Consumption Coagulopathy Medication
- Author: Vikramjit S Kanwar, MD, MBA, MRCP(UK), FAAP; Chief Editor: Robert J Arceci, MD, PhD more...
Medication Summary
Every effort is made to remove the underlying cause, but further management of childhood disseminated intravascular coagulation (DIC) varies. No evidence suggests that replacement blood products exacerbate the problem, and these should be aggressively used to provide hemostasis. The role of heparin is controversial, but it may be beneficial in purpura fulminans.
Activated protein C and protein C products have shown promising results in sepsis-related DIC. Protein C replacement therapy has been shown to lead to increased activated protein C levels, resolution of coagulopathy, and correction of hemostasis.[15, 16, 17, 18] Similarly, recombinant factor VIIa has also been successfully used in a small sample of neonates with DIC, and larger studies are awaited.[19, 20] However, these products are expensive and difficult to obtain, and their benefit in childhood DIC remains unproven.
Despite promising initial pilot studies, a randomized, double-blind, placebo-controlled trial (RESOLVE [REsearching severe Sepsis and Organ dysfunction in children: a gLobal perspectiVE]) of activated drotrecogin alfa (Xigris) in 477 pediatric patients with severe sepsis showed no decrease in mortality.[21]
Drotrecogin alfa (Xigris) was withdrawn from the worldwide market October 25, 2011. In the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS)-SHOCK clinical trial, drotrecogin alfa failed to demonstrate a statistically significant reduction in 28-day all-cause mortality in patients with severe sepsis and septic shock. Trial results observed a 28-day all-cause mortality rate of 26.4% in patients treated with activated drotrecogin alfa compared with 24.2% in the placebo group of the study.
Blood products
Class Summary
Blood products are administered for supportive care in children with severe DIC. The goal is to replace platelets, depleted coagulation factors, and fibrinogen.
Platelets
In patients with DIC, platelet activity may be abnormal because of fibrin or fibrinogen degradation products. Therefore, consider platelet transfusions at a platelet count of 50 X 109/L. Most institutions use apheresis-derived platelets.
Fresh-frozen plasma (FFP)
Considered first-line blood product in patients with bleeding from unknown etiology. In general, no data support use in DIC.
Cryoprecipitate
Contains high concentrations of factor VIII, von Willebrand factor, fibrinogen, and fibronectin. In DIC, main use is to increase fibrinogen levels in patients with hypofibrinogenemia. Some suggest use only in patients with DIC that is self-limited, resolving, or controlled with heparin. Concern is that no HIV-inactivated products are available.
Anticoagulants
Class Summary
In acute DIC, the value of intravenous heparin is uncertain, but it may be used in purpura fulminans. Low-molecular-weight heparin (LMWH) may be used in patients with chronic DIC. No randomized controlled trials have been performed to prove the value for heparin in DIC in adult settings, such as peripartum DIC.[22]
Heparin
Cofactor for antithrombin III; activating stops production of thrombin. Useful in chronic DIC but less effective in acute DIC. aPTT cannot be used to monitor levels of anticoagulation. Some monitor heparin levels. Target heparin levels 0.35-0.7 U/mL with antifactor-Xa method.
Enoxaparin (Lovenox)
Clinical benefit of LMWH primarily seen in chronic DIC.
Coagulation inhibitors
Class Summary
Antithrombin III and drotrecogin alfa (recombinant human-activated protein C) both have an antithrombotic effect, but their benefit in sepsis-related childhood DIC remains anecdotal. In the PROWESS-SHOCK trial, administration of recombinant human APC was not shown to improve mortality, and therefore, the drug was withdrawn from the worldwide market on October 25, 2011.
Antithrombin III (ATnativ, Thrombate III)
Concentrate has been used to treat adults with severe DIC resulting from sepsis. Infusion speeds resolution and reduces multiorgan dysfunction. Studies relatively small, and few have involved children. Some recommend use only with concurrent heparin therapy.
Drotrecogin alfa (Xigris)
October 25, 2011: Withdrawn from worldwide market. Recombinant human activated protein C. Was indicated to reduce mortality in patients with severe sepsis associated with acute organ dysfunction and at high risk of death. Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial showed a significant decrease in mortality in patients with sepsis and DIC treated with activated protein C. Exerts antithrombotic effect by inhibiting factors Va and VIIIa. Has indirect profibrinolytic activity by inhibiting PAI-1 and limiting formation of activated thrombin-activatable-fibrinolysis-inhibitor. May exert anti-inflammatory effect by inhibiting human TNF production by monocytes, blocking leukocyte adhesion to selectins, and limiting thrombin-induced inflammatory responses within microvascular endothelium.
Coagulation factors
Class Summary
Recombinant factor VII may help reduce active bleeding, but its benefit in childhood DIC remains anecdotal.
Recombinant coagulation factor VIIa (NovoSeven)
Indicated for hemophilia with inhibitors refractory to routine therapy and for congenital factor VII deficiency. Used off label for uncontrolled bleeding secondary to trauma or DIC and refractory to usual measures. Recombinant activated factor VII complexes with TF to activate factors IX and X, which converts prothrombin to thrombin.
Levi M, Ten Cate H. Disseminated intravascular coagulation. N Engl J Med. Aug 19 1999;341(8):586-92. [Medline].
Shimura M, Wada H, Wakita Y, et al. Plasma tissue factor and tissue factor pathway inhibitor levels in patients with disseminated intravascular coagulation. Am J Hematol. Aug 1997;55(4):169-74. [Medline].
Nieuwland R, Berckmans RJ, McGregor S, Boing AN, Romijn FP, Westendorp RG. Cellular origin and procoagulant properties of microparticles in meningococcal sepsis. Blood. Feb 1 2000;95(3):930-5. [Medline].
Morel N, Morel O, Petit L, et al. Generation of procoagulant microparticles in cerebrospinal fluid and peripheral blood after traumatic brain injury. J Trauma. Mar 2008;64(3):698-704. [Medline].
Langer F, Spath B, Haubold K, Holstein K, Marx G, Wierecky J. Tissue factor procoagulant activity of plasma microparticles in patients with cancer-associated disseminated intravascular coagulation. Ann Hematol. Jun 2008;87(6):451-7. [Medline].
Arbuthnot C, Wilde JT. Haemostatic problems in acute promyelocytic leukaemia. Blood Rev. Jun 3 2006;[Medline].
Asakura H, Ontachi Y, Mizutani T, et al. Elevated levels of free tissue factor pathway inhibitor antigen in cases of disseminated intravascular coagulation caused by various underlying diseases. Blood Coagul Fibrinolysis. Jan 2001;12(1):1-8. [Medline].
Grewal PK, Uchiyama S, Ditto D, Varki N, Le DT, Nizet V. The Ashwell receptor mitigates the lethal coagulopathy of sepsis. Nat Med. Jun 2008;14(6):648-55. [Medline].
Oren H, Cingoz I, Duman M. Disseminated intravascular coagulation in pediatric patients: clinical and laboratory features and prognostic factors influencing the survival. Pediatr Hematol Oncol. Dec 2005;22(8):679-88. [Medline].
Wada H. Disseminated intravascular coagulation. Clin Chim Acta. Jun 2004;344(1-2):13-21. [Medline].
Levi M, de Jonge E, Meijers J. The diagnosis of disseminated intravascular coagulation. Blood Rev. Dec 2002;16(4):217-23. [Medline].
Taylor FB, Toh CH, Hoots WK, et al. Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb Haemost. Nov 2001;86(5):1327-30. [Medline].
Dempfle CE, Wurst M, Smolinski M, et al. Use of soluble fibrin antigen instead of D-dimer as fibrin-related marker may enhance the prognostic power of the ISTH overt DIC score. Thromb Haemost. Apr 2004;91(4):812-8. [Medline].
Voves C, Wuillemin WA, Zeerleder S. International Society on Thrombosis and Haemostasis score for overt disseminated intravascular coagulation predicts organ dysfunction and fatality in sepsis patients. Blood Coagul Fibrinolysis. Sep 2006;17(6):445-51. [Medline].
Ettingshausen CE, Veldmann A, Beeg T, Schneider W, Jäger G, Kreuz W. Replacement therapy with protein C concentrate in infants and adolescents with meningococcal sepsis and purpura fulminans. Semin Thromb Hemost. 1999;25(6):537-41. [Medline].
White B, Livingstone W, Murphy C, Hodgson A, Rafferty M, Smith OP. An open-label study of the role of adjuvant hemostatic support with protein C replacement therapy in purpura fulminans-associated meningococcemia. Blood. Dec 1 2000;96(12):3719-24. [Medline].
Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. Mar 8 2001;344(10):699-709. [Medline].
Schellongowski P, Bauer E, Holzinger U, Staudinger T, Frass M, Laczika K. Treatment of adult patients with sepsis-induced coagulopathy and purpura fulminans using a plasma-derived protein C concentrate (Ceprotin). Vox Sang. May 2006;90(4):294-301. [Medline].
Yilmaz D, Karapinar B, Balkan C, Akisu M, Kavakli K. Single-center experience: use of recombinant factor VIIa for acute life-threatening bleeding in children without congenital hemorrhagic disorder. Pediatr Hematol Oncol. Jun 2008;25(4):301-11. [Medline].
Fischer D, Schloesser R, Buxmann H, Veldman A. Recombinant activated Factor VII as a hemostatic agent in very low birth weight preterms with gastrointestinal hemorrhage and disseminated intravascular coagulation. J Pediatr Hematol Oncol. May 2008;30(5):337-42. [Medline].
Nadel S, Goldstein B, Williams MD, et al. Drotrecogin alfa (activated) in children with severe sepsis: a multicentre phase III randomised controlled trial. Lancet. Mar 10 2007;369(9564):836-43. [Medline].
Marti-Carvajal AJ, Comunian-Carrasco G, Pena-Marti GE. Haematological interventions for treating disseminated intravascular coagulation during pregnancy and postpartum. Cochrane Database Syst Rev. Mar 16 2011;3:CD008577. [Medline].
Baratto F, Michielan F, Meroni M, Dal Palu A, Boscolo A, Ori C. Protein C concentrate to restore physiological values in adult septic patients. Intensive Care Med. Sep 2008;34(9):1707-12. [Medline].
Bick RL. Disseminated intravascular coagulation: objective clinical and laboratory diagnosis, treatment, and assessment of therapeutic response. Semin Thromb Hemost. 1996;22(1):69-88. [Medline].
de Jonge E, Dekkers PE, Creasey AA, et al. Tissue factor pathway inhibitor dose-dependently inhibits coagulation activation without influencing the fibrinolytic and cytokine response during human endotoxemia. Blood. Feb 15 2000;95(4):1124-9. [Medline].
Hazelzet JA, Risseeuw-Appel IM, Kornelisse RF, et al. Age-related differences in outcome and severity of DIC in children with septic shock and purpura. Thromb Haemost. Dec 1996;76(6):932-8. [Medline].
Levi M. Disseminated intravascular coagulation: What's new?. Crit Care Clin. Jul 2005;21(3):449-67. [Medline].
Sakuragawa N, Hasegawa H, Maki M, et al. Clinical evaluation of low-molecular-weight heparin (FR-860) on disseminated intravascular coagulation (DIC)--a multicenter co- operative double-blind trial in comparison with heparin. Thromb Res. Dec 15 1993;72(6):475-500. [Medline].
Sallah S, Husain A, Nguyen NP. Recombinant activated factor VII in patients with cancer and hemorrhagic disseminated intravascular coagulation. Blood Coagul Fibrinolysis. Oct 2004;15(7):577-82. [Medline].
Wang ZY, Chen Z. Acute promyelocytic leukemia: from highly fatal to highly curable. Blood. Mar 1 2008;111(5):2505-15. [Medline].
| Measure | Score | |||
| 0 | 1 | 2 | 3 | |
| Platelet count | >100 X 109/L | < 100 X 109/L | < 50 X 109/L | NA |
| PT prolongation, s | 0-3 | 3-6 | 6 | NA |
| Fibrinogen level (mg/dL) | >100 | < 100 | NA | NA |
| Fibrin split products | NA | NA | + | +++ |
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