Close
New

Medscape is available in 5 Language Editions – Choose your Edition here.

 

Protein C Deficiency Differential Diagnoses

  • Author: Adam Cuker, MD, MS; Chief Editor: Perumal Thiagarajan, MD  more...
 
Updated: Jan 21, 2016
 
 

Diagnostic Considerations

Patients who develop venous thromboembolism (VTE) in the absence of acquired risk factors may have protein C deficiency or some other congenital thrombophilia, or may have more than one congenital risk factor for VTE. In a retrospective analysis of prospectively gathered data on 58 outpatients with VTE (approximate mean age 39 years) without major acquired risk factors, 45 had at least one hereditary risk factor for VTE. Diagnoses in these patients were as follows[55] :

  • Protein C deficiency - 18 patients
  • Protein S deficiency - 17 patients
  • Factor V Leiden mutation - 30 patients (25 heterozygous and five 5 homozygous)
  • Prothrombin gene mutation - 16 patients
  • Methylenetetrahydrofolate reductase C677T mutation - 24 patients (19 heterozygous, 5 homozygous)
  • Antithrombin III deficiency - 14 patients
  • Hyperhomocysteinemia - 13 patients

Of the 18 patients with protein C deficiency, four also had protein S deficiency, two also had hyperhomocystinemia, and one had both protein S deficiency and hyperhomocysteinemia.

These authors concluded that thrombophilia testing should be performed in younger VTE patients without known acquired risk factors. Testing for protein C, protein S and prothrombin gene mutations should be followed by additional molecular assessment in patients with suspicious findings.[55]

Differential Diagnoses

 
 
Contributor Information and Disclosures
Author

Adam Cuker, MD, MS Assistant Professor of Medicine, Assistant Professor of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine

Adam Cuker, MD, MS is a member of the following medical societies: American College of Physicians, American Society of Hematology, Anticoagulation Forum, Hemostasis and Thrombosis Research Society, International Society on Thrombosis and Haemostasis

Disclosure: Received consulting fee from Genzyme for consulting; Received consulting fee from Amgen for consulting; Received grant/research funds from T2 Biosystems for other; Received grant/research funds from Spark Therapeutics for other. .

Coauthor(s)

Eleanor S Pollak, MD Associate Director of Special Coagulation, Associate Professor, Department of Pathology and Laboratory Medicine, Section of Hematology and Coagulation, University of Pennsylvania

Eleanor S Pollak, MD is a member of the following medical societies: American Society of Hematology, College of American Pathologists, National Multiple Sclerosis Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Perumal Thiagarajan, MD Professor, Department of Pathology and Medicine, Baylor College of Medicine; Director, Transfusion Medicine and Hematology Laboratory, Michael E DeBakey Veterans Affairs Medical Center

Perumal Thiagarajan, MD is a member of the following medical societies: American College of Physicians, American Society for Clinical Investigation, Association of American Physicians, American Society for Biochemistry and Molecular Biology, American Heart Association, American Society of Hematology, Royal College of Physicians

Disclosure: Nothing to disclose.

Additional Contributors

David Aboulafia, MD Medical Director, Bailey-Boushay House, Clinical Professor, Department of Medicine, Division of Hematology, Attending Physician, Section of Hematology/Oncology, Virginia Mason Clinic; Investigator, Virginia Mason Community Clinic Oncology Program/SWOG

David Aboulafia, MD is a member of the following medical societies: American College of Physicians, American Medical Association, AMDA - The Society for Post-Acute and Long-Term Care Medicine, American Society of Hematology, Infectious Diseases Society of America, Phi Beta Kappa

Disclosure: Nothing to disclose.

References
  1. Dahlback B. Advances in understanding pathogenic mechanisms of thrombophilic disorders. Blood. 2008 Jul 1. 112(1):19-27. [Medline]. [Full Text].

  2. Clouse LH, Comp PC. The regulation of hemostasis: the protein C system. N Engl J Med. 1986 May 15. 314(20):1298-304. [Medline].

  3. Walker FJ. Regulation of activated protein C by a new protein. A possible function for bovine protein S. J Biol Chem. 1980 Jun 25. 255(12):5521-4. [Medline]. [Full Text].

  4. Mosnier LO, Zlokovic BV, Griffin JH. The cytoprotective protein C pathway. Blood. 2007 Apr 15. 109(8):3161-72. [Medline]. [Full Text].

  5. Danese S, Vetrano S, Zhang L, Poplis VA, Castellino FJ. The protein C pathway in tissue inflammation and injury: pathogenic role and therapeutic implications. Blood. 2010 Feb 11. 115(6):1121-30. [Medline]. [Full Text].

  6. Reitsma PH, Bernardi F, Doig RG, Gandrille S, on behalf of the Subcommittee on Plasma Coagulation Inhibitors of the Scientific and Standardization Committee of the ISTH. Protein C deficiency: a database of mutations, 1995 update. Thromb Haemost. 1995 May. 73(5):876-89. [Medline].

  7. D'Ursi P, Marino F, Caprera A, Milanesi L, Faioni EM, Rovida E. ProCMD: a database and 3D web resource for protein C mutants. BMC Bioinformatics. 2007 Mar 8. 8 Suppl 1:S11. [Medline]. [Full Text].

  8. Bovill EG, Bauer KA, Dickerman JD, Callas P, West B. The clinical spectrum of heterozygous protein C deficiency in a large New England kindred. Blood. 1989 Feb 15. 73(3):712-7. [Medline]. [Full Text].

  9. Broekmans AW, Veltkamp JJ, Bertina RM. Congenital protein C deficiency and venous thromboembolism. A study of three Dutch families. N Engl J Med. 1983 Aug 11. 309(6):340-4. [Medline].

  10. Horellou MH, Conard J, Bertina RM, Samama M. Congenital protein C deficiency and thrombotic disease in nine French families. Br Med J (Clin Res Ed). 1984 Nov 10. 289(6454):1285-7. [Medline]. [Full Text].

  11. Reitsma PH, Poort SR, Allaart CF, Briet E, Bertina RM. The spectrum of genetic defects in a panel of 40 Dutch families with symptomatic protein C deficiency type I: heterogeneity and founder effects. Blood. 1991 Aug 15. 78(4):890-4. [Medline]. [Full Text].

  12. Mustafa S, Mannhalter C, Rintelen C,et al. Clinical features of thrombophilia in families with gene defects in protein C or protein S combined with factor V Leiden. Blood Coagul Fibrinolysis. 1998 Jan. 9(1):85-9. [Medline].

  13. Tait RC, Walker ID, Reitsma PH, et al. Prevalence of protein C deficiency in the healthy population. Thromb Haemost. 1995 Jan. 73(1):87-93. [Medline].

  14. Miletich J, Sherman L, Broze G Jr. Absence of thrombosis in subjects with heterozygous protein C deficiency. N Engl J Med. 1987 Oct 15. 317(16):991-6. [Medline].

  15. Mateo J, Oliver A, Borrell M, Sala N, Fontcuberta J. Laboratory evaluation and clinical characteristics of 2,132 consecutive unselected patients with venous thromboembolism--results of the Spanish Multicentric Study on Thrombophilia (EMET-Study). Thromb Haemost. 1997 Mar. 77(3):444-51. [Medline].

  16. Gladson CL, Scharrer I, Hach V, Beck KH, Griffin JH. The frequency of type I heterozygous protein S and protein C deficiency in 141 unrelated young patients with venous thrombosis. Thromb Haemost. 1988 Feb 25. 59(1):18-22. [Medline].

  17. Heijboer H, Brandjes DP, Buller HR, Sturk A, ten Cate JW. Deficiencies of coagulation-inhibiting and fibrinolytic proteins in outpatients with deep-vein thrombosis. N Engl J Med. 1990 Nov 29. 323(22):1512-6. [Medline].

  18. Ichiyama M, Ohga S, Ochiai M, Fukushima K, Ishimura M, Torio M, et al. Fetal hydrocephalus and neonatal stroke as the first presentation of protein C deficiency. Brain Dev. 2016 Feb. 38 (2):253-6. [Medline].

  19. Martinelli I, Mannucci PM, De Stefano V, et al. Different risks of thrombosis in four coagulation defects associated with inherited thrombophilia: a study of 150 families. Blood. 1998 Oct 1. 92(7):2353-8. [Medline]. [Full Text].

  20. Koster T, Rosendaal FR, Briet E, et al. Protein C deficiency in a controlled series of unselected outpatients: an infrequent but clear risk factor for venous thrombosis (Leiden Thrombophilia Study). Blood. 1995 May 15. 85(10):2756-61. [Medline]. [Full Text].

  21. Pabinger I, Schneider B, for the Gesellschaft fur Thrombose- und Hamostaseforschung (GTH) Study Group on Natural Inhibitors. Thrombotic risk in hereditary antithrombin III, protein C, or protein S deficiency. A cooperative, retrospective study. Arterioscler Thromb Vasc Biol. 1996 Jun. 16(6):742-8. [Medline]. [Full Text].

  22. de Bruijn SF, Stam J, Koopman MM, Vandenbroucke JP, for the Cerebral Venous Sinus Thrombosis Study Group. Case-control study of risk of cerebral sinus thrombosis in oral contraceptive users and in [correction of who are] carriers of hereditary prothrombotic conditions. BMJ. 1998 Feb 21. 316(7131):589-92. [Medline]. [Full Text].

  23. Momoi A, Komura Y, Kumon I, et al. Mesenteric venous thrombosis in hereditary protein C deficiency with the mutation at Arg169 (CGG-TGG). Intern Med. 2003 Jan. 42(1):110-6. [Medline]. [Full Text].

  24. Wysokinska EM, Wysokinski WE, Brown RD, et al. Thrombophilia differences in cerebral venous sinus and lower extremity deep venous thrombosis. Neurology. 2008 Feb 19. 70(8):627-33. [Medline].

  25. Melissari E, Kakkar VV. Congenital severe protein C deficiency in adults. Br J Haematol. 1989 Jun. 72(2):222-8. [Medline].

  26. McGehee WG, Klotz TA, Epstein DJ, Rapaport SI. Coumarin necrosis associated with hereditary protein C deficiency. Ann Intern Med. 1984 Jul. 101(1):59-60. [Medline].

  27. Bauer KA. Coumarin-induced skin necrosis. Arch Dermatol. 1993 Jun. 129(6):766-8. [Medline].

  28. Faraci PA, Deterling RA Jr, Stein AM, Rheinlander HF, Cleveland RJ. Warfarin induced necrosis of the skin. Surg Gynecol Obstet. 1978 May. 146(5):695-700. [Medline].

  29. Broekmans AW, Teepe RG, van der Meer FJ, Briet E, Bertina RM. Protein C (PC) and coumarin-induced skin necrosis. Thromb Res. 1986. 41(suppl 1):137.

  30. Teepe RG, Broekmans AW, Vermeer BJ, Nienhuis AM, Loeliger EA. Recurrent coumarin-induced skin necrosis in a patient with an acquired functional protein C deficiency. Arch Dermatol. 1986 Dec. 122(12):1408-12. [Medline].

  31. Sallah S, Abdallah JM, Gagnon GA. Recurrent warfarin-induced skin necrosis in kindreds with protein S deficiency. Haemostasis. 1998 Jan-Feb. 28(1):25-30. [Medline].

  32. Preston FE, Rosendaal FR, Walker ID, et al. Increased fetal loss in women with heritable thrombophilia. Lancet. 1996 Oct 5. 348(9032):913-6. [Medline].

  33. Vossen CY, Preston FE, Conard J, et al. Hereditary thrombophilia and fetal loss: a prospective follow-up study. J Thromb Haemost. 2004 Apr. 2(4):592-6. [Medline]. [Full Text].

  34. Rey E, Kahn SR, David M, Shrier I. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet. 2003 Mar 15. 361(9361):901-8. [Medline].

  35. Kohler J, Kasper J, Witt I, von Reutern GM. Ischemic stroke due to protein C deficiency. Stroke. 1990 Jul. 21(7):1077-80. [Medline]. [Full Text].

  36. Camerlingo M, Finazzi G, Casto L, et al. Inherited protein C deficiency and nonhemorrhagic arterial stroke in young adults. Neurology. 1991 Sep. 41(9):1371-3. [Medline].

  37. Peterman MA, Roberts WC. Syndrome of protein C deficiency and anterior wall acute myocardial infarction at a young age from a single coronary occlusion with otherwise normal coronary arteries. Am J Cardiol. 2003 Sep 15. 92(6):768-70. [Medline].

  38. Douay X, Lucas C, Caron C, Goudemand J, Leys D. Antithrombin, protein C and protein S levels in 127 consecutive young adults with ischemic stroke. Acta Neurol Scand. 1998 Aug. 98(2):124-7. [Medline].

  39. Munts AG, van Genderen PJ, Dippel DW, van Kooten F, Koudstaal PJ. Coagulation disorders in young adults with acute cerebral ischaemia. J Neurol. 1998 Jan. 245(1):21-5. [Medline].

  40. Boekholdt SM, Kramer MH. Arterial thrombosis and the role of thrombophilia. Semin Thromb Hemost. 2007 Sep. 33(6):588-96. [Medline].

  41. Folsom AR, Ohira T, Yamagishi K, Cushman M. Low protein C and incidence of ischemic stroke and coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) Study. J Thromb Haemost. 2009 Nov. 7(11):1774-8. [Medline]. [Full Text].

  42. Kenet G, Lütkhoff LK, Albisetti M, Bernard T, Bonduel M, Brandao L, et al. Impact of thrombophilia on risk of arterial ischemic stroke or cerebral sinovenous thrombosis in neonates and children: a systematic review and meta-analysis of observational studies. Circulation. 2010 Apr 27. 121(16):1838-47. [Medline].

  43. Komai H, Shindo S, Sato M, Ogino H. Reduced Protein C Activity Might be Associated With Progression of Peripheral Arterial Disease. Angiology. 2014 Aug 12. [Medline].

  44. Seligsohn U, Berger A, Abend M, et al. Homozygous protein C deficiency manifested by massive venous thrombosis in the newborn. N Engl J Med. 1984 Mar 1. 310(9):559-62. [Medline].

  45. Peters C, Casella JF, Marlar RA, Montgomery RR, Zinkham WH. Homozygous protein C deficiency: observations on the nature of the molecular abnormality and the effectiveness of warfarin therapy. Pediatrics. 1988 Feb. 81(2):272-6. [Medline].

  46. Marciniak E, Wilson HD, Marlar RA. Neonatal purpura fulminans: a genetic disorder related to the absence of protein C in blood. Blood. 1985 Jan. 65(1):15-20. [Medline]. [Full Text].

  47. Patel RK, Ford E, Thumpston J, Arya R. Risk factors for venous thrombosis in the black population. Thromb Haemost. 2003 Nov. 90(5):835-8. [Medline].

  48. Sakata T, Kario K, Katayama Y, et al. Studies on congenital protein C deficiency in Japanese: prevalence, genetic analysis, and relevance to the onset of arterial occlusive diseases. Semin Thromb Hemost. 2000. 26(1):11-6. [Medline].

  49. Nardi M, Karpatkin M. Prothrombin and protein C in early childhood: normal adult levels are not achieved until the fourth year of life. J Pediatr. 1986 Nov. 109(5):843-5. [Medline].

  50. van Teunenbroek A, Peters M, Sturk A, Borm JJ, Breederveld C. Protein C activity and antigen levels in childhood. Eur J Pediatr. 1990 Aug. 149(11):774-8. [Medline].

  51. Lensen RP, Rosendaal FR, Koster T, et al. Apparent different thrombotic tendency in patients with factor V Leiden and protein C deficiency due to selection of patients. Blood. 1996 Dec 1. 88(11):4205-8. [Medline]. [Full Text].

  52. Mitchell CA, Rowell JA, Hau L, Young JP, Salem HH. A fatal thrombotic disorder associated with an acquired inhibitor of protein C. N Engl J Med. 1987 Dec 24. 317(26):1638-42. [Medline].

  53. Gordon B, Haire W, Ruby E, et al. Prolonged deficiency of protein C following hematopoietic stem cell transplantation. Bone Marrow Transplant. 1996 Mar. 17(3):415-9. [Medline].

  54. Gerson WT, Dickerman JD, Bovill EG, Golden E. Severe acquired protein C deficiency in purpura fulminans associated with disseminated intravascular coagulation: treatment with protein C concentrate. Pediatrics. 1993 Feb. 91(2):418-22. [Medline].

  55. Yilmaz S, Gunaydin S. Inherited risk factors in low-risk venous thromboembolism in patients under 45 years. Interact Cardiovasc Thorac Surg. 2014 Oct 17. [Medline].

  56. Michiels JJ, Hamulyak K. Laboratory diagnosis of hereditary thrombophilia. Semin Thromb Hemost. 1998. 24(4):309-20. [Medline].

  57. Dolan G, Neal K, Cooper P, Brown P, Preston FE. Protein C, antithrombin III and plasminogen: effect of age, sex and blood group. Br J Haematol. 1994 Apr. 86(4):798-803. [Medline].

  58. Martinoli JL, Stocker K. Fast functional protein C assay using Protac, a novel protein C activator. Thromb Res. 1986 Aug 1. 43(3):253-64. [Medline].

  59. Jones DW, Mackie IJ, Winter M, Gallimore M, Machin SJ. Detection of protein C deficiency during oral anticoagulant therapy--use of the protein C:factor VII ratio. Blood Coagul Fibrinolysis. 1991 Jun. 2(3):407-11. [Medline].

  60. Linn YC, Tien SL. Detection of protein C or protein S deficiency in patients on warfarin therapy--a study of nine patients. Ann Acad Med Singapore. 1994 Sep. 23(5):775-80. [Medline].

  61. Schramm W, Spannagl M, Bauer KA, et al. Treatment of coumarin-induced skin necrosis with a monoclonal antibody purified protein C concentrate. Arch Dermatol. 1993 Jun. 129(6):753-6. [Medline].

  62. 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 Nov 28. 325(22):1565-8. [Medline].

  63. Conard J, Bauer KA, Gruber A, et al. Normalization of markers of coagulation activation with a purified protein C concentrate in adults with homozygous protein C deficiency. Blood. 1993 Aug 15. 82(4):1159-64. [Medline]. [Full Text].

  64. Dreyfus M, Ladouzi A, Chambost H, et al, for the PROTEXEL Study Group. Treatment of inherited protein C deficiency by replacement therapy with the French purified plasma-derived protein C concentrate (PROTEXEL). Vox Sang. 2007 Oct. 93(3):233-40. [Medline].

  65. Hartman KR, Manco-Johnson M, Rawlings JS, Bower DJ, Marlar RA. Homozygous protein C deficiency: early treatment with warfarin. Am J Pediatr Hematol Oncol. 1989 Winter. 11(4):395-401. [Medline].

  66. Minford AM, Parapia LA, Stainforth C, Lee D. Treatment of homozygous protein C deficiency with subcutaneous protein C concentrate. Br J Haematol. 1996 Apr. 93(1):215-6. [Medline].

  67. Lee MJ, Kim KM, Kim JS, Kim YJ, Lee YJ, Ghim TT. Long-term survival of a child with homozygous protein C deficiency successfully treated with living donor liver transplantation. Pediatr Transplant. 2009 Mar. 13 (2):251-4. [Medline].

  68. Crowther MA, Ageno W, Garcia D, et al. Oral vitamin K versus placebo to correct excessive anticoagulation in patients receiving warfarin: a randomized trial. Ann Intern Med. 2009 Mar 3. 150(5):293-300. [Medline].

  69. Klein TE, Altman RB, Eriksson N, et al, for the International Warfarin Pharmacogenetics Consortium. Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med. 2009 Feb 19. 360(8):753-64. [Medline]. [Full Text].

 
Previous
Next
 
The protein C pathway. APC = activated protein C; PC = protein C; S= protein S; T = thrombin; TM = thrombomodulin; Va = factor Va; VIII = factor VIIIa.
A patient with warfarin-induced skin necrosis.
A patient with neonatal purpura fulminans.
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2016 by WebMD LLC. This website also contains material copyrighted by 3rd parties.