients underwent a second APG (T2) and a third (T3) one month later, as well as answering questionnaires. A final venous severity score was assigned. Results: Eleven patients (7M, 4F), 22 limbs, 14 with CVI and eight without CVI, mean age 60, made up this study. Only two patients suffered from postphlebitic syndrome. In all, 10/11 subjects completed the entire protocol. Although no significant differences were noted in any of the APG parameters between T1 and T2 or T2 and T3, there were significant differences when segregating into C2 (n = 6 patients with eight involved limbs) and C4, 5 (n = 5 patients with six involved limbs). Concerning the affected extremities, statistically significant decreases in venous volume (VV) with stockings on between T1 and T2, which reverted back to baseline at T3, and in venous filling index (VFI) between T2 and T3 without stockings were noted (P<0.05) in C2 limbs. Similar findings were not observed in the C4, C5 limbs, with actual increases in these parameters. Greater increases in ejection fraction were noted in C2 limbs than in C4, C5 limbs. Despite the decrease in reflux in C2 limbs, residual volume fraction (RVF) increased in C2 limbs at T2 both with (P<0.05) and without stockings, while it decreased in C4, C5 limbs with stockings in place. Finally, outflow fraction (OF) increased only in C2 limbs without stockings in place. Regarding the other parameters, all patients noted improvement in swelling by Aberdeen questionnaire, physical health was improved by SF-12 and patients lost a mean of 3.8 lb of weight. Conclusions: An exercise programme along with compression stockings resulted in a decrease in reflux, especially during the supervised exercise programme, in patients with mild (C2) chronic venous disease. For more extensive disease (C4, C5), the programme tended to decrease RVF.