Options for management of SCPCD*

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

Treating the manifestations of Severe Protein C Deficiency (SCPCD) usually involves anti-coagulation and/or protein C (PC) replacement, depending on the circumstances.¹ Due to the small number of cases, long-term management of SCPCD is poorly understood.^2·3 Evidence is usually derived from case reports, case series or retrospective clinical trials; ail of which have limitations in terms of comparing results and extrapolating to a wider population.

The acute management of SCPCD involves PC replacement. Anticoagulants may be added concomitantly or during the transition to long-term management. Maintenance can be achieved through oral anticoagulants or a combination of oral anticoagulants and PC replacement. Curative treatment has been achieved with liver transplantation.^4,5
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.⁵ Replacement of PC can be achieved with infusions of fresh frozen plasma (FFP), cryoprecipitate, PC-rich prothrombin-complex concentrate or PC concentrate^1-4,6 FFP contains ail plasma components (water, electrolytes, albumin immunoglobulins coagulation factors and factors of the complement system) including PC in a non-concentrated form.^5,7

In 2018, the ASH guideline panel suggested using protein C replacement rather than anticoagulation in paediatric patients with purpura fulminans due to congenital homozygous PC deficiency (conditional recommendation based on very low certainty in the evidence of effects). However, in these same patients, the guideline suggested using anticoagulation combined with protein C replacement, rather than anticoagulation alone (conditional recommendation based on very low certainty in the evidence of effects). For long-term treatment, when protein C replacement cannot be followed for pragmatic or cost reasons, providing patients with combined pro tein C replacement and anticoagulation, rather than anticoagulation alone, may reduce the intensity of anticoagulation and therefore reduce the risk of bleeding.⁸ Another guideline, published by the American College of Chest Physicians (ACCP) for antithrombotic therapy in neonates and children, recommended in the acute setting the administra tion of either FFP or PC concentrate, when available, until the clinical lesions resolve. This same guideline also recommended, for long-term treatment: vitamin k antagonists, low-weight molecular heparin, protein C replacement, or liver transplantation.⁹

PC replacement therapy temporarily increases a patient’s PC levels, slowing down the clotting process and preventing thrombotic events associated with excess blood coagulation.¹⁰

SELECTED treatment options*

Protein C REPLACEMENT
- Fresh frozen plasma - Protein C concentrate	ACUTE TREATMENT (RECOMMENDATION GRADING)	LONG-TERM TREATMENT (RECOMMANDATION GRADING)
	Grade 1A⁹ i Grade 1A¹¹ (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 1B⁹ i Grade 1B¹¹ (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
- Coumarin derivatives - Low molecular weight heparin	ACUTE TREATMENT (RECOMMENDATION GRADING)	LONG-TERM TREATMENT (RECOMMANDATION GRADING)
	Conditional recommendation⁸ i Conditional recommendation⁸ 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 1C^9*

TRANSPLANT
- Liver transplantation	ACUTE TREATMENT (RECOMMENDATION GRADING)	LONG-TERM TREATMENT (RECOMMANDATION GRADING)
	-	Grade 1C⁹ i Grade 1C¹¹ (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

*TREATMENTS MAY NOT BE IN LINE WITH APPROVED PRODUCT LABELS IN ALL COUNTRIES. PLEASE CONSULT YOUR LOCAL PRESCRIBING INFORMATION.

References:

Pescatore SL. Clinical management of protein C deficiency. Expert opinion on pharmacotherapy. 2001;2(3):431–439.
Mathias M, et al. Subcutaneous administration of protein C concentrate. Pediatric hematology and oncology. 2004;21(6):549–554.
Monagle K, et al. Long-term follow-up of homozygote protein C deficiency after multimodal therapy. Journal of pediatric hematology/oncology. 2014;36(7):e452–455.
Price VE, et al. Diagnosis and management of neonatal purpura fulminans. Semin Fetal Neonatal Med. 2011;16(6):318-22.
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.
Knoebl PN. Human protein C concentrates for replacement therapy in congenital and acquired protein C deficiency. Drugs of Today. 2008;44(6):429–441.
Mercer University School of Medicine. The Internet Pathology Laboratory for Medical Education. Blood Products. Available at: http://library.med.utah.edu/WebPath/TUTORIAL/BLDBANK/BBPROD.html; Last accessed: May 2018.
Monagle P, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: treatment of pediatric venous thromboembolism. Blood Adv. 2(22):3292-3316.
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.
Goldenberg N, Manco-Johnson M. Protein C deficiency. Haemophilia. 2008;14(6):1214-1221.
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;141:53s-70s.

C-ANPROM /INT/ /5460- January 2020

Options for management of SCPCD*

SELECTED treatment options*

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