Options to manage and treat Severe Congenital Protein C Deficiency (SCPCD)

Options for Management of SCPCD

What are some of the different options for treating Severe Congenital
Protein C Deficiency?

Treating the manifestations of Severe Congenital Protein C Deficiency (SCPCD) usually involves anti-coagulation and/or Protein C (PC) replacement, depending on the circumstances and phase of management.¹ Each treatment option, either individually or in combination, is a viable choice for both acute and long-term management.²
PC replacement is an established method for treating Purpura Fulminans (PF) and warfarin-induced skin necrosis and can also be used for prophylaxis in patients with SCPCD.³ It is used to temporarily increase a patient’s PC levels, slowing down the clotting process and preventing thrombotic events associated with excess blood coagulation.⁴ Replacement of PC can be achieved with infusions of fresh frozen plasma (FFP), cryoprecipitate, PC-rich prothrombin-complex concentrate or PC concentrate.^3,5,6

While anticoagulants can be an effective form of treatment for SCPCD and its associated symptoms during the acute phase, use of protein C replacement is suggested.² This ASH guidance was passed in 2018 for pediatric patients with purpura fulminans due to congenital homozygous PC deficiency (conditional recommendation based on very low certainty in the evidence of effects). In these same patients, the guideline also suggested using anticoagulation combined with protein C replacement, rather than anticoagulation alone (conditional recommendation based on very low certainty in the evidence of effects).² Another guideline, published by the American College of Chest Physicians (ACCP) for antithrombotic therapy in neonates and children, recommended in the acute setting the administration of either FFP or PC concentrate, when available, until the clinical lesions resolve.⁷

During the transition from acute management to long-term management of SCPCD, anticoagulants may be added concomitantly or amid the conversion. Once fully transitioned, maintenance of SCPCD can be achieved through oral anticoagulants or a combination of oral anticoagulants and PC replacement, while curative treatment can be achieved via liver transplantation.⁶ The CHEST guidelines put out by the American College of Chest Physicians (ACCP) recommend vitamin K antagonists, low-weight molecular heparin, protein C replacement, or liver transplantation for long-term management of SCPCD. When PC replacement cannot be followed for pragmatic or cost reasons, providing patients with combined protein C replacement and anticoagulation, rather than anticoagulation alone, may reduce the intensity of anticoagulation and therefore reduce the risk of bleeding.^2,7 However, due to the small number of cases, long-term management of SCPCD is still poorly understood.^5-8 Evidence is usually derived from case reports, case series or retrospective clinical trials; all of which have limitations in terms of comparing results and extrapolating to a wider population.

TREATMENT OPTIONS FROM CHEST AND ASH GUIDELINES*

Protein C REPLACEMENT i PC replacement therapy temporarily increases a patient’s PC levels, slowing down the clotting process and preventing thrombotic events associated with excess blond coagulation.⁴
- Fresh frozen plasma - Protein C concentrate	ACUTE TREATMENT (RECOMMENDATION GRADING)	LONG-TERM TREATMENT (RECOMMANDATION GRADING)
	Grade 1A⁷ i Grade 1A¹² (Strong recommendation, high-quality evidence) Benefit vs. Risk and burdens Benefits clearly outweigh risk and burdens or vice versa. Methodologic Strength of Supporting Evidence Consistent evidence from randomised controlled trials without important limitations or exceptionally strong evidence from observational studies. Implications Recommendations can apply to most patients in most circumstances. Further research is very unlikely to change our confidence in the estimate effect.	Grade 1B⁷ i Grade 1B¹² (Strong recommendation, moderate-quality evidence) Benefit vs. Risk and burdens Benefits clearly outweigh risk and burdens or vice versa Methodologic Strength of Supporting Evidence Evidence from randomised controlled trials with important limitations (inconsistent results, methodological flaws, indirect or imprecise) or very strong evidence from observational studies. Implications Recommendations can apply to most patients in most circumstances. Higher-quality research may well have an important impact on our confidence in the estimate of effect and may change the estimate

ANTICOAGULANTS i Coumarins produce their anticoagulant effect by inhibiting the vitamin K conversion cycle, thereby causing hepatic production of partially carboxylated and decarboxylated proteins with reduced procoagulant activity.⁹ Low Molecular Weight Heparin is a derivative of Heparin, which inhibits the coagulation process by binding to Antithrombin (AT). This binding leads to a conformational change that converts AT from a slow, progressive thrombin inhibitor to a very rapid inhibitor of factor Xa and thrombin.¹⁰
- Coumarin derivatives - Low molecular weight heparin	ACUTE TREATMENT (RECOMMENDATION GRADING)	LONG-TERM TREATMENT (RECOMMANDATION GRADING)
	Conditional recommendation² i Conditional recommendation² The ASH guideline panel suggests using anticoagulation plus protein C replacement rather than anticoagulation alone in pediatric patients with congenital purpura fulminans due to homozygous protein C deficiency (conditional recommendation based on very low certainty in the evidence of effects). Remarks: This recommendation applies in an acute setting (acute episode of purpura fulminans) in which protein C replacement plus anticoagulation is considered a better opinion than anticoagulation alone.	Grade 1C⁷ i Grade 1C¹² (Strong recommendation, low-or-very-low-quality evidence) Benefit vs. Risk and burdens Benefits clearly outweigh risk and burdens or vice versa. Methodologic Strength of Supporting Evidence Evidence for at least one critical outcome from observational studies, case series, or randomized controlled trials with serious flaws or indirect evidence. Implications Recommendations can apply to most patients in many circumstances. Higher-quality research is likely to have an important impact on our confidence in the estimate of effect and may well change the estimate.

TRANSPLANT i A liver transplant represents a curative therapy for SCPCD. Since PC is synthesized in the liver, PC activity can be normalized in PC deficient recipient of a liver graft.^3,8,11
- Liver transplantation	ACUTE TREATMENT (RECOMMENDATION GRADING)	LONG-TERM TREATMENT (RECOMMANDATION GRADING)
	No recommendation provided	Grade 1C⁷ i Grade 1C¹² (Strong recommendation, moderate-quality evidence) Benefit vs. Risk and burdens Benefits clearly outweigh risk and burdens or vice versa Methodologic Strength of Supporting Evidence Evidence for at least one critical outcome from observation studies, case series, or randomised controlled trials with serious flaws or indirect evidence. Implications Recommendations can apply to most patients in most circumstances. Higher-quality research may well have an important impact on our confidence in the estimate of effect and may change the estimate

*GUIDELINES MAY NOT BE IN LINE WITH APPROVED PRODUCT LABELS. PLEASE CONSULT INDIVIDUAL PRODUCT PRESCRIBING INFORMATION.

References:

Pescatore SL. Clinical management of protein C deficiency. Expert opinion on pharmacotherapy. 2001;2(3):431–439.
Monagle P, et al. American Society of Hematology 2018 Guidelines for management of venous thromboembolism: treatment of pediatric venous thromboembolism. Blood Adv. 2018;2(22):3292-3316.
Kroiss S, Albisetti M. Use of human protein C concentrates in the treatment of patients with severe congenital protein C deficiency. Biologics: Targets & Therapy. 2010;4:51-60.
Goldenberg N, Manco-Johnson M. Protein C deficiency. Haemophilia. 2008;14(6):1214-1221.
Mathias M, et al. Subcutaneous administration of protein C concentrate. Pediatric hematology and oncology. 2004;21(6):549-554.
Price VE, et al. Diagnosis and management of neonatal purpura fulminans. Semin Fetal Neonatal Med. 2011;16(6):318-322.
Monagle P, et al. Antithrombotic therapy in neonates and children: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e737S-e801S.
Monagle P, et al. Long-term follow-up of homozygote protein C deficiency after multimodal therapy. Journal of pediatric hematology/oncology. 2014;36(7):e452-455.
Hirsh J, et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest. 2001;119(1 Suppl):8S-21S.
Hirsh J, et al. Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. Chest. 2001;119(1 Suppl):64S-94S.
Mosnier LO, et al. Protein C, Protein S, Thrombomodulin, and the Endothelial Protein C Receptor Pathways. In: Marder, VJ, et al. (eds.) Hemostasis and Thrombosis: Basic Principles and Clinical Practice. 6th ed. Philadelphia, PA, USA: Wolters Kluwer Health; 2012.
Guyatt GH, et al. Methodology for the development of antithrombotic therapy and prevention of thrombosis guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):53S-70S.

Options for Management of SCPCD

TREATMENT OPTIONS FROM CHEST AND ASH GUIDELINES*

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