From the Guidelines
Low protein C activity can be caused by several factors, including liver disease, vitamin K deficiency, warfarin therapy, and genetic mutations in the PROC gene, with liver disease being a significant cause as demonstrated by a procoagulant imbalance in cirrhotic patients due to decreased levels of protein C 1.
Causes of Low Protein C Activity
The causes of low protein C activity can be broadly categorized into inherited and acquired forms. Inherited forms are due to genetic mutations in the PROC gene, which encodes for protein C, and can be passed down in families as an autosomal dominant trait. Acquired causes are more common and include:
- Liver disease, as protein C is synthesized in the liver, and cirrhosis has been shown to lead to decreased levels of protein C, increasing the risk of venous thromboembolism (VTE) 1
- Vitamin K deficiency, as protein C is vitamin K-dependent
- Warfarin therapy, which inhibits vitamin K-dependent proteins, including protein C, and can lead to a rapid decrease in protein C levels, potentially causing warfarin-induced skin necrosis or venous limb gangrene 1
- Disseminated intravascular coagulation (DIC)
- Sepsis
- Acute thrombotic events
- Certain medications like oral contraceptives, hormone replacement therapy, and chemotherapy
- Conditions like inflammatory bowel disease, HIV infection, and post-surgical states may temporarily decrease protein C activity
Management and Clinical Implications
Low protein C activity increases thrombotic risk as protein C normally functions as an anticoagulant by inactivating factors Va and VIIIa. Management depends on the underlying cause, ranging from genetic counseling for inherited forms to treating the underlying condition for acquired deficiencies, with some cases requiring anticoagulation therapy or protein C concentrate during high-risk situations. It is essential to identify the underlying cause of low protein C activity to provide appropriate management and prevent thrombotic complications. In cases of warfarin-induced skin necrosis, a reasonable approach is to restart warfarin therapy at a low dose under the coverage of therapeutic doses of parenteral anticoagulants and gradually increase the warfarin dose over 1 or more weeks 1.
From the Research
Causes of Low Protein C Activity
- Hereditary protein C deficiency is caused by a mutation in the PC (PROC) gene located on chromosome 2q14.3 2
- Acquired protein C deficiency can be caused by various factors, including vitamin K antagonist treatment or liver disease 3
- Low protein C activity can also be caused by other conditions, such as disseminated intravascular coagulation (DIC) 4
- Laboratory testing for protein C deficiency can be affected by various interferences, including lupus anticoagulants and direct thrombin inhibitors, which can result in falsely low or normal protein C activity levels 5
Types of Protein C Deficiency
- Hereditary protein C deficiency can be further categorized as heterozygous, homozygous, or doubly heterozygous 6
- Heterozygous protein C deficiency is more common than homozygous deficiency, and patients may present with purpura fulminans, venous thrombosis, and/or pulmonary embolism 6
- Homozygous protein C deficiency is usually associated with severe and often fatal purpura fulminans and DIC during the neonatal period 6
Laboratory Testing for Protein C Deficiency
- The recommended initial laboratory test for protein C deficiency measures protein C activity using either clot-based or chromogenic methods 2
- The chromogenic assay is recommended due to its good specificity, but it may not detect rare types of protein C deficiency, such as type 2b deficiency 3
- The clotting-based assay can detect type 2b deficiency, but it has reduced specificity 3