Skip to main content

A Comparative Double-Blind Randomized Trial of Activated Protein C and Unfractionated Heparin in the Treatment of Disseminated Intravascular Coagulation


A randomized prospective double-blind trial was performed to compare the safety and efficacy of human activated protein C (APC) and unfractionated heparin for the treatment of disseminated intravascular coagulation (DIC). One hundred thirty-two patients with DIC were enrolled in this study: 63 patients received APC (12.5 U [2.5 μg]/kg body wt per hour) and 69 patients received heparin (8 U/kg body wt per hour) by intravenous infusion for 6 days. Forty-nine APC-treated patients and 55 heparintreated patients were evaluated for efficacy, and 52 APC-treated patients and 55 heparin-treated patients were evaluated for safety. The 2 groups were similar with respect to sex, age, body weight, underlying diseases, and coagulation/fibrinolysis parameters before treatment. Aggravation of bleeding was seen after treatment in 8 patients receiving heparin, but in none of the patients receiving APC. The number of patients who showed alleviation of bleeding was significantly higher in the APC group than the heparin group (P = .009). The effects on DIC-related organ dysfunction were not significantly different between the 2 groups. Fibrinogen-fibrin degradation products, D-dimer, thrombin-antithrombin complex (TAT), and plasmin-plasmin inhibitor complex (PIC) were all significantly decreased by treatment in both groups. Fibrinogen, protein C, and antithrombin were significantly increased in the APC group, whereas only protein C was significantly increased in the heparin group. Platelet count in the nonleukemic group was significantly increased in those patients receiving APC but not increased in those patients receiving heparin. Improvement of coagulation/ fibrinolysis was assessed by scoring 4 parameters (soluble fibrin monomers, D-dimer, TAT, and PIC), and the results indicated that the APC group showed significantly greater improvement than the heparin group (P = .046). There was, however, no significant difference in the rate of complete recovery from DIC between the 2 groups. The rate of death from any cause within 28 days after treatment was 20.4% in the APC group, significantly lower than the 40% death rate observed in the heparin group (P < .05). There were no severe adverse events in either group. These results suggest that APC in a relatively small dosage can improve DIC more efficiently than can heparin, without increasing bleeding, and may be a better alternative.

This is a preview of subscription content, access via your institution.


  1. Kisiel W. Human plasma protein C: isolation, characterization, and mechanism of activation by alpha-thrombin.J Clin Invest. 1979;64: 761–769.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Esmon CT. The roles of protein C and thrombomodulin in the regulation of blood coagulation.J Biol Chem. 1989;264:4743–4746.

    CAS  PubMed  Google Scholar 

  3. Comp PC, Esmon CT. Activated protein C inhibits platelet prothrombin-converting activity.Blood. 1979;54:1272–1281.

    CAS  PubMed  Google Scholar 

  4. Branson H, Katz J, Marble R, Griffin JH. Inherited protein C deficiency and coumarin responsive chronic relapsing purpura fulminans in a newborn infant.Lancet. 1983;2:1165–1168.

    Article  CAS  PubMed  Google Scholar 

  5. Marlar RA, Endres-Brooks J, Miller C. Serial studies of protein C and its plasma inhibitor with disseminated intravascular coagulation.Blood. 1985;66:59–63.

    PubMed  CAS  Google Scholar 

  6. Grey S.T, Hau H, Salem HH, Hancock WW. Selective effects of protein C on activation of human monocytes by lipopolysaccharide, interferon-γ, or PMA: modulation of effects on CD11b and CD14 but not CD 25 or CD54 induction.Transplant Proc. 1993;25:2913–2914.

    CAS  PubMed  Google Scholar 

  7. Grey ST, Tsuchida A, Hau H, Orthner CL, Salem HH, Hancock WW. Selective inhibitory effects of the anticoagulant activated protein C on the responses of human mononuclear phagocytes to LPS, IFN-γ, or phorbol ester.J Immunol. 1994;153:3664–3672.

    PubMed  CAS  Google Scholar 

  8. Ryan J, Genczy C. Coagulation and the expression of cell-mediated immunity.Immunol Cell Biol. 1987;65:127–139.

    Article  PubMed  CAS  Google Scholar 

  9. Taylor FB Jr, Chang A, Esmon CT, DAngelo A, Vigano-DAngelo S, Blick KE. Protein C prevents the coagulopathic and lethal effects of Escherichia coli infusion in the baboon.J Clin Invest. 1987;79:918–925.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Okajima K, Imamura H, Koga S, Inoue M, Takatsuki K, Aoki N. Treatment of patients with disseminated intravascular coagulation by protein C.Am J Hematol. 1990;33:277–278.

    Article  PubMed  CAS  Google Scholar 

  11. Bernard GR, Vincent J-L, Leterre P-F, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis.N Engl J Med. 2001;344:699–709.

    Article  PubMed  CAS  Google Scholar 

  12. Kobayashi N, Maekawa T, Takada M, et al. Criteria for diagnosis of DIC based on the analysis of clinical and laboratory findings in 345 DIC patients collected by the Research Committee on DIC in Japan.Bibl Haematol. 1987;49:265–275.

    Google Scholar 

  13. Wada H, Wakita Y, Nakase T, et al. Outcome of disseminated intravascular coagulation in relation to the score when treatment was begun.Thromb Haemost. 1995;74:848–852.

    Article  PubMed  CAS  Google Scholar 

  14. Wada H, Minamikawa K, Wakita Y, et al. Hemostatic molecular markers before the onset of disseminated intravascular coagulation.Am J Hematol. 1999;60:273–278.

    Article  PubMed  CAS  Google Scholar 

  15. Nakahira S, Miyata K, Sugawara K, et al. Characterization of purified protein C derived from human plasma [in Japanese].Iyakuhin Kenkyu. 1994;25:1087–1097.

    CAS  Google Scholar 

  16. Takamiya O, Ishida F, Kodaira H, Kitano K. APC-resistance and Mnl I genotype (Gln506) of coagulation factor V are rare in Japanese population.Thromb Haemost. 1995;74:996.

    Article  PubMed  CAS  Google Scholar 

  17. Fujimura H, Kambayashi J, Monden M, Kato H. Coagulation factor V Leiden mutation may have a racial background.Thromb Haemost. 1995;74:1381–1382.

    Article  PubMed  CAS  Google Scholar 

  18. Ro A, Hara M,Takada A.The factor V Leiden mutation and the prothrombin G20210A mutation was not found in Japanese patients with pulmonary thromboembolism.Thromb Haemost. 1999;82:1769.

    PubMed  CAS  Google Scholar 

  19. Aoki N, Takatsuki K, Matsuda T, et al. Studies on the treatment of disseminated intravascular coagulation with activated protein C (CTC-111). Late phase II [in Japanese].Shinyaku To Rinsho. 1998; 47:425–447.

    Google Scholar 

  20. Matsuda T. Therapy of DIC [in Japanese].Igaku No Ayumi. 1997; 109:91–96.

    Google Scholar 

Download references

Author information

Authors and Affiliations


Corresponding author

Correspondence to Nobuo Aoki.

About this article

Cite this article

Aoki, N., Matsuda, T., Saito, H. et al. A Comparative Double-Blind Randomized Trial of Activated Protein C and Unfractionated Heparin in the Treatment of Disseminated Intravascular Coagulation. Int J Hematol 75, 540–547 (2002).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

Key words