What are the implications of Activated Protein C (APC) deficiency?

From the Guidelines

Activated protein C deficiency is a rare cause of adult stroke, but it may play a larger role in pediatric stroke, and management should focus on preventing blood clots through anticoagulation therapy and lifestyle modifications. The link between activated protein C resistance and arterial stroke is tenuous in adults, but it may be more significant in juvenile stroke 1. Inherited thrombophilias, such as protein C deficiency, rarely contribute to adult stroke but may be more common in pediatric stroke.

Key Considerations

• The presence of venous thrombosis is an indication for short- or long-term therapy, depending on the clinical and hematologic circumstances 1.
• For acute thrombotic events, heparin followed by warfarin is typically used, and long-term management may include oral anticoagulants like warfarin with a target INR of 2.0-3.0, or direct oral anticoagulants (DOACs) like rivaroxaban or apixaban.
• Patients with severe deficiency might require protein C concentrate during acute episodes, and liver transplantation may be considered in pediatric patients with congenital purpura fulminans due to homozygous protein C deficiency 1.
• Lifestyle modifications are also important, including regular exercise, maintaining a healthy weight, avoiding prolonged immobility, and not smoking.

Management and Prevention

• Women with this condition should avoid estrogen-containing contraceptives and discuss pregnancy management with their healthcare provider, as pregnancy increases clotting risk.
• Regular monitoring of anticoagulation therapy is essential to prevent both clotting and bleeding complications.
• The optimal therapy depends on the values and preferences of the family, as well as local health service factors, and discussion of potential pathways of care should be determined early before progressive organ damage has been sustained 1.

From the FDA Drug Label

Known or suspected deficiency in protein C mediated anticoagulant response Hereditary or acquired deficiencies of protein C or its cofactor, protein S, have been associated with tissue necrosis following warfarin administration. Inherited resistance to activated protein C has been described in many patients with venous thromboembolic disorders but has not yet been evaluated as a risk factor for tissue necrosis.

Activated Protein C Deficiency is a condition that may increase the risk of tissue necrosis when taking warfarin.

• The FDA drug label recommends caution when administering warfarin to patients with known or suspected deficiency in protein C mediated anticoagulant response.
• Hereditary or acquired deficiencies of protein C have been associated with tissue necrosis following warfarin administration.
• However, inherited resistance to activated protein C has not been evaluated as a risk factor for tissue necrosis 2.

From the Research

Activated Protein C Deficiency

• Activated protein C (APC) is a natural anticoagulant that plays a crucial role in preventing the formation of blood clots by inactivating factors Va and VIIIa in the clotting cascade 3, 4.
• Protein C deficiency is a rare autosomal recessive disorder that can present with purpura fulminans, disseminated intravascular coagulation (DIC), and venous thromboembolism (VTE) 3, 4.
• The severity of protein C deficiency can vary, with severe deficiency (homozygous or compound heterozygous) often presenting in the neonatal period with life-threatening complications, while mild deficiency (heterozygous) may be asymptomatic or present with recurrent VTE episodes 3, 4.

Clinical Management

• Management of acute thrombotic events in severe protein C deficiency typically requires replacement with protein C concentrate and therapeutic anticoagulation 3, 5.
• Long-term management of severe protein C deficiency involves anticoagulation with or without a protein C replacement regimen, and may include the use of fresh frozen plasma, low-molecular weight heparin, and liver transplantation 3, 4, 5.
• Activated protein C has been shown to be effective in the treatment of disseminated intravascular coagulation (DIC), with improved outcomes compared to unfractionated heparin 6.

Therapeutic Strategies

• Activated protein C-based therapeutic strategies are being explored for the treatment of chronic diseases, including diabetic nephropathy, neurodegeneration, and wound healing 7.
• The use of cytoprotective-selective APC variants may circumvent the limitation of increased bleeding risk associated with APC therapy, and revive interest in APC as a therapeutic agent 7.