Protein C and Protein S Deficiencies

A 22-year-old Caucasian male presents to the emergency room with left lower leg swelling and pain. He has had multiple episodes with this presentation. Which of the following underlying disorders is most likely responsible for these recurrent symptoms? A. Antiphospholipid syndrome B. Factor V Leiden C. Malignancy D. Protein C deficiency E. Prothrombin gene mutation

B. Factor V Leiden

A 44-year-old female presents to the office for a follow-up visit. She has had several episodes of deep vein thrombosis (DVT) and was ultimately found to have a deficiency of protein C. Which of the following mechanisms causes this patient's recurrent DVTs? A. Factor Va resistant to deactivation B. Increased blood stasis C. Increased factor Va and VIIIa activity D. Increased prothrombin production E. Loss of cofactor activity

C. Increased factor Va and VIIIa activity

A 3-day-old male is admitted to the hospital with widespread purpura and a low platelet count. His family history is significant for a father who had recurrent deep vein thromboses, and a mother who suffered a severe skin condition after taking an anticoagulant medication. Which of the following is the most likely diagnosis? A. Hemophilia B B. Immune thrombocytopenic purpura C. Purpura fulminans D. Thrombotic thrombocytopenic purpura E. Warfarin-induced skin necrosis

C. Purpura fulminans

A 30-year-old African-American female presents to the emergency department and is diagnosed with a deep vein thrombosis (DVT) complicated by a pulmonary embolism. She has a history of three past DVTs. Which of the following tests would most definitively diagnose her condition? A. Clinical history B. Factor Va activity C. Partial thromboplastin time (PTT) D. Protein C assay E. Prothrombin time (PT)

D. Protein C assay

What are patients with purpura fulminanc at risk of developing?

DIC

What is the most common presentation of protein C and protein S deficiency?

DVT

A 26-year-old male with a past medical history significant for multiple deep vein thrombosis (DVT) and protein C deficiency presents to the emergency department with symptoms similar to those of his previous DVTs. Which of the following is the most likely chief complaint for his emergency department visit? A. Black and blue skin B. Gum bleeding C. Headache D. Knee swelling E. Unilateral leg swelling

E. Unilateral leg swelling

A patient presents with his second unprovoked deep vein thrombosis. What is the most likely disorder responsible for this?

Factor V Leiden

What is the most common inherited thrombophilia?

Factor V leiden

Which coagulation factors are inactivated by protein C?

Factors Va and Factor VIIIa

Why is there a period of hypercoagulability in initiating treatment with warfarin?

Protein C and protein S become deficient before factors II, VII, IX, and X are deficient

How is purpura fulminans distinguished from disorders such as immune thrombocytopenia purpura?

Rapid development of necrosis and bullae

Proteins C and S deficiencies share features with which other hereditary and acquired thrombophilias?

factor V leiden, antiphospholipid antibody syndrome, antithrombin deficiency

What are the causes of inherited deficiencies?

genetic mutation in gene for either protein C or S can cause decreased amount of protein or non-functioning protein

What is administered to avoid patients from developing warfarin-induced skin necrosis?

heparin bridge

Deficiencies in proteins C and S lead to...

increased risk for thrombosis

What can lead to acquired deficiencies?

liver disease, Vitamin K deficiency, chemotherapy agents

What can homozygous patients develop (in addition to what heterozygous patients develop)?

more severe syndrome purpura fulminans

Diagnosis criteria for protein C/S deficiency

patients with protein C levels that are 50% or less of normal are likely to have protein C deficiency individuals with a personal or family history of thromboembolic disease or events, such as DVTs, free protein S level less than 60 units/dL are indicative of deficiency patients who have one or no instances of thromboembolism, less than 33 units/dL of protein S are suggestive of a deficiency

What are provoked DVTs?

those that occur in presence of known thrombosis risk factors (immobility, cancer, recent surgery)

What is purpura fulminans?

acute disorder characterized by nonstop thrombotic complications

What is the least common inherited thrombophilia?

antithrombin deficiency

What is the normal function of protein S?

cofactor to enable function of protein C

What is the function of vitamin K epoxide reductase?

converts oxidized form of vitamin K to the reduced form

How are protein C and S deficiencies diagnosed?

direct protein assay of protein blood levels

What does protein C do once it is activated?

directly inactivates factors Va and VIIIa

Symptoms of purpura fulminans

present suddenly, usually with hemorrhagic necrosis and infarction of skin due to widespread, multiple thrombi initial presentation may mimic immune thrombocytopenic purpora or thrombotic thrombocytopenic purpura progresses to necrosis much more rapidly, initial bruising and erythematous lesions quickly progress to black/blue bullae and irregular necrotic plaques

What are heterozygous patients at risk of?

problematic clotting (usually in the form of DVT, pulmonary embolism) can also develop ischemic-strokes and Budd-Chiari syndrome

Which deficiency is more common: protein C or protein S?

protein C is more common (protein S = 0.2-0.5% of population)

What are the first factors or proteins to decrease in amount after warfarin administration? Why?

proteins C and S b/c they have the shortest half-life (puts the patient in hypercoagulable state) after a few days, other vitamin-K dependent factors offset the depletion of proteins C and S (for healthy individuals)

What is the second most common inherited thrombophilia?

prothrombin G20210A

Purpura fulminans can also occur with which other conditions?

sepsis, disorders that reduce protein synthesis capacity (i.e. liver disease)

What is the normal process for producing vitamin-K dependent coagulation factors?

vitamin-K dependent factors require carboxylation of glutamate residues to be functional vitamin K needs to be reduced for carboxylation to happen, but once this occurs vitamin K becomes oxidized vitamin K quickly returns to its reduced state via vitamin K epoxide reductase vitamin-K dependent factors can be synthesized (factors 2, 7, 9, 10, proteins C and S)

Why are patients with protein C and S deficiencies at such high risk for warfarin-induced skin necrosis?

warfarin blocks the production of vitamin-K dependent coagulation factors (includes proteins C and S) by inhibiting vitamin K epoxide reductase

What are the risks associated with patients with protein C/S deficiencies who take warfarin?

warfarin-induced skin necrosis (causes skin and subcutaneous tissue thrombosis and necrosis)