Protein C is a vitamin K-dependent coagulation inhibitor produced by the hepatocytes. It is activated by the Thrombin-Thrombomodulin Complex, and in association with its cofactor, Protein S, induces proteolysis and inactivates Factor Va and Factor VIIIa thus limiting thrombin production.
Congenital protein C deficiency may be inherited as an autosomal dominant disorder. Asymptomatic Protein C deficiency has been reported to be prevalent in 1 in 200 to 500 of healthy individuals, whereas the incidence of symptomatic deficiency is 1 in 20000. Autosomal recessive inheritance has been estimated to be around 1 in 4 million.
We report a case of a 19 year old male, ex 33 week-premature first twin baby from Thailand, diagnosed with severe Protein C Deficiency after presenting to a local hospital with an acute manifestation of bilateral leg swelling and purpura fulminans when he was 2 years old. At that time, his Protein C activity was 2%. He was initially treated with quarantined FFP replacement 10-15ml/kg weekly and LMWH and later warfarin. MRI done at that time showed evidence of prior ischemic events.
Upon arrival to the US at 16 years of age his treatment with warfarin was continued. During the following year, he presented several times with complications including deep venous thrombosis, warfarin skin necrosis, bleeding and transient neurological deficits. He was started on rivaroxaban - a direct thrombin inhibitor- 20mg orally daily at 17 years of age. For the following two years he did well and had no other acute thrombotic, bleeding events or medication side effects. Follow up brain MRI showed no new areas of infarct.
No well-defined general guidelines are available for the treatment of symptomatic patients with severe congenital protein C deficiency. Current treatment for this condition focuses on to Protein C replacement with Fresh Frozen Plasma or an infusion of a human plasma-derived, viral inactivated protein C concentrate - such as ceprotin.
It has been shown that patients with severe congenital Protein C deficiency were more effectively treated with Protein C concentrates than those treated with FFP or conventional anticoagulants. Nevertheless, Protein C concentrates requires supervision of an experienced physician and long-term treatments require the need of a central venous access. Side effects include higher risk of infections due to frequent transfusions, fluid overload, allergic reactions, high sodium intake, heparin induced thrombocytopenia and high cost. New anticoagulation medications open a window of possibilities for management of this medical condition.
There is no literature on the use of rivaroxaban in children. Few studies have been done and most of them are case reports. In 2013, Martinelli et al published a case report of a 6 year old girl with severe protein S deficiency. Initially started on warfarin but had recurrent episodes of warfarin-induced skin necrosis. Her hypercoagulable state was due to warfarin-induced reduction of protein C so the switch of anticoagulant therapy to rivaroxaban resulted in the disappearance of skin necrosis at 1 year of follow-up.
Our case demonstrates an autosomal recessive Protein C deficiency successfully managed with the use of direct Xa inhibitor- rivaroxaban- given orally on a daily basis. This treatment approach appears to be safe and effective and could be studied in prospective large cohorts of patients with Protein C deficiency.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.