Etanercept and venous thromboembolism: a case series.

INTRODUCTION: The treatment with antitumor necrosis factor agents has often been associated with the induction of autoantibodies (antinuclear antibodies, anti-double stranded DNA antibodies and antiphospholipid antibodies). The clinical significance of these antibodies remains unclear, but they may predispose to antiphospholipid syndrome with thromboembolic complications. The association of etanercept with thromboembolic events has not been reported previously in the literature. CASE PRESENTATION: We describe the cases of three patients with rheumatoid arthritis, psoriatic arthritis and seronegative inflammatory arthritis who were treated with etanercept. They developed deep vein thrombosis and/or pulmonary embolism one to three years after the initiation of etanercept therapy. All three patients had a prolonged activated partial thromboplastin time with a positive lupus anticoagulant that persisted even after 12 weeks. CONCLUSION: Although the clinical significance of antiphospholipid antibodies during treatment with antitumor necrosis factor agents remains unclear, they may predispose patients to develop antiphospholipid syndrome when associated with prolonged activated partial thromboplastin time, lupus anticoagulant positivity, or the presence of anti-beta2 glycoprotein I. Clinicians must keep this in mind during therapy with antitumor necrosis factor agents in order to prevent, detect and treat potential consequences such as deep vein thrombosis and pulmonary embolism.

Assessment of specific risks for the recurrence of deep vein thrombosis: a case report.

INTRODUCTION: Venous thromboembolism is a multifactorial disease defined by multiple interactions between genetic and environmental components. It is managed by oral anticoagulation with warfarin sodium (Coumadin), a drug that targets the vitamin K epoxide reductase to prevent the recycling of vitamin K epoxide to the reduced form of vitamin K. The reduced form of vitamin K is an essential cofactor in the formation of active clotting factors II, VII, IX, X and regulatory factors protein C, and cofactor protein S through gamma-glutamyl carboxylation. The duration of Coumadin treatment, three to six months or life-long, should be based on the individual risk for recurrent deep vein thrombosis and on the associated increased risk for bleeding complications. CASE PRESENTATION: A previously healthy 50-year-old white male developed a deep vein thrombosis consequent to surgical placement of a titanium rod to correct a fracture of the femur and he was maintained for over a year on daily oral doses of Coumadin 9 mg and aspirin 325 mg. When he began to bruise spontaneously with multiple large hematomas appearing without provocation, he requested that his primary care physician reconsider the anticoagulation. Because of his age, sex, and the possibility of an inherited or acquired anticoagulant protein deficiency he was maintained on Coumadin and a thrombophilia work up was ordered. Test results were interpreted as deficiencies in both protein C and protein S and he was instructed that life-long therapy with Coumadin was necessary. Is this a correct evaluation by his primary care physician? CONCLUSION: This case illustrates that Coumadin, a vitamin K agonist, was exerting a therapeutically acceptable negative influence on plasma activity levels of vitamin K-dependent protein C and protein S. Relying on the outcome of a thrombophilia work-up for a decision to maintain or cease Coumadin treatment of patients at risk for recurrent deep vein thrombosis has pitfalls that can be avoided. The use of real-time B-mode venous ultrasonography to verify complete restoration of venous flow before ceasing Coumadin treatment is not always considered in the long-term management of a patient with a first thrombosis, despite the well documented significant risk of deep vein thrombosis recurrence associated with an unresolved thrombosis.

Thrombophilia and hypercoagulability.

This is a review of less well-known aspects of thrombophilia and hypercoagulability as they relate to thrombosis. Thrombosis is an abnormal fibrin clot that develops in circulating blood with clinical symptoms of one or more arterial and/or venous obstructions exclusively identified by imaging techniques. The terms thrombophilia and hypercoagulability are often used indiscriminately when they are in fact separate entities. Thrombophilia is an inherited or acquired clinical phenotype manifesting in selected individuals as a greater risk to develop recurrent thrombosis at a younger age than the general population, with considerable differences in the magnitude of risks among individuals in the same family with the same thrombophilic gene defect. Hypercoagulability is a laboratory phenotype whereby in vivo activation of clotting, fibrinolysis, endothelial cells and platelets is identified in vitro by specialized clotting techniques and by specific antibodies directed at biomarkers of clotting activation and damaged vasculature. Hypercoagulability may be provoked by drugs to treat bleeding in hemophilia, by sepsis, inflammation, surgery, blood stasis, atherosclerosis, and it manifests selectively in inherited and acquired thrombophilia. A chronology of the discovery of acquired and inherited thrombophilia puts in perspective the data analyzed in two representative large family studies that address whether venous and arterial thrombosis are a necessary outcome in thrombophilia, and the question, whether patients with inherited antithrombin, protein C and protein S deficiencies need to be treated after a first episode of thrombosis. The liberal use of case vignettes emphasizes a close relationship and the distinction between thrombosis, thrombophilia and hypercoagulability.

Discordant hemodynamic and fibrinolytic adaptations following a 6-week cardiac rehabilitation program.

The present study evaluated changes in hemodynamics and fibrinolysis during 6 weeks of participation in an exercise-based cardiac rehabilitation program. Fourteen patients trained for 3 days per week for 6 weeks using American College of Sports Medicine guidelines for intensity and duration. Blood samples were taken at baseline and after 3 and 6 weeks of participation and analyzed for tissue plasminogen activator (t-PA) activity and antigen, plasminogen activator inhibitor-1 (PAI-1) activity and antigen, and relative quantification of t-PA and PAI-1 RNA. Data were analyzed using repeated measures analysis of variance. Training elicited significant decreases in submaximal exercise heart rate and systolic blood pressure and resting systolic blood pressure (p<.05). There were no significant changes in plasma concentrations of t-PA or PAI-1, and no change was observed in t-PA or PAI-1 gene expression. The present findings suggest that favorable hemodynamic adaptations may occur after only 6 weeks of exercise-based cardiac rehabilitation, but longer training periods may be needed to elicit positive hemostatic adaptations.

Upper extremity deep venous thrombosis.

Upper extremity deep venous thrombosis (UEDVT) makes up approximately 1-4% of all episodes of deep venous thrombosis (DVT). Risk factors for UEDVT include central venous catheterization, strenuous upper extremity exercise or anatomic abnormalities causing venous compression, inherited thrombophilia, and acquired hypercoagulable states including pregnancy, oral contraceptive use, and cancer. Unexplained or recurrent UEDVT should prompt a search for inherited hypercoagulable states or underlying malignancy. Clinical presentations include arm, neck, and shoulder pain; edema; skin discoloration; tenderness; and venous distension. Because UEDVT is frequently asymptomatic until complications ensue, a high index of suspicion is required for patients with one or more risk factors for thrombosis. Pulmonary embolism and post-thrombotic syndrome are the most common sequelae of UEDVT. Early detection and treatment of UEDVT decrease complications, morbidity, and mortality. Compressive ultrasonography is an effective and economical means of confirming the clinical diagnosis in most patients. Traditional anticoagulant therapy of UEDVT is giving way to a multimodal approach involving transcatheter thrombolytic therapy followed by a minimum of 3 months of warfarin sodium anticoagulant therapy, venous decompression as needed, and balloon angioplasty with stenting for treatment of residual stricture. Low-dose anticoagulant therapy can safely and effectively mitigate the increased risk of UEDVT associated with the use of central venous catheters.

Proteolysis of protein C in pooled normal plasma and purified protein C by activated protein C (APC).

Protein C is a vitamin-K dependent zymogen of the anti-coagulant serine protease activated protein C (APC). In this paper, we report four lines of evidence that APC can activate protein C in pooled normal plasma, and purified protein C. First, the addition of APC to protein C-deficient plasma supplemented with protein C produces a prolongation of the clotting time of plasma that is proportional to the amount of protein C. This behavior was observed with APC from the Chromogenix APC resistance kit (Dia Pharm, Franklin, OH, USA) and from APC derived from the thrombin activation of human protein C (Enzyme Research Laboratories, South Bend, IN, USA). Secondly, using immunoblotting after gel electrophoresis, the disappearance of epitopes for monoclonal antibodies that recognize protein C but not APC indicates a time course for the activation by APC of protein C in pooled normal plasma and protein C purified from plasma. Thirdly, the same time course for the disappearance of protein C specific epitope can be followed using ELISA. Finally, protein C can be activated by APC as indicated by the increase in APC specific synthetic substrate Tryp-Arg-Arg-p nitroaniline hydrolysis. Kinetic data indicate a value of 4.7+/-0.4 mM(-1) s(-1) for the activation of protein C by APC under physiological conditions and in the presence of calcium. These observations document that APC must function not only in the inactivation of activated factors V and VIII, but also in the activation of protein C. This additional action of APC may be important to consider more broadly because of APC in the treatment of sepsis.