Biology and pathogenesis of thrombosis and procoagulant activity in invasive infections caused by group A streptococci and Clostridium perfringens

Abstract

Group A streptococcal necrotizing fasciitis/myonecrosis and Clostridium perfringens gas gangrene are two of the most fulminant gram-positive infections in humans. Tissue destruction associated with these infections progresses rapidly to involve an entire extremity. Multiple-organ failure is common, and morbidity and mortality remain high. Systemic activation of coagulation and dysregulation of the anticoagulation pathways contribute to the pathogenesis of many diverse disease entities of infectious etiology, and it has been our hypothesis that microvascular thrombosis contributes to reduced tissue perfusion, hypoxia, and subsequent regional tissue necrosis and organ failure in these invasive gram-positive infections. This article reviews the coagulation, anticoagulation, and fibrinolytic systems from cellular players to cytokines to novel antithrombotic therapies and discusses the mechanisms contributing to occlusive microvascular thrombosis and tissue destruction in invasive group A streptococcal and C. perfringens infections. A thorough understanding of these mechanisms may suggest novel therapeutic targets for patients with these devastating infections.

FIG. 1.

Schematic of the coagulation-anticoagulation system with known interactions of GAS. Solid lines indicate pathways that contribute to coagulation; and jagged lines indicate pathways that inhibit coagulation or contribute to fibrinolysis. M type 1 and 3 GAS stimulate tissue factor production from endothelial cells (ECs) and monocytes (MOs) (21); in addition, direct or indirect injury to ECs by SLO or streptococcal pyrogenic exotoxin B may expose extravascular TF (interaction 1). In experimental GAS necrotizing fasciitis induced by an M type 1 strain of GAS (85) and in humans with StrepTSS (84), the level of factor XII is decreased and the APTT is prolonged; however, the PT is normal, and experimental animals display a hypercoagulable state (85) (interaction 2). Streptokinase binds plasminogen, and GAS M protein binds fibrinogen; this quaternary complex has potent plasminogen activator activity (51, 104) (tPA, tissue plasminogen activator) (interaction 3). In a nonhuman primate model of M type 3 GAS necrotizing fasciitis and myonecrosis, animals had increased circulating levels of fibrin degradation products (FDP [interaction 4a]) and thrombin-AT III complexes (interaction 4b), indicating systemic activation of the coagulation system (92) (interaction 4). Some strains of GAS, but notably not M type 1 or 3, bind protein S in plasma (96) (interaction 5). Administration of TFPI to experimental animals with gram-negative bacteremia or in humans with sepsis has proven benefits; however, the efficacy of TFPI in StrepTSS remains to be determined (interaction 6). (Reprinted from reference .)

FIG. 2.

Principal receptor-ligand pairs promoting platelet-leukocyte complex formation. PSGL-1; P-selectin glycoprotein 1.

FIG. 3.

Intramuscular injection of PLC causes a rapid and irreversible decline in skeletal muscle perfusion. Rat abdominal muscles were injected with 0.1 ml of either normal sterile saline, 10 μM phenylephrine, or 8 U of PLC. Blood flow was measured for 40 min with a laser Doppler blood perfusion monitor and is expressed as the percentage of baseline perfusion ± standard error. Reprinted from reference with permission.

FIG. 4.

Histopathology of skeletal muscle following injection of PLC. Routine hemotoxylin-eosin staining of rat abdominal muscles 2 min (A) or 20 min (B) after injection with PLC is shown. Reprinted from reference with permission.

FIG. 4.

Histopathology of skeletal muscle following injection of PLC. Routine hemotoxylin-eosin staining of rat abdominal muscles 2 min (A) or 20 min (B) after injection with PLC is shown. Reprinted from reference with permission.