protein C deficiency

PHYSIOLOGY: Protein C is a vitamin K-dependent serine protease made in the liver (along with factors II, VII, IX, X and protein S). Thrombin binds thrombomodulin on endothelium, and this complex activates protein C (aPC). Activated protein C, with protein S as cofactor, cleaves and inactivates factors Va and VIIIa, which limits clot propagation. Factor V Leiden is resistant to this cleavage, which is why it causes a similar hypercoagulable state.

GENETICS/EPIDEMIOLOGY: Autosomal dominant with variable penetrance (PROC gene, chromosome 2). Heterozygotes (about 0.2-0.4% of the population) have about 50% protein C activity and an increased risk of VTE. Homozygous or compound heterozygous deficiency (protein C <1%) is rare and severe. Acquired causes include liver disease, DIC, vitamin K deficiency, warfarin therapy, sepsis, and asparaginase.

CLINICAL FEATURES: - Recurrent DVT/PE, often at a young age or in unusual sites (cerebral venous sinus, mesenteric veins). Arterial thrombosis is less common. - Warfarin-induced skin necrosis: Warfarin lowers protein C first because it has the shortest half-life (about 6-8 hours) among the vitamin K-dependent factors. This causes a transient hypercoagulable state before factors II, IX and X fall. The result is painful, well-demarcated erythematous skin lesions that progress to hemorrhagic necrosis, typically on days 3-5. They favor fatty areas (breasts, thighs, buttocks) and are caused by microvascular thrombosis in the subcutaneous fat. - Neonatal purpura fulminans: Homozygous infants develop widespread skin necrosis and DIC within hours to days of birth.

DIAGNOSIS: Measure protein C activity (functional chromogenic assay) and antigen levels. Do not test during acute thrombosis, during warfarin therapy, or with DIC or liver disease, because protein C will be falsely low. Test after anticoagulation has been stopped or stabilized and the acute illness has resolved. PT and PTT are normal. Type I is a quantitative deficiency (low activity and antigen). Type II is qualitative (low activity, normal antigen).

MANAGEMENT: - Acute thrombosis: start heparin (LMWH or UFH) first, then overlap with warfarin. Continue the heparin until the INR is therapeutic for at least 2 days and for at least 5 days of overlap. - Long-term: warfarin or a DOAC, depending on the thrombotic history. Duration depends on whether the VTE was provoked and on recurrence. - Warfarin-induced skin necrosis: stop warfarin, give vitamin K, give heparin, and give protein C concentrate or FFP if needed. - Neonatal purpura fulminans: protein C concentrate or FFP, followed by anticoagulation. Liver transplant is curative.

HIGH-YIELD COMPARISONS: - Protein S deficiency also causes VTE and warfarin skin necrosis. Protein S is a cofactor for protein C, and it is also reduced in nephrotic syndrome and pregnancy. - Factor V Leiden is the most common inherited thrombophilia. It shows a normal protein C level but an abnormal aPC resistance assay. - Antithrombin III deficiency causes heparin resistance (a failure of PTT to rise). - Prothrombin G20210A mutation causes increased prothrombin levels. - Antiphospholipid syndrome shows a prolonged PTT that does not correct on mixing, and it is associated with recurrent miscarriage.

BOARD PEARL: A patient develops painful skin lesions a few days after starting warfarin. Think protein C (or S) deficiency. The fix is to avoid starting warfarin without a heparin bridge.