Protein C Deficiency

I. Review - Protein C:

It is a Vitamin K-dependent protein synthesized in the liver and is an inhibitor of the procoagulant system.
It is synthesized in the liver as an inactive form. Activated Protein C is a serine protease which functions to inactivate Factors Va and VIIIa.
Protein C is activated to Protein Ca when thrombin binds to thrombomodulin. This binding alters the conformation of thrombin to a form that readily activates Protein C.
The activity of Protein C is markedly enhanced by its cofactor Protein S.

II. Mechanisms of Inhibition

A. Congenital deficiency of Protein C

1. Inherited as an autosomal dominant disorder and may account for up to 5-10% of patients with early clotting problems.

2. Heterozygous individuals have Protein C levels of 30 to 60% of normal, while homozygotes have little to no Protein C.

3. There are two types of congenital deficiencies:

Type I - Decreased levels of Protein C
Type II - rare - There is normal level of Protein C, but decreased functional activity.

4. Clinical features:

Increased risk of thromboembolism, primarily deep venous thrombosis and pulmonary embolism.
Thromboembolic events begin in mid-late teenage years. Homozygous patients often die of thrombosis in early infancy. Clotting is common in heterozygotes.
In addition to the deep veins of the lower extremities, thrombosis can also occur in the cerebral veins, retinal veins, mesenteric veins, renal veins, and the inferior vena cava.
Clotting may be further precipitated by surgery, trauma, pregnancy, or oral contraceptive use.
Arterial thrombotic events are rare.
Neonatal purpura fulminans:

It is a condition associated with Protein C deficiency that is seen in homozygotes and double heterozygotes for type I and II.

In this disorder, the neonate develops ecchymoses on the head, trunk and extremities. These skin lesions coalesce and then slowly ulcerate leading to necrosis. This is often accompanied with cerebral infarction.

Overall, this condition is usually fatal. Immediate treatment can be attempted with Factor IX concentrates (which contain Proteins C and S) and heparin.

Coumadin Skin Necrosis

This is a condition also associated with congenital Protein C Deficiency.

Skin and fat necrosis occurs when warfarin is given. Treatment is by stopping warfarin and instituting heparin.

B. Acquired Protein C Deficiency

1. Seen in patients with:

DVT, PE
Acute DIC
Post-operative State
Severe liver disease
Malignancy
Infection
Hemolytic-uremic syndrome
Adult Respiratory Distress Syndrome
Vitamin K Deficiency and/or Warfarin

2. Clinical features are similar to congenital Protein C deficiency and Antithrombin III deficiency.

III. Treatment of Protein C Deficiency

A. Acute thrombosis should be treated with heparin.

B. Long term prophylaxis can be undertaken with warfarin. However ....

C. When starting warfarin, very low doses must be used initially to prevent skin and fat necrosis.

D. Long-term low dose subcutaneous heparin can be used as an alternative to warfarin.

E. Protein C concentrates are also available. Factor IX concentrates also contain Protein C.

Go to Antithrombin III Deficiency

Go to Antiphospholipid Syndrome

Go to Protein S Deficiency

Go to Activated Protein C Resistance

Go Back to Hypercoagulable States

Go to Prothrombin 20210 Defect

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