Anticoagulant therapy for septic coagulopathy and disseminated intravascular coagulation: where do KyberSept and SCARLET leave us?

Abstract

The use of antithrombin and thrombomodulin to restore impaired anticoagulant pathways in septic coagulopathy has been shown to significantly increase the resolution rate of disseminated intravascular coagulation. In KyberSept and SCARLET, two large, international, randomized controlled trials in patients with sepsis, these anticoagulants have not shown significantly reduced mortality. The aim of this assessment was to compare the heterogeneity in responses to treatment in the two trials according to different patient phenotypes. Results of the KyberSept and SCARLET trials reported in original and post-hoc publications were analyzed and directly compared for treatment effects in various patient subgroups. In both KyberSept and SCARLET, the septic coagulopathy phenotype that benefited most from endogenous anticoagulant supplementation showed markers of excessive activation of coagulation. Interaction between concomitant thromboprophylactic heparin and the endogenous anticoagulants abrogated the efficacy of both antithrombin and thrombomodulin. In both trials, higher disease severity was associated with better treatment outcome. In conclusion, in two landmark studies of endogenous anticoagulants in patients with sepsis, similar findings of beneficial effects in the coagulopathy phenotype and interactions with heparin comedication and disease severity support the potential roles that thrombomodulin and antithrombin might play in treating septic coagulopathy and disseminated intravascular coagulation. Further prospective validation is warranted. Future trial designs to definitively establish the therapeutic relevance of antithrombin and thrombomodulin in septic coagulopathy should focus on involvement of patients characterized by coagulopathy and disease severity as well as interactions between endogenous anticoagulants and exogenous heparin.

Study of alteplase for respiratory failure in severe acute respiratory syndrome coronavirus 2/COVID‐19: Study design of the phase IIa STARS trial

“…The mechanistic rationale for the administration of t-PA (alteplase) is based on (i) autopsy findings of patients who succumbed to COVID- 19 ARDS showing presence of microthrombi in the lungs and other organs 1,3 ; (ii) COVID-19 poor outcomes associated with hypercoagulability/hypofibrinolysis [43][44][45] ; (iii) the high rate of pulmonary thrombotic complications while on prophylactic heparin dosing 46 ; (iv) and…”

“…The worldwide incidence of coronavirus disease 2019 (COVID- 19) continues to rise, taxing the health care and economic resources of countries throughout the developed world. Based on the clinical experience in China and Italy, it is estimated that 5% to 27% of hospitalized patients with COVID-19 will require prolonged intensive care, [1][2][3][4][5][6] with 50% to 99% requiring mechanical ventilation (MV) for viral-induced pneumonitis progressing to acute hypoxemic respiratory failure and acute respiratory distress syndrome (ARDS). 2,7,8 In patients requiring MV, the reported mortality exceeds 50% 7,9 and approached 90% in a recent report from New York City.…”

“…10 There is no specific treatment for COVID-19 ARDS other than routine mechanical ventilation, although prone positioning seems to be particularly effective in this population, 11 as well as fibrin-platelet microthrombi in the pulmonary vasculature. 1,3 The concept of accumulation of pulmonary microthrombi leading to death dates back to 1845. 13 The angiographic appearance of filling defects of the pulmonary vasculature in patients with ARDS has been associated with a high mortality rate for decades.…”

Disseminated intravascular coagulation: A devastating systemic disorder of special concern with COVID ‐19

“…24 Therapy of DIC is not directed at the skin, but rather at the management of the causative condition. 1,24,[43][44][45][46]-associated DIC therapy should follow accepted strategy employing thromboembolic prophylaxis for critically ill hospitalized patients and standard supportive care measures. 47 However, a lack of thrombocytopenia may mean that COVID-19 DIC is not always a typical consumptive coagulopathy with additional strategies possibly necessary.…”

“…Treatment of DIC usually requires a multidisciplinary approach in an intensive care unit 24 . Therapy of DIC is not directed at the skin, but rather at the management of the causative condition 1,24,43‐46 . COVID‐19‐associated DIC therapy should follow accepted strategy employing thromboembolic prophylaxis for critically ill hospitalized patients and standard supportive care measures 47 .…”