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Thromb Haemost 2016; 116(01): 58-68
DOI: 10.1160/TH15-10-0786
Coagulation and Fibrinolysis
Schattauer GmbH

Efficacy and safety of protein C concentrate to treat purpura fulminans and thromboembolic events in severe congenital protein C deficiency

Marilyn J. Manco-Johnson
1   Children’s Hospital Colorado and the University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
,
Lisa Bomgaars
2   Baylor College of Medicine, Texas Children’s Hospital Hematology Center, Texas Children’s Hospital, Houston, Texas, USA
,
Joseph Palascak
3   University of Cincinnati, Hemophilia Treatment Center, Cincinnati, Ohio, USA
,
Amy Shapiro
4   Indiana Hemophilia & Thrombosis Center, Indianapolis, Indiana, USA
,
John Geil
5   |University of Kentucky Chandler Medical Center, Lexington, Kentucky, USA
,
Sandor Fritsch
6   Baxalta Innovations GmbH, Vienna, Austria
,
Borislava G. Pavlova
6   Baxalta Innovations GmbH, Vienna, Austria
,
David Gelmont
7   Baxalta US Inc., Westlake Village, California, USA
› Author Affiliations Financial support: This study was funded by Baxalta US, Inc.
Further Information

Publication History

Received: 09 October 2015

Accepted after major revision: 27 March 2016

Publication Date:
27 November 2017 (online)

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Summary

Severe congenital protein C (PC) deficiency (SCPCD) is associated with disseminated intravascular coagulation (DIC), purpura fulminans (PF), and vascular thromboembolic events (TE), often leading to organ failure and death. PC replacement therapy offers a safe, effective treatment for thromboembolic complications of SCPCD and secondary prophylaxis for recurrent DIC, PF, and TEs. A prospective, multi-centre, open-label, phase 2/3 study was conducted to demonstrate the safety and efficacy of protein C concentrate for treatment of PF and acute TEs. Fifteen enrolled patients with SCPCD received protein C concentrate; 11 received treatment for acute TEs (PF, 18 events; PF and other coumarin-related vascular thromboembolic events [coumarin-induced skin necrosis; CISN], 1 event; venous thrombosis, 5 events). Predefined efficacy criteria for treatment of acute TEs were compared with a historical control arm (i. e. patients receiving conventional therapy without protein C replacement). PF/CISN was demonstrated by pre-defined primary and secondary efficacy ratings. Primary ratings of protein C concentrate–treated episodes were significantly higher (p=0.0032) than in the historical control. For 19 PF/CISN episodes in 11 patients, 94.7 % of treatments were rated effective and 5.3 % effective with complications (not related to protein C concentrate). In a secondary efficacy rating, all treatments were rated effective (68.4 % excellent; 21.1 % good; 10.5 % fair). For 5/24 vascular thrombosis episodes, 80 % of treatments were rated excellent and 20 % were rated good. No treatment-related adverse events or serious adverse events occurred. In conclusion, protein C concentrate provides an efficacious, safe treatment for PF, CISN, and other TEs in SCPCD patients.

Keywords

Disseminated intravascular coagulation - protein C deficiency - congenital thrombotic disease due to protein C deficiency - purpura fulminans - therapeutics

 

  • References

  • 1 Goldenberg NA, Manco-Johnson MJ. Protein C deficiency. Haemophilia 2008; 14: 1214-1221.
    CrossrefPubMedGoogle Scholar
  • 2 Marlar RA, Mastovich S. Hereditary protein C deficiency: a review of the genetics, clinical presentation, diagnosis and treatment. Blood Coagul Fibrinolysis 1990; 01: 319-330.
    CrossrefPubMedGoogle Scholar
  • 3 Abu-Amero KK, Al-Hamed MH, Al-Batniji FS. Homozygous PCD with purpura fulminans: report of a new case and a description of a novel mutation. Blood Coagul Fibrinolysis 2003; 14: 303-306.
    PubMedGoogle Scholar
  • 4 Manco-Johnson MJ, Abshire TC, Jacobson LJ. et al. Severe neonatal protein C deficiency: prevalence and thrombotic risk. J Pediatr 1991; 119: 793-798.
    CrossrefPubMedGoogle Scholar
  • 5 Levi M, Toh CH, Thachil J. et al. Guidelines for the diagnosis and management of disseminated intravascular coagulation. British Committee for Standards in Haematology. Br J Haematol 2009; 145: 24-33.
    CrossrefPubMedGoogle Scholar
  • 6 Pescatore SL. Clinical management of protein C deficiency. Expert Opin Pharmacother 2001; 02: 431-439.
    CrossrefPubMedGoogle Scholar
  • 7 Loop M, Ferster A, Corazza F. et al. Late onset of clinical symptoms and recurrent ecchymotic skin lesions in a 12-year-old girl with a severe double heterozygous protein C deficiency. J Pediatr Hematol Oncol 2004; 26: 2-4.
    CrossrefPubMedGoogle Scholar
  • 8 Guérin V, Ryman A, Pedespan JM. et al. Oral anticoagulant therapy initiation in a severely protein C deficient infant: use of human protein c concentrate. Blood. 2003 102. 122b (Abstract)
    PubMedGoogle Scholar
  • 9 Harenberg J, Hoffmann U, Huhle G. et al. Cutaneous reactions to anticoagulants. Recognition and management Am J Clin Dermatol 2001; 02: 69-75.
    PubMedGoogle Scholar
  • 10 Imberti D, Pierfranceschi MG. Successful protein C concentrate administration during initiation of oral anticoagulation in adult patients with severe congenital protein C deficiency: report of two cases. Pathophysiol Haemost Thromb 2008; 36: 53-57.
    PubMedGoogle Scholar
  • 11 Zimbelman J, Lefkowitz J, Schaeffer C. et al. Unusual complications of warfarin therapy: skin necrosis and priapism. J Pediatr 2000; 137: 266-268.
    CrossrefPubMedGoogle Scholar
  • 12 Manco-Johnson M, Nuss R. Protein C concentrate prevents peripartum thrombosis. Amer J Hematol 1992; 40: 69-70.
    CrossrefPubMedGoogle Scholar
  • 13 Sanz-Rodriguez C, Gil-Fernandez JJ, Zapater P. et al. Long-term management of homozygous protein C deficiency: replacement therapy with subcutaneous purified protein C concentrate. Thromb Haemost 1999; 81: 887-890.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 14 Groncy PK, Oseas RS, Marlar RA. Intraperitoneal administration of prothrombin complex concentrates in the treatment of severe protein C deficiency. Blood. 1985 01 Suppl 996 (Abstract)
    PubMedGoogle Scholar
  • 15 FDA. U.S. Food and Drug Administration. Vaccines, Blood & Biologics. Blood & blood products. Last updated March 10, 2014. Available at: http://www.fda.gov/BiologicsBloodVaccines/BloodBloodProducts/ Accessed June 18, 2015
    PubMedGoogle Scholar
  • 16 Casella JF, Lewis JH, Bontempo FA. et al. Successful treatment of homozygous protein C deficiency by hepatic transplantation. Lancet 1988; 01: 435-438.
    PubMedGoogle Scholar
  • 17 Lee MJ, Kim KM, Kim JS. et al. Long-term survival of a child with homozygous protein C deficiency successfully treated with living donor liver transplantation. Pediatr Transplant 2009; 13: 251-254.
    CrossrefPubMedGoogle Scholar
  • 18 Angelis M, Pegelow CH, Khan FA. et al. En bloc heterotopic auxiliary liver and bilateral renal transplant in a patient with homozygous protein C deficiency. J Pediatr 2001; 138: 120-122.
    CrossrefPubMedGoogle Scholar
  • 19 Dreyfus M, Magny JF, Bridey F. et al. Treatment of homozygous protein C deficiency and neonatal purpura fulminans with a purified protein C concentrate. N Engl J Med 1991; 325: 1565-1568.
    CrossrefPubMedGoogle Scholar
  • 20 Schramm W, Spannagl M, Schwarz HP. Neue Konzentrate zur Substitution von Gerinnungsund Fibrinolysefaktoren. 20. Hämophilie-Symposion Hamburg. 1989 (Abstract)
    PubMedGoogle Scholar
  • 21 World Medical Association General Assembly. WMA Declaration of Helsinki-Ethical Principles for Medical Research Involving Human Subjects. Amended by the 59th WMA General Assembly, Seoul, October 2008. Available at: http://www.wma.net/en/30publications/10policies/b3/ Accessed June 18, 2015
    PubMedGoogle Scholar
  • 22 Neyman J. Outline of a theory of statistical estimation based on the classical theory of probability, in Philosophical Transactions of the Royal Society, Series A. 1937; 236: 333-380.
    PubMedGoogle Scholar
  • 23 Von Collani E, Drager K. Binomial Distribution Handbook for Scientists and Engineers, in Anonymous. Boston: Birkhauser; 2001: 59-96.
    Google Scholar
  • 24 Majer RV, Chisholm M, Hickton MC. Replacement therapy for protein C deficiency using fresh frozen plasma. Br J Haematol 1989; 72: 475.
    CrossrefPubMedGoogle Scholar
  • 25 Minford A, Behnisch W, Brons P. et al. Subcutaneous protein C concentrate in the management of severe protein C deficiency--experience from 12 centres. Br J Haematol 2014; 164: 414-421.
    CrossrefPubMedGoogle Scholar
  • 26 de Kort EH, Vrancken SL, van Heijst AF. et al. Long-term subcutaneous protein C replacement in neonatal severe protein C deficiency. Pediatrics 2011; 127: e1338-1342.
    CrossrefPubMedGoogle Scholar
  • 27 Ceprotin (protein C concentrate (human)) lyophilized powder for solution for injection prescribing information. Baxter Healthcare Corporation. Westlake Village, CA: 2011
    PubMedGoogle Scholar
  • 28 Dreyfus M, Masterson M, David M. et al. Replacement therapy with a monoclonal antibody purified protein C concentrate in newborns with severe congenital protein C deficiency. Semin Thromb Hemost 1995; 21: 371-381.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 29 Salonvaara M, Kuismanen K, Mononen T. et al. Diagnosis and treatment of a newborn with homozygous protein C deficiency. Acta Paediatr 2004; 93: 137-139.
    CrossrefPubMedGoogle Scholar
  • 30 Gatti L, Carnelli V, Rusconi R. et al. Heparin-induced thrombocytopenia and warfarin-induced skin necrosis in a child with severe protein C deficiency: successful treatment with dermatan sulfate and protein C concentrate. J Thromb Haemost 2003; 01: 387-388.
    CrossrefPubMedGoogle Scholar
  • 31 Knoebl PN. Severe congenital protein C deficiency: the use of protein C concentrates (human) as replacement therapy for life-threatening blood-clotting complications. Biologics 2008; 02: 285-296.
    PubMedGoogle Scholar
  • 32 Moritz B, Rogy S, Tonetta S. et al. Efficacy and safety of a high purity protein C concentrate in the management of patients with severe congenital protein C deficiency. In: Scharrer I, Schramm W. 31st Hemophilia Symposium Hamburg 2000, Springer Berlin Heidelburg. Chapter 12, 101-109.
    Google Scholar
  • 33 Nadel S, Goldstein B, Williams MD. et al. Researching severe sepsis and organ dysfunction in children: a global perspective (RESOLVE) study group. Drotrecogin alfa (activated) in children with severe sepsis: a multicentre phase III randomised controlled trial. Lancet 2007; 369: 836-843.
    CrossrefPubMedGoogle Scholar
  • 34 Schmidt B, Gillie P, Mitchell L. et al. A placebo-controlled randomized trial of antithrombin therapy in neonatal respiratory distress syndrome. Am J Respir Crit Care Med 1998; 158: 470-476.
    CrossrefPubMedGoogle Scholar
  • 35 Palareti G, Legnani C, Cosmi B. et al. Risk of venous thromboembolism recurrence: high negative predictive value of D-dimer performed after oral anticoagulation is stopped. Thromb Haemost 2002; 87: 7-12.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 36 Manco-Johnson MJ, Wang M, Goldenberg NA. et al. Treatment, survival, and thromboembolic outcomes of thrombotic storm in children. J Pediatr 2012; 161: 682-688.
    CrossrefPubMedGoogle Scholar
  • 37 Levi M. Disseminated intravascular coagulation (DIC) in pregnancy and the peri-partum period. Thromb Res. 2009; 123 Suppl S63-S64.
    PubMedGoogle Scholar