Protein C deficiency
Synonyms and keywords: Protein C deficiency disorder

# Overview
Protein C deficiency is hyper-coagulopathy in which a person develops increased tendency of forming abnormal blood clots, especially in peripheral extremities (legs and arms). These clots can dislodge and ascend into the lungs, causing a life threatening condition, pulmonary embolism. Protein C is one of vitamin K dependent anticoagulants, which upon activation inactivates the clotting factors Va and factor VIIIa and hence plays role its role as anticoagulant. The manifestations of the disease can be mild which don't develop deep venous thrombosis; however, it has an increased risk of developing warfarin-induced skin necrosis and neonatal purpura fulminans in which widespread clots are formed in the body leading to necrosis and after utilization of all the clotting factors leads to massive bleeding. Protein C deficiency can be hereditary or acquired. Hereditary variant is associated with mutation in PROC gene, which is transmitted in an autosomal dominant pattern. People carrying two alleles of the mutant gene tend to develop more aggressive disease.

# Historical Perspective
- Protein C deficiency was first discovered by Stenflo, a Swedish chemist, in 1976.
- In 1982, Bertina was the first to discover the association between thrombosis and protein C deficiency.
- The association between thrombosis and protein C deficiency was again confirmed in 1993 by Dahlback et al and 1994 by Bertina et al 1994.

# Classification
Protein C deficiency may be classified according to etiology:
- Congential protein C deficiency:
Heterozygous protein deficiency
Type I disease: Generally mild form. It has decreased levels of protein C.
Type II disease: It has normal or near normal levels of protein C but reduced functional activity.
Homozygous protein C deficiency: It is severe form of disease. It presents with neonatal purpura fulminans.
Acquired protein C deficiency.
- Heterozygous protein deficiency
Type I disease: Generally mild form. It has decreased levels of protein C.
Type II disease: It has normal or near normal levels of protein C but reduced functional activity.
- Type I disease: Generally mild form. It has decreased levels of protein C.
- Type II disease: It has normal or near normal levels of protein C but reduced functional activity.
- Homozygous protein C deficiency: It is severe form of disease. It presents with neonatal purpura fulminans.
- Acquired protein C deficiency.

# Pathophysiology
- The protein C is a vitamin K dependent glycoprotein, 62 kD, synthesized in the liver.
- It circulates as zymogen and is activated to activated protein C (APC).
- Synthesis of gamma-carboxylic acid on protein C requires vitamin K. The Gla domains bind to calcium leading to structural change that facilitates phospholipid binding which is important for protein function.
- Activated protein C is catalyzed by thrombine-thrombmomdulin complex when it is binds to endothelial proteoglycan.
Protein C after its activation has following functions:
- The primary role of protein C is to inactivate factor Va and factor VIIIa, both of these factors are essential for activation of thrombin and factor Xa which forms clots.
- When protein C is deficient or inactive it leads to uncontrolled clot formation.
- The inhibitory effect of factor protein C is enhanced by protein S. Both perform similar functions.
- Activated protein C indirectly increases the profibrinolytic activity by activating to tissue plasminogen activator (tPA) after binding to plasminogen activator inhibitor (PAI). The reduced thrombin generation thus decreases the activation of TAFI (thrombin activatable fibrinolysis inhibitor) hence resulting in enhanced profibrinolytic potential.
- The other role of protein C is its anti inflammatory effect. The reactions are mediated by epithelial protein cell receptors (EPCR) and protease activated receptor 1 (PAR -1) that play primary role in cytoprotective, anti inflammatory effects and barrier stabilizing effects.
- The deficiency of protein C creates procoagulant effect generally in areas with slow moving venous blood flow, such as extremities leading to thrombosis which manifest as deep venous thrombosis.

# Causes
- The cause of protein C deficiency is PROC miss sense or nonsense mutation gene mutation of chromosome 2 at 14q3.
- Other types of mutations have also been described, including promoter mutations, splice site abnormalities, in-frame deletions, frameshift deletions, in-frame insertions, and frameshift insertions.
- Protein C consumption:
Disseminated intravascular coagulation
Surgery
Decreased synthesis of protein C in liver disease
Vitamin K deficiency
Nephrotic syndrome
Infection
Autoantibodies
Cancer
- Disseminated intravascular coagulation
- Surgery
- Decreased synthesis of protein C in liver disease
- Vitamin K deficiency
- Nephrotic syndrome
- Infection
- Autoantibodies
- Cancer

# Differentiating Protein C deficiency from Other Diseases
Protein C deficiency must be differentiated from other diseases that cause symptoms of DVT and pulmonary embolism such as:
- Factor V Leiden mutation
- Antithrombin III deficiency
- Protein S deficiency
- Prothrombin gene mutation
- Disseminated intravascular coagulation (DIC)
- Antiphospholipid antibody syndrome
For more information on differentiating protein C deficiency, click here.

# Epidemiology and Demographics
- The incidence of protein C deficiency is approximately 142 per 100,000 individuals, worldwide.
- The prevalence of protein C deficiency was estimated to be 145 per 100,000 annually.

## Age
- The median age of a first episode is typically in third to fourth decade with family history; while, individuals without a family history tend to develop first episode in their fourth to fifth decade.

# Risk Factors
- The most potent risk factor in the development of protein C deficiency is consanguineous marriage.
- Hereditary variant is associated with mutation in PROC gene, which is transmitted in an autosomal dominant pattern.

# Screening
- There is insufficient evidence to recommend routine screening for protein C deficiency, however in patients with positive family history, it is recommended to check protein C activity (functional) assay which is either clotting time based or chromogenic.

# Natural History, Complications, and Prognosis
- If left untreated, the patients of protein C deficiency manifest as unprovoked episodes of venous thromboembolism.
- The probability of manifestation of disease is enhanced in presence of the precipitating factors such as immobility, prolonged use of oral contraceptives, and pelvic surgery.

### Common complications of protein C deficiency include:
- Deep venous thrombosis
Warfarin-induced skin necrosis
Neonatal purpura fulminans
Pulmonary embolism and thrombosis in unusual sites such as  cerebral, mesenteric, splenic and hepatic veins.
- Deep venous thrombosis
- Warfarin-induced skin necrosis
- Neonatal purpura fulminans
- Pulmonary embolism and thrombosis in unusual sites such as  cerebral, mesenteric, splenic and hepatic veins.

### Less common complications include:
- Impaired fetal growth and miscarriage has also been reported with homozygous protein C deficiency.
- Neonatal purpura fulminans is observed with homozygous variant of protein C deficiency.
- Severe complications such as arterial thrombosis is seen resulting in ischemic stroke in young patient with heterozygous protein C deficiency.

### Prognosis
- Prognosis of protein C deficiency is generally good with anticogulation therapy survival rate of patients with protein C deficiency is improved.

# Diagnosis

## Diagnostic Study of Choice
Following are the two tests that are performed to reach the absolute diagnosis:
- Functional assays such as aPTT based assay, factor Xa based (enzymatic assay that uses a chromogenic substrate to check the amidolytic cleavage of a synthetic protein (snake venom) are used to determine function of protein C.
- Antigenic determination of protein C levels. This can detect low levels of protein C as well as the anticoagulant effects.
- Clotting based assays (aPTT and factor Xa) may be used; however, the results may be affected heparin and other anticoagulants. Hence chromogenic assays are preferred. The only exception is when the patient is using vitamin K antagonists which lowers the activity of protein C activity in any assay.
- If functional assays do not reveal the reduced function of protein C especially when clinical suspicion is high, alternative methods should be considered.
- Some people have normal levels of protein C with reduced or near normal anticoagulant function, but normal or near normal amidolytic activity, this indicates reduced ability of protein C to interact with substrate such as factor V, platelet membrane and factor VIII.

## History and Symptoms
- The majority of patients with protein C deficiency are asymptomatic.
- The probability of developing venous thromboembolism is especially increased in patients with protein C deficiency in the presence of risk factors such as,  factor V Leiden mutation, prolonged immobility, surgery, and prolonged use of oral contraceptives.
- Initial episode of venous thromboembolism is spontaneous in 2/3rd of cases, however, it tends to be recurrent.
- In deep venous thrombosis, a clot is formed in deep veins of leg with potential to ascend upwards to right heart and pulmonary arteries, if dislodged may manifest as pulmonary embolism.
- The patients with acquired disease tend to develop skin changes after the use of anticoagulants such as warfarin.
- For symptoms of deep venous thrombosis click here.
- For symptoms of pulmonary embolism click here.
- Other symptoms include following:
Purpura and skin changes
Abnormal pigmentation
Neurologic abnormalities
Superficial thrombophlebitis
- Purpura and skin changes
- Abnormal pigmentation
- Neurologic abnormalities
- Superficial thrombophlebitis

## Physical Examination
- For physical signs  related to deep venous thrombosis click here.
- For physical signs related to pulmonary embolism click here.
- Warfarin-induced necrosis can present with erythematous macules which begins on the torso and extremities which can become purpuric and necrotic.
- Homozygous cases may present with more severe disease such as neonatal purpura fulminans which is seen as diffuse ecchymoses, if left untreated it can progress to necrotic bullae.

## Laboratory Findings
- The diagnosis of protein C deficiency is based on the clinical presentation in addition to strong familial history.
- Various tests are conducted to document protein C deficiency in addition to baseline clotting profile including:
Bleeding time (BT)
Clotting time (CT)
Prothrombin time (PT)
Activated prothrombin time (aPTT)
- Bleeding time (BT)
- Clotting time (CT)
- Prothrombin time (PT)
- Activated prothrombin time (aPTT)
- It is important to mention that testing should be done after the episode has settled because it can lead to falsely lower protein C measurements.
- The diagnostic tests of choice have been described above.
- Genetic testing for mutations in PROC gene.

## Electrocardiogram
- Protein C deficiency may be associated with development of myocardial infarction in young patients.
- Following are the ECG findings:
- ST segment elevations in leads II, III, and aVF with reciprocal ST depression in lead V46.
Loss of R wave
- ST segment elevations in leads II, III, and aVF with reciprocal ST depression in lead V46.
- Loss of R wave

## X-ray
- There are no specific x-ray findings associated with protein C deficiency.
- For specific x-ray findings seen with pulmonary embolism, click here.

## Echocardiography or Ultrasound
- There are no specific echocardiography or ultrasound findings associated with protein C deficiency.
- For ultrasound findings related to deep vein thrombosis, click here.
- For echocardiography findings associated with pulmonary embolism, click here.

## CT scan
- There are no specific CT scan findings associated with protein C deficiency.
- For CT scan findings related to pulmonary embolism, click here.

## MRI
- There are no MRI findings associated with protein C deficiency.

## Other Imaging Findings
- There are no other imaging findings associated with protein C deficiency.

## Other Diagnostic Studies
- There are no other diagnostic studies associated with protein C deficiency.

# Treatment

## Medical Therapy
- Pharmacologic medical therapy is recommended among patients with warfarin-induced skin necrosis, neonatal purpura fulminans and pulmonary embolism.

### Management of venous thromboembolism:
- Anticoagulation is primarily recommended.
- For longer duration, it is suggested to bridge warfarin and heparin.
- However, oral anticoagulants such as factor Xa inhibitors can also be used depending on compliance of patient in addition to severity of disease.
- The duration of anticoagulation varies according to case.
- In case of unprovoked episode of thromboembolism or once the diagnosis of protein C has been established, life long anticoagulation therapy is suggested.
- For provoked episodes and in presence of precipitating factors 6 months of warfarin therapy bridged with heparin is recommended.
- For more information related to management of deep venous thrombosis, click here.

## Management of pulmonary embolism:
- Warfarin is suggested for patients with complicated disease such as in case of pulmonary embolism.
- For management of pulmonary embolism click here.

### Management of warfarin-induced skin necrosis:
- Once the episode of warfarin induced skin necrosis sets in, it needs immediate therapy to prevent the further complications.
Stop warfarin.
Administer vitamin K intravenously.
Administer unfractionated heparin.
Administer a source of protein C such as protein C concentrate or fresh frozen plasma.
For skin lesions consult a Dermatologist.
- Stop warfarin.
- Administer vitamin K intravenously.
- Administer unfractionated heparin.
- Administer a source of protein C such as protein C concentrate or fresh frozen plasma.
- For skin lesions consult a Dermatologist.

## Surgery
- Surgical consultation is recommended for the complication of protein C deficiency such as management of skin lesions in warfarin-induced skin necrosis.
- Liver transplantation was performed in neonatal purpura fulminans that resulted in permanent cure.

## Primary Prevention
- There are no established measures for the primary prevention of protein C deficiency.

## Secondary Prevention

### Prophylaxis of warfarin-induced skin necrosis:
- Start warfarin at a low dose, gradually increase from 2 mg to therapeutic dose.
Other anticoagulants such as dabigatran, rivaroxaban, apaxaban, or edoxaban may be used.
Overlapping of warfarin with heparin during the first several days of warfarin administration is recommended.
Use of warfarin in patients of protein C deficiency: Protein C concentrate should be used unless the required level of anticoagulation is achieved. After which warfarin can be administered again.
- Start warfarin at a low dose, gradually increase from 2 mg to therapeutic dose.
- Other anticoagulants such as dabigatran, rivaroxaban, apaxaban, or edoxaban may be used.
- Overlapping of warfarin with heparin during the first several days of warfarin administration is recommended.
- Use of warfarin in patients of protein C deficiency: Protein C concentrate should be used unless the required level of anticoagulation is achieved. After which warfarin can be administered again.

### Prophylaxis for recurrent thromboembolism:
- Prophylactic anticoagulation should be considered in patients having risk factors for venous thromboembolism such as recurrent episodes of VTE, prolonged use of oral contraceptives, and surgeries.
- Other effective measures for secondary prevention of protein C deficiency include:
Avoid prolonged use of oral contraceptives.
Avoid immobilization.
Education concerning signs and symptoms of venous thromboembolic events.
- Avoid prolonged use of oral contraceptives.
- Avoid immobilization.
- Education concerning signs and symptoms of venous thromboembolic events.