hirudin and Systemic-Inflammatory-Response-Syndrome

Protease activated receptor 1 (PAR1) signaling can play opposing roles in sepsis, either promoting dendritic cell (DC)-dependent coagulation and inflammation or reducing sepsis lethality due to activated protein C (aPC) therapy. To further define this PAR1 paradox, we focused on the vascular effects of PAR1 signaling. Pharmacological perturbations of the intravascular coagulant balance were combined with genetic mouse models to dissect the roles of endogenously generated thrombin and aPC during escalating systemic inflammation. Acute blockade of the aPC pathway with a potent inhibitory antibody revealed that thrombin-PAR1 signaling increases inflammation-induced vascular hyperpermeability. Conversely, aPC-PAR1 signaling and the endothelial cell PC receptor (EPCR) prevented vascular leakage, and pharmacologic or genetic blockade of this pathway sensitized mice to LPS-induced lethality. Signaling-selective aPC variants rescued mice with defective PC activation from vascular leakage and lethality. Defects in the aPC pathway were fully compensated by sphingosine 1 phosphate receptor 3 (S1P3) deficiency or by selective agonists of the S1P receptor 1 (S1P1), indicating that PAR1 signaling contributes to setting the tone for the vascular S1P1/S1P3 balance. Thus, the activating proteases and selectivity in coupling to S1P receptor subtypes determine vascular PAR1 signaling specificity in systemic inflammatory response syndromes in vivo.

Topics: Animals; beta-Alanine; Capillary Leak Syndrome; Capillary Permeability; Disseminated Intravascular Coagulation; Endothelial Protein C Receptor; Endothelium, Vascular; Endotoxins; Enzyme Activation; Glycoproteins; Hirudins; Mice; Mice, Inbred C57BL; Mice, Knockout; Nerve Tissue Proteins; Protein C; Receptor, PAR-1; Receptors, Cell Surface; Receptors, Lysosphingolipid; Signal Transduction; Specific Pathogen-Free Organisms; Sphingosine-1-Phosphate Receptors; Systemic Inflammatory Response Syndrome; Thiophenes; Thrombin; Thromboplastin

Lepirudin is a potent, direct thrombin inhibitor used for anticoagulation in patients with heparin-induced thrombocytopenia type II (HIT). The half-life of lepirudin is prolonged in patients with renal insufficiency. Preliminary studies suggest that it is safe to use lepirudin in patients being treated with intermittent hemodialysis but information regarding its use with continuous renal replacement therapy (CRRT) is scarce. CRRT is used in acute care settings to remove fluid and uremic toxins in patients with renal failure with hemodynamic instability. Patients with HIT, renal failure, and hemodynamic instability pose a complex situation for clinical management. These patients require anticoagulation with nonheparin agents with simultaneous CRRT. There are no guidelines in the literature regarding the management of this patient group. We report our experience with lepirudin at managing four such patients with HIT, being treated with CRRT.

Topics: Aged; Aged, 80 and over; Anticoagulants; Drug Evaluation; Female; Half-Life; Heparin; Hirudins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Multiple Organ Failure; Postoperative Complications; Purpura, Thrombocytopenic, Idiopathic; Recombinant Proteins; Renal Dialysis; Retrospective Studies; Systemic Inflammatory Response Syndrome