Severe Congenital Protein C Deficiency (SCPCD)

A rare condition with often life-threatening complications1
Protein C Deficiency Can Be Caused by
Hereditary Mutations3

Congenital Protein C deficiency is caused by mutations in the Protein C gene (PROC) located on chromosome 2(q13-14). The condition can be divided into 2 types: type I is characterized by a decrease in both Protein C activity and Protein C plasma concentration compared to normal levels; type II is characterized by near normal Protein C plasma concentration, but decreased Protein C activity.3

3 subtypes of congenital Protein C deficiency4
  • Homozygous

    Both chromosomes 2 carry the same PROC mutation

  • Mixed heterozygous

    Different PROC mutation on each of the chromosomes 2

  • Heterozygous

    Only one chromosome 2 has a PROC mutation

Cause of Protein C Deficiency: 3 subtypes of congenital Protein C deficiency
CEPROTIN® [Protein C Concentrate (Human)] is the only nonactivated Protein C concentrate approved by the US FDA for use in people with severe congenital Protein C deficiency.5
Congenital PC Deficiency
Subtype Frequency4
5.1% 5.6% 1.3% 88%
  • Heterozygous
    • 76% type I
    • 12% type II
  • Mixed heterozygous
    • 3% type I
    • 0.6% type II
    • 1.5% type I/II
  • Homozygous
    • 5% type I
    • 0.6% type II
  • Unknown
    • 1.3%
Clinical Manifestations of Congenital Protein C Deficiency

Clinical manifestations of Protein C deficiency are driven by a shift in balance between pro- and anticoagulation factors resulting in excess coagulation, which causes thrombosis and subsequent symptoms.4 Severe congenital Protein C deficiency can manifest as purpura fulminans, disseminated intravascular coagulation, and arterial and venous thrombosis.3 Consider treating or preventing purpura fulminans or venous thrombosis with CEPROTIN.

Purpura fulminans in neonateNeonatal Purpura Fulminans picture
Warfarin-induced skin necrosis4Warfarin Induced Skin Necrosis picture
VENOUS THROMBOSIS RISK FOR
INDIVIDUALS WITH SCPCD
6–10 times
HIGHER RELATIVE RISK
of developing venous thrombosis
compared to the general population10
At least
50%by
age 40
HAVE EXPERIENCED
A THROMBOTIC
EVENT10
Venous thromboses associated with severe congenital Protein C deficiency (SCPCD) include venous thromboembolism (constituting deep vein thrombosis and pulmonary embolism), 6 mesenteric thrombosis, 7 portal vein thrombosis, 8,9 and Budd-Chiari syndrome. 8,9
Severe Congenital Protein C Deficiency Diagnosis Is Essential to Effective Management

Protein C deficiency should be confirmed using multiple methods. Testing in family members is recommended to determine if the deficiency is congenital.16 The severity of Protein C deficiency is determined by remaining Protein C activity levels. In healthy individuals, Protein C activity levels increase with age.1

Severe congenital Protein C deficiency may initially become apparent because newborns present with purpura fulminans within hours after birth.1,16 Mean Protein C Activity Levels in Healthy Individuals1
Newborn
6-month old
Adult
% of upper limit of normal adult levels
% of upper limit of normal adult levels
Normal adult ranges of Protein C level are reached after puberty
Protein C Activity Levels and Severity
Adult Protein C Activity Levels and Severity of Protein C Deficiency1
Protein C Activity Level (IU/dL) Severity
65-135No deficiency
21-64Mild
1-20Moderate
< 1Severe

CEPROTIN is indicated for pediatric and adult patients with severe congenital Protein C deficiency for the prevention and treatment of venous thrombosis and purpura fulminans.5

Prompt treatment of clinical manifestations is critical4,17
Treating the manifestations of severe congenital Protein C deficiency typically involves:1
  • Protein C replacement therapy
  • Anticoagulation

In some individuals with severe congenital Protein C deficiency, continuous, long-term prophylactic treatment may also be necessary.12,17

CEPROTIN is the only nonactivated Protein C replacement therapy FDA approved for use in both treatment and prophylaxis in pediatric and adult patients with severe congenital Protein C deficiency.5

Potential Limitations
Potential limitations to treatment

Although capable of alleviating severe conditions related to severe congenital Protein C deficiency, Protein C replacement therapies and certain anticoagulants, such as fresh frozen plasma, cryoprecipitate, prothrombin-complex concentrate, and Protein C concentrate, have limitations.

Standard modalities:
  • Fresh frozen plasma, cryoprecipitate, and prothrombin-complex concentrate have not been approved for use in people with severe congenital Protein C deficiency
  • The infusion of fresh frozen plasma or cryoprecipitate once or twice daily over numerous days is necessary to improve symptoms.17 Repeated administration may lead to fluid overload17,18
  • Prothrombin-complex concentrate is limited due to the inconsistent amount of Protein C in each batch, and it carries a risk of allergic reactions and thromboembolic events19-21
Protein C concentrate
  • An increase in the risk of major bleeding, especially if administered with concurrent anticoagulation medications or tissue plasminogen activator5,16
  • Reports of allergy and hypersensitivity3
  • Risk of inhibiting antibody formation or heparin-induced thrombocytopenia3
  • Risk of transmitting infectious agents because it is derived from human plasma5
    REFERENCES:
  1. Goldenberg NA, Manco-Johnson MJ. Protein C deficiency. Haemophilia. 2008;14(6):1214-1221
  2. Manco-Johnson MJ, Bomgaars L, Palascak J, et al. Efficacy and safety of protein C concentrate to treat purpura fulminans and thromboembolic events in severe congenital protein C deficiency. Thromb Haemost. 2016;116(1):58-68.
  3. 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;2(2):285-296.
  4. Knoebl PN. Blood Coagulation and Inflammation in Critical Illness: the Importance of the Protein C Pathway. UNI-MED Verlag; 2008.
  5. Baxalta. CEPROTIN [Protein C Concentrate (Human)]: Prescribing information.
  6. Limperger V, Klostermeier UC, Kenet G, et al. Clinical and laboratory characteristics of children with venous thromboembolism and protein C-deficiency: an observational Israeli-German cohort study. Br J Haematol. 2014;167(3):385-393.
  7. Rharrit D, Harmouche H, Baroudi S, et al. Protein C deficiency and mesenteric venous thrombosis. Can J Surg. 2009;52(2):E35-E37.
  8. Bhattacharyya M, Makharia G, Kannan M, Ahmed RP, Gupta PK, Saxena R. Inherited prothrombotic defects in Budd-Chiari syndrome and portal vein thrombosis: a study from North India. Am J Clin Pathol. 2004;121(6):844-847.
  9. Janssen HL, Meinardi JR, Vleggaar FP, et al. Factor V Leiden mutation, prothrombin gene mutation, and deficiencies in coagulation inhibitors associated with Budd-Chiari syndrome and portal vein thrombosis: results of a case-control study. Blood. 2000;96(7):2364-2368.
  10. Khan S, Dickerman JD. Hereditary thrombophilia. Thromb J. 2006;4:15.
  11. Gürgey A, Aytac S, Kanra G, Secmeer G, Ceyhan M, Altay C. Outcome in children with purpura fulminans: report on 16 patients. Am J Hematol. 2005;80(1):20-25.
  12. Chalmers E, Cooper P, Forman K, et al. Purpura fulminans: recognition, diagnosis and management. Arch Dis Child. 2011;96(11):1066-1071.
  13. Chan YC, Valenti D, Mansfield AO, Stansby G. Warfarin induced skin necrosis. Br J Surg. 2000;87(3):266-272.
  14. Stewart A. Warfarin-induced skin necrosis treated with protein C concentrate (human). Am J Health Syst Pharm. 2010;67(11):901-904.
  15. Gladson CL, Groncy P, Griffin JH. Coumarin necrosis, neonatal purpura fulminans, and protein C deficiency. Arch Dermatol. 1987;123(12):1701a-1706a.
  16. Price VE, Ledingham DL, Krümpel A, Chan AK. Diagnosis and management of neonatal purpura fulminans. Semin Fetal Neonatal Med. 2011;16(6):318-322.
  17. Kroiss S, Albisetti M. Use of human protein C concentrates in the treatment of patients with severe congenital protein C deficiency. Biologics. 2010;4:51-60.
  18. Muller FM, Ehrenthal W, Hafner G, Schranz D. Purpura fulminans in severe congenital protein C deficiency: monitoring of treatment with protein C concentrate. Eur J Pediatr. 1996;155(1):20-25.
  19. Mathias M, Khair K, Burgess C, Liesner R. Subcutaneous administration of protein C concentrate. Pediatr Hematol Oncol. 2004;21(6):549-554.
  20. Franchini M, Lippi G. Prothrombin complex concentrates: an update. Blood Transfus. 2010;8(3):149-154.
  21. Sorensen B, Spahn DR, Innerhofer P, Spannagl M, Rossaint R. Clinical review: Prothrombin complex concentrates—evaluation of safety and thrombogenicity. Crit Care. 2011;15(1):201.

Indication and Important Safety Information

WARNINGS and PRECAUTIONS
  • Hypersensitivity/Allergic reactionsCEPROTIN® [Protein C Concentrate (Human)] may contain trace amounts of mouse protein and/or heparin as a result of the manufacturing process. Allergic reactions to mouse protein and/or heparin cannot be ruled out. In case of hypersensitivity/allergic reaction, discontinue CEPROTIN administration immediately and institute appropriate treatment.
  • Transmission of infectious agentsCEPROTIN is made from human plasma. It may carry a risk of transmitting infectious agents, e.g. viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent.
  • Bleeding episodesSeveral bleeding episodes have been observed in clinical studies. Concurrent anticoagulant medication may have been responsible for these bleeding episodes. CEPROTIN administration may have further contributed to these bleeding events. Simultaneous administration of CEPROTIN and tissue plasminogen activator (tPA) may further increase the risk of bleeding from tPA.
  • Heparin-induced thrombocytopenia (HIT)CEPROTIN contains trace amounts of heparin that may lead to HIT, which can be associated with a rapid decrease of thrombocytes. If HIT is suspected, determine the platelet count immediately and discontinue CEPROTIN administration.
  • Low sodium diet/Renal impairmentPatients on a low sodium diet or who have renal impairment should be informed that the quantity of sodium in the maximum daily dose of CEPROTIN exceeds 200 mg. Monitor patients with renal impairment closely for sodium overload.
ADVERSE REACTIONS

The common adverse reactions related to CEPROTIN treatment observed in clinical trials were the following hypersensitivity or allergic reactions: lightheadedness, itching and rash.

Indication

CEPROTIN® [Protein C Concentrate (Human)] is indicated for pediatric and adult patients with severe congenital Protein C deficiency for the prevention and treatment of venous thrombosis and purpura fulminans

Please review the CEPROTIN Prescribing Information for full prescribing details.