protein S deficiency

**Physiology** - Protein S is a vitamin K–dependent (factors II, VII, IX, X, protein C, protein S; require gamma-carboxylation) anticoagulant synthesized in the liver (also endothelium, megakaryocytes). - It acts as a cofactor for activated protein C (APC), which proteolytically inactivates factors Va and VIIIa. It also acts as a cofactor for TFPI (inhibiting factor Xa and the TF-VIIa complex). - About 60% circulates bound to C4b-binding protein (inactive); about 40% is free (active). Only free protein S functions as a cofactor.

**Pathophysiology** - Loss of protein S means less APC activity. Unopposed Va and VIIIa lead to increased thrombin generation and a hypercoagulable state, mostly venous. - Inheritance is autosomal dominant (PROS1 gene). Heterozygotes have about 50% levels and are symptomatic. Homozygous or compound heterozygous deficiency causes neonatal purpura fulminans, which is life-threatening. - Types: - Type I (quantitative): low total and free protein S, and low activity. - Type II (qualitative): normal antigen levels, low activity. - Type III: normal total protein S, low free protein S, and low activity (increased C4b-BP binding). - Acquired causes of low protein S: - Pregnancy and estrogen therapy (OCPs, HRT) - Acute thrombosis or DIC - Liver disease - Vitamin K deficiency or warfarin - Nephrotic syndrome (urinary loss) - Acute inflammation (increased C4b-BP, which lowers free protein S) - HIV, SLE

**Clinical features** - Recurrent DVT, PE, and unusual sites (cerebral venous sinus, mesenteric, portal veins). - Pregnancy loss or complications (recurrent miscarriage). - Warfarin-induced skin necrosis: - Occurs in the first days after starting warfarin without a heparin bridge. - Protein S and protein C have short half-lives (protein C about 8 h), so levels fall before factors II, IX, and X do. A transient hypercoagulable state results, with microvascular thrombosis and painful, well-demarcated skin necrosis (fat-rich areas: breasts, thighs, buttocks). - Risk is greatest in protein C deficiency, but it also occurs in protein S deficiency. - Arterial thrombosis is uncommon.

**Diagnosis** - Normal PT/aPTT and platelet count. - Measure free and total protein S antigen and functional activity. - Test when the patient is not acutely thrombosed, not pregnant, not on warfarin, and not on heparin. Results are unreliable in these states because the level falls. Repeat low values to confirm.

**Management** - Acute VTE: heparin (LMWH/UFH) or a DOAC, followed by anticoagulation for 3–6 months. Consider indefinite anticoagulation for recurrent or unprovoked events. - Avoid warfarin monotherapy at initiation; overlap with heparin until INR is therapeutic, which prevents warfarin skin necrosis. - Pregnancy: use LMWH, because warfarin is teratogenic. - Purpura fulminans (neonatal): protein replacement, fresh frozen plasma, or protein C concentrate. - Prophylactic anticoagulation in high-risk situations (surgery, immobilization).

**High-yield comparisons** - Factor V Leiden is the most common inherited thrombophilia. It causes APC resistance, so the mutant factor Va is not degraded. - Protein C deficiency presents similarly (autosomal dominant, warfarin skin necrosis). - Antithrombin III deficiency causes heparin resistance (the aPTT does not rise with heparin). - Prothrombin G20210A mutation increases prothrombin levels. - Board clue: a young patient with recurrent DVT, necrotic skin lesions after starting warfarin, and a normal baseline coagulation profile points to protein C or S deficiency.