Potential therapeutics for disseminated intravascular coagulation (DIC).Table modified from Dempfle.12
| Agent and rationale . | Comment . |
|---|---|
| The Heparins | |
| If thrombosis is a risk or a problem, then inhibiting thrombin’s action seems plausible | No randomized controlled trials published. Venous thromboembolism prophylaxis is ICU standard and seems rational. Heparin may worsen bleeding if used with ATIII therapy. If using heparin for therapy, do not use PTT to monitor; use heparin levels. |
| Antithrombin III | |
| ATIII is consumed in nearly all reports of DIC. Bolstering its level might increase clearance of thrombin | Large KyberSept13 trial showed no benefit yet increased bleeding when used with low-dose heparin. In septic DIC and in patients not receiving heparin, ATIII reduced mortality 15%.14 A systematic review15 of three studies gives odds ratio of 0.65 for DIC septic patients not receiving heparin. ATIII infusions decreased mortality by 25% in a group of 32 burn patients with DIC features.16 |
| Human Activated Protein C (APC) | |
| Theoretically inhibits thrombin generation mostly at microvascular level. By decreasing WBC release of tumor necrosis factor-alpha (TNFα), APC may also be anti-inflammatory | Aoki et al11 compared APC to heparin, finding increased bleeding in heparin group and decreased bleeding with APC group compared with bleeding at study entry but no effect on multiorgan dysfunction syndrome with either. Their battery of coagulation studies all improved, APC greater than heparin, but no difference in complete recovery from DIC. Death rate was 20% in APC group and 40% in heparin group. |
| Drotrecogin Alfa (DrotAA) (recombinant activated ProC) | |
| Rationale similar to human APC | Generally used in sepsis independent of DIC. DrotAA decreased mortality (risk ratio [RR] 0.71 in overt DIC and RR of 0.81 in non-overt DIC) in PROWESS study10 with trend to more bleeding but less overt thrombosis. |
| Activated Recombinant Human Factor VII (rhFVIIa) | |
| Typically used as a final option to increase production of thrombin in hemorrhaging patient resistant to all other efforts | If circulating thrombin is thought to be a major culprit, rhFVIIa could be dangerous to administer in DIC. In order to work, thrombin must be able to be generated so might be expected to not work in massive heparin overdosage or in situations having no fibrinogen and/or platelets. Several small case series17 –19 suggest possible efficacy in patients with DIC. |
| Recombinant Human Soluble Thrombomodulin (ART-123) | |
| Thrombomodulin (TM) is an endothelial-bound sink for circulating thrombin. | Aoki’s group20 compared infusion of ART-123 against low-dose heparin infusion in DIC from cancer or infection. ART-123 compared to heparin gave better improvements in coagulation tests and clinical bleeding yet no significant decrease in mortality. Side effects fewer with ART-123 than with heparin infusion |
| Agent and rationale . | Comment . |
|---|---|
| The Heparins | |
| If thrombosis is a risk or a problem, then inhibiting thrombin’s action seems plausible | No randomized controlled trials published. Venous thromboembolism prophylaxis is ICU standard and seems rational. Heparin may worsen bleeding if used with ATIII therapy. If using heparin for therapy, do not use PTT to monitor; use heparin levels. |
| Antithrombin III | |
| ATIII is consumed in nearly all reports of DIC. Bolstering its level might increase clearance of thrombin | Large KyberSept13 trial showed no benefit yet increased bleeding when used with low-dose heparin. In septic DIC and in patients not receiving heparin, ATIII reduced mortality 15%.14 A systematic review15 of three studies gives odds ratio of 0.65 for DIC septic patients not receiving heparin. ATIII infusions decreased mortality by 25% in a group of 32 burn patients with DIC features.16 |
| Human Activated Protein C (APC) | |
| Theoretically inhibits thrombin generation mostly at microvascular level. By decreasing WBC release of tumor necrosis factor-alpha (TNFα), APC may also be anti-inflammatory | Aoki et al11 compared APC to heparin, finding increased bleeding in heparin group and decreased bleeding with APC group compared with bleeding at study entry but no effect on multiorgan dysfunction syndrome with either. Their battery of coagulation studies all improved, APC greater than heparin, but no difference in complete recovery from DIC. Death rate was 20% in APC group and 40% in heparin group. |
| Drotrecogin Alfa (DrotAA) (recombinant activated ProC) | |
| Rationale similar to human APC | Generally used in sepsis independent of DIC. DrotAA decreased mortality (risk ratio [RR] 0.71 in overt DIC and RR of 0.81 in non-overt DIC) in PROWESS study10 with trend to more bleeding but less overt thrombosis. |
| Activated Recombinant Human Factor VII (rhFVIIa) | |
| Typically used as a final option to increase production of thrombin in hemorrhaging patient resistant to all other efforts | If circulating thrombin is thought to be a major culprit, rhFVIIa could be dangerous to administer in DIC. In order to work, thrombin must be able to be generated so might be expected to not work in massive heparin overdosage or in situations having no fibrinogen and/or platelets. Several small case series17 –19 suggest possible efficacy in patients with DIC. |
| Recombinant Human Soluble Thrombomodulin (ART-123) | |
| Thrombomodulin (TM) is an endothelial-bound sink for circulating thrombin. | Aoki’s group20 compared infusion of ART-123 against low-dose heparin infusion in DIC from cancer or infection. ART-123 compared to heparin gave better improvements in coagulation tests and clinical bleeding yet no significant decrease in mortality. Side effects fewer with ART-123 than with heparin infusion |