What are the implications of Protein C deficiency on hypercoagulability?

From the Guidelines

Protein C deficiency should be managed with anticoagulation plus protein C replacement in pediatric patients with congenital purpura fulminans due to homozygous protein C deficiency, as this approach is considered superior to anticoagulation alone in the acute setting. This recommendation is based on the American Society of Hematology 2018 guidelines for management of venous thromboembolism, which suggests using anticoagulation plus protein C replacement rather than anticoagulation alone in pediatric patients with congenital purpura fulminans due to homozygous protein C deficiency 1.

Key Considerations

• Protein C replacement is very expensive, especially as the child increases in age, and may not be feasible in many health systems 1.
• The use of combination protein C and anticoagulation reduces the cost of replacement therapy and reduces the intensity of anticoagulation required, hence reducing the bleeding risk 1.
• Patients with severe deficiency may require protein C concentrate, and lifelong anticoagulation is generally recommended for those with recurrent thrombosis, while those with a first unprovoked event typically receive 3-6 months of treatment.

Management Options

• Anticoagulation therapy, with options including low molecular weight heparin, unfractionated heparin, or direct oral anticoagulants (DOACs) like rivaroxaban, apixaban, or dabigatran.
• For long-term management, warfarin is commonly used at doses adjusted to maintain an INR of 2.0-3.0, though initial warfarin therapy should be overlapped with heparin to prevent warfarin-induced skin necrosis.
• Protein C is a vitamin K-dependent anticoagulant protein that inactivates factors Va and VIIIa, and deficiency disrupts this natural anticoagulant pathway, leading to increased thrombin generation and clot formation.

Special Considerations

• During pregnancy, management requires specialized care with low molecular weight heparin as the preferred agent.
• All patients should be counseled on avoiding additional risk factors such as smoking, oral contraceptives, and prolonged immobility.
• The likelihood of stroke from most prothrombotic states seems to be relatively low, but the stroke risk increases when a prothrombotic disorder occurs in children with other risk factors 1.

From the Research

Protein C Deficiency and Hypercoagulable State

• Protein C deficiency is a condition that increases the risk of developing venous thrombosis, as it is a vital component in the regulation of blood coagulation 2, 3.
• Patients with protein C deficiency often present with deep venous thrombosis, which can be recurrent, and may also develop thrombosis in unusual sites such as the mesenteric or splanchnic veins 3, 4.
• The condition can be inherited in an autosomal dominant pattern, and affected individuals usually develop thrombotic events as adults 3.

Diagnosis and Treatment

• Diagnosis of protein C deficiency involves measuring protein C levels, which are typically low in affected individuals (range, 34 to 67 U/dL; normal, 70 to 130 U/dL) 3.
• Treatment of protein C deficiency usually involves anticoagulation therapy, with warfarin being the traditional mainstay of treatment 2, 3.
• However, the use of direct oral anticoagulants (DOACs) such as apixaban has been explored as an alternative to warfarin, with some studies suggesting its effectiveness in preventing recurrent thrombotic events 2.
• In some cases, protein C concentrate may be used to supplement anticoagulation therapy, particularly during the initiation of oral anticoagulation, to prevent thromboembolic complications 5.

Clinical Presentation and Complications

• Protein C deficiency can present with a range of clinical manifestations, including deep venous thrombosis, pulmonary embolism, and thrombosis in unusual sites such as the renal or splanchnic veins 3, 4.
• Patients with protein C deficiency are also at risk of developing peripheral arterial insufficiency, which can be characterized by long segment thrombotic occlusion of a main peripheral artery without evidence of atherosclerosis 6.
• The condition requires long-term anticoagulation therapy to prevent recurrent thrombotic events, and patients who discontinue anticoagulation therapy are at risk of developing further complications such as graft occlusion and limb loss 6.