eMedicine Specialties > Hematology > Coagulation, Hemostasis, and Disorders

Protein C Deficiency

Adam Cuker, MD, Fellowship in Hematology/Oncology, Hospital of the University of Pennsylvania
Eleanor S Pollak, MD, Associate Director of Special Coagulation, Associate Professor, Department of Pathology and Laboratory Medicine, Section of Hematology and Coagulation, University of Pennsylvania

Updated: Jun 11, 2009

Introduction

Background

The inherited thrombophilias are a heterogeneous group of genetic disorders associated with an elevated risk of venous thromboembolism (VTE) (see also the eMedicine articles Deep Venous Thrombosis [in the Vascular Surgery section], Pulmonary Embolism [in the Pulmonology section]). Causes of inherited thrombophilia include the factor V Leiden mutation, the prothrombin gene mutation, dysfibrinogenemia, and deficiencies of protein C, protein S, and antithrombin.

This article will focus on the pathophysiology, prevalence, clinical manifestations, diagnosis, and treatment of hereditary protein C deficiency. Causes of acquired protein C deficiency are also addressed (see Causes). The other inherited thrombophilias are discussed elsewhere (see Further Reading).

For excellent patient education resources, visit eMedicine's Circulatory Problems Center and Lung and Airway Center. Also, see eMedicine's patient education articles Blood Clot in the Legs and Pulmonary Embolism.

Pathophysiology

The Protein C Pathway

Protein C is a 62-kD, vitamin K-dependent glycoprotein synthesized in the liver. It circulates in the blood as an inactive zymogen at a concentration of 4 μg/mL. Its activation into the serine-protease-like enzyme, activated protein C (aPC), is catalyzed by thrombin when it is bound to the endothelial proteoglycan thrombomodulin.^1,2

The protein C pathway. APC = activated protein C; PC = protein C; S= protein S; T = thrombin; TM = thrombomodulin; Va = factor Va; VIII = factor VIIIa.

Frequency

United States

The frequency of protein C deficiency in the United States is similar to that found internationally.

International

Protein C deficiency by plasma level alone is found in 1 in 200 to 1 in 500 persons in the general population.^12,13 However, many affected individuals remain asymptomatic throughout life. Protein C deficiency is present in approximately 2-5% of patients presenting with VTE.^14,15,16 Severe homozygous or compound heterozygous protein C deficiency occurs in approximately 1 in 500,000 to 1 in 750,000 live births.

Mortality/Morbidity

Clinical manifestations of heterozygous protein C deficiency include VTE and warfarin-induced skin necrosis (WISN). Whether the risk of pregnancy loss is increased in this disorder is controversial. Arterial thrombosis does not appear to be associated with heterozygous protein C deficiency. 

Homozygous and compound heterozygous protein C deficiency are classically associated with neonatal purpura fulminans (NPF). Occasionally, patients present with VTE in childhood or adolescence.

Venous Thromboembolism

The cardinal clinical manifestation of heterozygous protein C deficiency is VTE. The risk of VTE in this population is roughly seven-fold over that of the general population.^17,18 Approximately 40% of patients with VTE have one of the usual thrombotic risk factors, such as pregnancy, the postpartum state, hormonal therapy, surgery, or immobilization.¹⁹ The remaining 60% present with unprovoked VTE. 

The most common sites of thrombosis are the deep veins of the lower extremities, although an elevated risk of mesenteric vein and cerebral sinus thrombosis is also well-documented.^20,21,22 Approximately 40% of patients with protein C deficiency present with evidence of pulmonary embolism, and roughly 60% suffer recurrent thrombosis if anticoagulation is discontinued.¹⁹ The risk of VTE increases with age and, among heterozygotes, thrombosis is unusual before age 20 years. Rare homozygotes and compound heterozygotes who do not manifest NPF in infancy may present with VTE later in childhood or adolescence.²³     

Warfarin-Induced Skin Necrosis

WISN is a potentially catastrophic complication of warfarin therapy that arises as a consequence of the different half-lives of the vitamin K-dependent proteins. One day after initiation of usual doses of warfarin, protein C activity is reduced by approximately 50%. Owing to their longer half-lives, the levels of the vitamin K-dependent clotting factors II, IX, and X decline more slowly (factor VII activity declines at approximately the same rate as protein C). The reduced level of protein C activity relative to these other procoagulant molecules creates a transient hypercoagulable state. This effect is more pronounced when large loading doses of warfarin are administered. Indeed, WISN typically occurs during the first few days of warfarin therapy, often when daily doses in excess of 10 mg are administered.^24,25

The skin lesions of WISN arise on the extremities, torso, breasts, and penis. They begin as erythematous macules and, if appropriate therapy is not initiated promptly, evolve to become purpuric and necrotic (see Image 2 or below). Dermal biopsy demonstrates ischemic necrosis of the cutaneous tissue with cutaneous vessel thrombosis and surrounding interstitial hemorrhage.²⁶  

A patient with warfarin-induced skin necrosis.

A patient with neonatal purpura fulminans.

Race

Congenital protein C deficiency is recognized as a cause of thrombophilia around the world. Studies in blacks and Asians suggest that its prevalence in these populations is on par with its frequency of occurrence in whites.^42,43  In contrast, the factor V Leiden and prothrombin gene mutations (see Hypercoagulability: Hereditary Thrombophilia and Lupus Anticoagulants Associated With Venous Thrombosis and Emboli) occur with substantially greater frequency in white than in nonwhite populations.

Sex

As would be expected for an autosomal genetic disorder, the prevalence of hereditary protein C deficiency is similar in men and women. However, pregnancy, the postpartum state, and estrogen-containing hormonal therapy are important risk factors for the development of VTE that are unique to women.

Age

Preterm infants have protein C levels approximately 10-15% of normal adult levels; neonates, approximately 35%; and adolescents, 80%. Protein C levels increase approximately 4% per decade in adulthood^44,45 ; nonetheless, the risk of thrombosis in individuals with heterozygous protein C deficiency increases with age. The median age at onset of VTE in heterozygous individuals is 30-40 years, and thrombosis is rare before age 20 years.⁴⁶  

In contrast, homozygous or compound heterozygous protein C deficiency classically manifests as NPF in the first several hours to days of life. Rare patients with homozygous or compound heterozygous deficiency may present with VTE during childhood or adolescence.²³

Clinical

History

Patients with previously diagnosed or suspected protein C deficiency should be queried about their personal history, family history, and laboratory testing.

Personal history

• Is there a previous history of VTE? At what anatomic site(s)? At what age(s) did VTE occur? Were there any antecedent provoking factors (eg, postoperative state, pregnancy, postpartum state, trauma, estrogen therapy, immobilization), or did VTE occur spontaneously?
• Have there been previous thrombotic challenges (eg, surgeries, pregnancies, traumas, use of estrogen therapy, immobilization) that the patient has undergone without developing VTE? If so, at what age(s) did these occur? Was thromboprophylaxis used?
• Has the patient been treated with anticoagulation in the past? Is there a history of WISN? Was there bleeding or other complications of anticoagulation therapy?
• Is there a history of pregnancy loss or other obstetric complications (eg, prematurity, preeclampsia, eclampsia)? At what gestational age(s) did pregnancy loss occur? Was a cause of pregnancy loss ever identified?

Family history

• Is there a family history of VTE? In which family member(s)? At what anatomic site(s)? At what age(s)? Were there any antecedent provoking factors, or did VTE occur spontaneously?
• Have family members been treated with anticoagulation? Is there a family history of WISN?
• Is there a family history of pregnancy loss or other obstetric complications (eg, prematurity, preeclampsia, eclampsia)? At what gestational age(s) did pregnancy loss occur? Was a cause of pregnancy loss ever identified?
• Is there a family history of NPF?

Laboratory testing

• What laboratory tests (ie, functional and/or immunologic protein C assays) (see Workup, Laboratory Studies) were performed and what were the results? Have abnormal tests been repeated? Have family members been tested?
• Was a cause of acquired protein C deficiency (see Acquired Protein C Deficiency in Causes) present during laboratory testing? If so, laboratory testing generally must be repeated in the absence of such causes before a diagnosis of hereditary protein C deficiency can be rendered.
• Was laboratory testing performed to assess for other hypercoagulable states (eg, factor V Leiden, prothrombin gene mutation, protein S deficiency, antithrombin deficiency, antiphospholipid antibody syndrome, dysfibrinogenemia)?  

Physical

Patients with symptomatic hereditary protein C deficiency may present with VTE or WISN. Homozygotes and compound heterozygotes frequently present with NPF during the first hours of life.

Venous thromboembolism

Findings of acute VTE on physical examination are discussed in topics elsewhere (see Further Reading). Deep venous thrombosis of the lower extremity may be complicated by postthrombotic syndrome, a chronic condition associated with swelling, pain, discoloration, and venous insufficiency of the lower extremity. 

Warfarin-induced skin necrosis

The skin lesions of WISN occur on the extremities, torso, breasts, and penis. They begin as erythematous macules and, if appropriate therapy is not initiated promptly, evolve to become purpuric and necrotic bullae.

A patient with warfarin-induced skin necrosis.

A patient with neonatal purpura fulminans.

Causes

Protein C deficiency may be congenital or acquired. The genetic basis of congenital protein C deficiency is reviewed in Pathophysiology, above.

Acquired Protein C Deficiency

Causes of acquired protein C deficiency include:

• Acute thrombosis
• Warfarin therapy
• Liver disease
• Vitamin K deficiency
• Sepsis
• Disseminated intravascular coagulation (DIC)
• Certain chemotherapeutic agents (eg, L-asparaginase)

Cases of acquired protein C deficiency in association with the development of a protein C auto-antibody⁴⁷ and hematopoietic stem cell transplantation⁴⁸ have also been reported. A severe form of acquired protein C deficiency associated with purpura fulminans may be observed in patients with meningococcemia and other causes of severe sepsis.⁴⁹ Administration of human recombinant activated protein C (aPC), drotrecogin alpha, has been shown to reduce mortality in severe sepsis (see Septic Shock). 

Differential Diagnoses

Workup

Laboratory Studies

Assays

A variety of immunologic and functional protein C assays are available.

Immunologic assays

Immunologic methods for the measurement of protein C antigen include enzyme-linked immunosorbent assays (ELISAs), radioimmunoassays (RIAs), and electroimmunoassays.⁵⁰ Logarithms of protein C antigen levels in the healthy, nonpregnant, adult population show a Gaussian distribution.⁵¹  The protein C antigen reference range is defined as the mean +/- 2 standard deviations (SDs) of this distribution and approximates 70-140% of the protein C antigen level of normal pooled plasma.¹³  As noted earlier, neonates and infants have lower levels of protein C than their adult counterparts, and age-based normal ranges must therefore be derived separately for these populations.⁴⁵

Functional assays

Functional protein C assays make use of the venom of the southern copperhead snake (Agkistrodon contortrix), which activates the protein C zymogen to activated protein C (aPC).⁵² Activated protein C (aPC) activity can then be measured by means of a clotting assay or a chromogenic substrate. The adult reference range for protein C activity tends to be slightly lower than the immunologic normal range. 

Screening

A decreased protein C activity level is required to make the diagnosis of protein C deficiency. However, owing to the broad normal ranges of protein C antigen and activity, diagnosis of heterozygous protein C deficiency can be challenging. Patients with levels less than 50% are likely to have a true hereditary deficiency, whereas levels between 55% and 65% may reflect heterozygous deficiency or the low end of the normal distribution.¹³ A functional protein C assay should be employed for screening purposes, as it will identify both type I and type II defects. In the event of a low protein C activity, a reflexive immunologic assay should be performed to distinguish between these types. 

As described in Causes, above, there are a number of acquired causes of protein C deficiency. To the extent possible, laboratory testing should be performed in the absence of such causes to confirm that deficiency, when identified, is due to a genetic defect rather than an acquired cause. The timing of testing with respect to acute thrombosis and warfarin therapy deserves special mention.

Acute thrombosis

The levels of protein C, protein S, and antithrombin are reduced in the setting of acute thrombosis. Therefore, these levels should generally not be performed at the time of presentation with acute VTE. However, a normal protein C activity in this setting essentially rules out hereditary protein C deficiency.

Warfarin

Because protein C is a vitamin K-dependent protein, its levels are reduced with warfarin administration. Therefore, it is recommended that protein C testing not be performed unless the patient has been off vitamin K antagonist therapy for at least 2 weeks. If the patient has a severe thrombotic diathesis that does not permit discontinuation of anticoagulation, the patient may be temporarily transitioned to low molecular weight heparin (LMWH) for testing purposes or, alternatively, the diagnosis may be inferred through testing of family members.
 
Several investigators have developed ratio methods for diagnosing protein C deficiency in the context of warfarin therapy by comparing the protein C level with that of other vitamin K-dependent clotting factors.^53,54 However, such methods have not been broadly validated.

Treatment

Medical Care

As noted earlier, a substantial proportion of individuals with protein C deficiency remain asymptomatic throughout life and require no specific therapy. However, thromboprophylaxis may be considered in such individuals, particularly if there is a strong family history of thrombosis, for situations associated with a high thrombotic risk such as pregnancy and the postpartum state, surgery, and trauma.

For those patients who do develop clinical manifestations of hereditary protein C deficiency, treatment depends on the particular clinical syndrome:

Venous Thromboembolism 

VTE in patients with protein C deficiency is managed in much the same way as it is for patients with VTE due to other causes (see Further Reading). Because the risk of recurrent VTE in protein C – deficient patients may be as high as 60%,¹⁹ long-term anticoagulation is often recommended, particularly following a spontaneous thromboembolic event. 

Warfarin-Induced Skin Necrosis

WISN is a medical emergency that requires treatment as soon as it is recognized. Therapy consists of immediate discontinuation of warfarin, administration of vitamin K, and initiation of therapeutic doses of heparin. If the patient is protein C deficient, administration of exogenous protein C should be administered, either in the form of fresh frozen plasma (FFP) or, preferably, as purified protein C concentrate (Ceprotin) with the goal of expeditiously normalizing plasma protein C activity.⁵⁵

Neonatal Purpura Fulminans 

Like WISN, NPF is a medical emergency that requires rapid normalization of plasma protein C activity. Although fresh frozen plasma has been used as a source of exogenous protein C in the treatment of NPF, frequent administration is required to maintain adequate plasma levels, thereby limiting its usefulness in this setting. Highly purified protein C concentrate (Ceprotin) represents an attractive alternative that does not subject patients to the high volume and protein load of fresh frozen plasma.^56,57,58  

After treatment of the acute phase of NPF, patients are transitioned to anticoagulation therapy, on which they must remain indefinitely. Warfarin may be used in this setting, provided that exogenous protein C is administered during its initiation in order to avoid the development of WISN.⁵⁹ For patients with breakthrough thrombosis despite anticoagulation, protein C concentrate may be infused at home. A subcutaneous formulation of protein C requiring administration every 3 days has been used successfully in this context.⁶⁰

Consultations

Consultation with a hematologist is warranted for the care of patients with congenital protein C deficiency.

Diet

There are no special dietary requirements for individuals with protein C deficiency. However, patients on warfarin should consume a steady diet and avoid large day-to-day fluctuations in the amount of vitamin K they ingest. 

Activity

There are no specific restrictions with respect to physical activity that are recommended for individuals with protein C deficiency. All individuals should ambulate regularly during prolonged travel to reduce the risk of VTE. Patients on anticoagulation therapy should avoid contact sports to reduce the risk of major bleeding. 

Medication

Anticoagulant Agents

Anticoagulation is the mainstay of therapy for the treatment and prevention of VTE in patients with protein C deficiency.

Unfractionated Heparin

Primarily used during the treatment of an acute thrombotic event or before initiating oral anticoagulant therapy.

Heparin mediates anticoagulant effects by augmenting the effect of the anticoagulant protein antithrombin.
Higher doses are needed in infants and children due to their low antithrombin levels.

Dosing

Adult

5000 U (USP) IV bolus initially, then 30,000 U/d adjusted to achieve a heparin concentration of 0.2-0.4 U/mL (by protamine titration of the thrombin time) or 0.3-0.7 antifactor Xa U/mL

A weight-adjusted nomogram can be used instead at a dose of 80 U/kg bolus followed by 18 U/kg/h

Therapeutic dosage most commonly monitored by an elevation of 1.5- to 2.5-times patient's normal pretreatment aPTT; patients with pretreatment elevations of the aPTT may need monitoring with heparin levels.

Heparin can be administered SC after an initial dose of 5000 U IV; SC dose is 17,500 U q12h

Pediatric

Suggested dosage schedule for neonatal thrombosis varies for the maturity of the infant.

Preterm infants <28 weeks: Bolus of 25 U/kg followed by a maintenance dosage of 15 U/kg/h

Preterm infants 28-36 weeks: Bolus of 50 U/kg followed by a maintenance dosage of 20 U/kg/h

Full-term infants: Bolus of 100 U/kg followed by a maintenance dosage of 25 U/kg/h

Children: Bolus of 75 U/kg IV over a 10-min period (initial recommended), followed by 28 U/kg/h for infants (<1 y), 20 U/kg/h for young children, and 18 U/kg/h for older children

Interactions

Digoxin, nicotine, tetracycline, and antihistamines may decrease effects; NSAIDs, ASA, dextran, dipyridamole, and hydroxychloroquine may increase heparin toxicity.

Contraindications

Documented hypersensitivity; subacute bacterial endocarditis, active bleeding, history of heparin-induced thrombocytopenia

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

In neonates, preservative-free heparin is recommended to avoid possible toxicity (gasping syndrome) by benzyl alcohol, which is used as a preservative; caution in patients with severe hypotension and shock; monitor for bleeding in peptic ulcer disease, menstruation, increased capillary permeability, and when giving IM injections.

Enoxaparin (Lovenox)

Produced by partial chemical or enzymatic depolymerization of unfractionated heparin (UFH). Binds to antithrombin, enhancing its therapeutic effect. The heparin-antithrombin complex binds to and inactivates activated factor X (Xa) and factor II (thrombin).

Does not actively lyse but is able to inhibit further thrombogenesis. Prevents reaccumulation of clot after spontaneous fibrinolysis.

Advantages include intermittent dosing and decreased requirement for monitoring. Heparin anti–factor Xa levels may be obtained if needed to establish adequate dosing.

LMWH differs from UFH by having a higher ratio of antifactor Xa to antifactor IIa compared with UFH.

Prevents DVT, which may lead to pulmonary embolism in patients undergoing surgery who are at risk for thromboembolic complications. Used for prevention in hip replacement surgery (during and following hospitalization), knee replacement surgery, or abdominal surgery in those at risk of thromboembolic complications, or in nonsurgical patients at risk of thromboembolic complications secondary to severely restricted mobility during acute illness.

Used to treat DVT or PE in conjunction with warfarin for inpatient treatment of acute DVT with or without PE or for outpatient treatment of acute DVT without PE.

No utility in checking aPTT (drug has wide therapeutic window and aPTT does not correlate with anticoagulant effect).

May be used during the treatment of an acute thrombotic event, before initiating PO anticoagulant therapy, or SC as an outpatient medication.

Dosing

Adult

VTE treatment: 1 mg/kg SC q12h
Thromboprophylaxis: 40 mg SC qd

If creatinine clearance < 30 mL/min:
VTE treatment: 1 mg/kg SC qd
Thromboprophylaxis: 30 mg SC qd

Pediatric

Not well-established.

VTE treatment for infants < 2 mo:
1.5 mg/kg SC q12h recommended

VTE treatment for infants >2 mo and children <18 y:
1 mg/kg SC q12h recommended

Interactions

Platelet inhibitors or oral anticoagulants such as dipyridamole, salicylates, aspirin, NSAIDs, sulfinpyrazone, and ticlopidine may increase the risk of bleeding.

Contraindications

Documented hypersensitivity to heparin or pork products; major bleeding, thrombocytopenia

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Decrease the dose if CrCl <30 mL/min; if thromboembolic event occurs despite LMWH prophylaxis, discontinue drug and initiate alternate therapy; elevation of hepatic transaminases may occur but is reversible; heparin-associated thrombocytopenia may occur with fractionated low-molecular-weight heparins; 1 mg of protamine sulfate will reverse effect of approximately 1 mg of enoxaparin if significant bleeding complications develop; cases of epidural/spinal hematomas have been reported in adults receiving spinal or epidural anesthesia (holding 2 doses before LP or surgery is recommended); obtain hemostasis at the puncture site before sheath removal after PCI.

Dalteparin (Fragmin)

Enhances inhibition of factor Xa and thrombin by increasing antithrombin activity. In addition, preferentially increases inhibition of factor Xa.

Except in overdoses, no utility exists in checking PT or aPTT because aPTT does not correlate with anticoagulant effect of fractionated LMWH.

Average duration of treatment is 7-14 d.

Dosing

Adult

Abdominal surgery: 2500 IU SC qd for 5-10 d

High-risk patients undergoing abdominal surgery: 5000 IU SC qd for 5-10 d

Hip arthroplasty: 2500 IU SC 4-8 h following surgery, then 5000 IU SC qd for up to 14 d

Pediatric

Not established

Interactions

Platelet inhibitors or oral anticoagulants such as dipyridamole, salicylates, aspirin, NSAIDs, sulfinpyrazone, and ticlopidine may increase the risk of bleeding.

Contraindications

Documented hypersensitivity; major bleeding, thrombocytopenia; regional anesthesia

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

If a thromboembolic event occurs despite LMWH prophylaxis, discontinue the drug and initiate alternate therapy; elevation of hepatic transaminases may occur but is reversible; heparin-associated thrombocytopenia may occur with fractionated low-molecular-weight heparins; protamine sulfate will reverse effect if significant bleeding complications develop; cases of epidural/spinal hematomas have been reported in adults receiving spinal or epidural anesthesia (holding 2 doses before LP or surgery is recommended); when using for extended treatment in patients with cancer, if the platelet count decreases to <100,000/mm³, reduce the dose by 2500 IU until platelet count recovers, and discontinue if platelet count is <50,000/mm³ (may resume previous dose when platelets recover); reduce the dose in patients with impaired renal function (monitor anti-Xa levels)

Tinzaparin (Innohep)

Enhances inhibition of factor Xa and thrombin by increasing antithrombin activity. In addition, preferentially increases inhibition of factor Xa.

Dosing

Adult

DVT treatment:
175 units/kg SC qd

Pediatric

Not established

Interactions

Platelet inhibitors or oral anticoagulants such as dipyridamole, salicylates, aspirin, NSAIDs, sulfinpyrazone, and ticlopidine may increase the risk of bleeding.

Contraindications

Documented hypersensitivity; major bleeding, thrombocytopenia

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

If a thromboembolic event occurs despite LMWH prophylaxis, discontinue the drug and initiate alternate therapy; elevation of hepatic transaminases may occur but is reversible; heparin-associated thrombocytopenia may occur with fractionated low-molecular-weight heparins; 1 mg of protamine sulfate will reverse the effect of approximately 100 U of tinzaparin if significant bleeding complications develop; cases of epidural/spinal hematomas have been reported in adults receiving spinal or epidural anesthesia (holding 2 doses before LP or surgery is recommended). May require dose reduction in the presence of renal impairment (creatinine clearance < 30 mL/min)

Fondaparinux (Arixtra)

Synthetic anticoagulant, which works by inhibiting factor Xa, a key component involved in blood clotting. Provides highly predictable response. Bioavailability is 100%, has a rapid onset of action, and a half-life of 14-16 h, allowing for sustained antithrombotic activity over 24-h period. Does not affect prothrombin time or activated partial thromboplastin time, nor does it affect platelet function or aggregation.

Prevents DVT, which may lead to pulmonary embolism, in patients undergoing orthopedic surgery who are at risk for thromboembolic complications.

Dosing

Adult

Acute DVT/PE treatment:

<50 kg: 5 mg SC qd
50-100 kg: 7.5 mg SC qd
>100 kg: 10 mg SC qd

Pediatric

Not established

Interactions

None reported; increased risk of bleeding possible with concurrent administration of platelet inhibitors, oral anticoagulants, or thrombolytic agents

Contraindications

Documented hypersensitivity; creatinine clearance <30 mL/min; weight <110 lb; patients given spinal anesthesia or spinal puncture

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

When spinal anesthesia or spinal puncture employed, may develop blood clot in spine, which can result in long-term or permanent paralysis (holding 2 doses before LP or surgery is recommended); major bleeding risk is increased when initiated before 6 h following surgery; elimination is decreased in elderly patients and those with renal impairment

Warfarin (Coumadin)

Acts by preventing proper functional synthesis of the vitamin K–dependent procoagulant proteins prothrombin; factors VII, IX, and X; and anticoagulant proteins C and S.

Tailor dose to maintain an INR in the range of 2 to 3.

Dosing

Adult

5-10 mg PO qd depending on patient weight, dietary consumption of vitamin K, concomitant medications, and genetic factors.

Average maintenance dose: 0.04-0.08 mg/kg/d PO

Pediatric

Initial loading dose 0.2 mg/kg (maximum 10 mg).
Then adjust maintenance dose by INR.

Average maintenance doses by age group are as follows:
Infants: 0.32 mg/kg/d PO
Children: 0.2 mg/kg/d PO
Teenagers: 0.09 mg/kg/d PO

Interactions

Drugs that may decrease the anticoagulant effects include griseofulvin, carbamazepine, glutethimide, estrogens, nafcillin, phenytoin, rifampin, barbiturates, cholestyramine, colestipol, vitamin K, spironolactone, oral contraceptives, and sucralfate.

Medications that may increase the anticoagulant effects of warfarin include oral antibiotics, capecitabine, phenylbutazone, salicylates, sulfonamides, chloral hydrate, clofibrate, diazoxide, anabolic steroids, ketoconazole, ethacrynic acid, miconazole, nalidixic acid, sulfonylureas, allopurinol, chloramphenicol, cimetidine, disulfiram, metronidazole, phenylbutazone, phenytoin, propoxyphene, sulfonamides, gemfibrozil, acetaminophen and sulindac.

Contraindications

Documented hypersensitivity; severe liver or kidney disease; open wounds or GI ulcers

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Patients with protein C or S deficiency are at risk of developing warfarin-induced skin necrosis upon initiation of warfarin therapy. Recommend overlap with unfractionated or low molecular weight heparin for at least 5 days and until INR has been at least 2.0 for at least 2 days to prevent this complication.

Do not switch brands after achieving therapeutic response; caution in patients with active tuberculosis or diabetes; caution when initiating or discontinuing enteral feeding or vitamin supplement containing vitamin K (adjust dose).

Sources of Exogenous Protein C

A source of exogenous protein C in the form of either fresh frozen plasma or the protein C concentrate Ceprotin is used in the management of NPF and may also be employed in the treatment of WISN.

Protein C concentrate (Ceprotin)

A decision to administer protein C concentrate should take into consideration the protein C activity concentration, the severity of symptomatology, the cost, and the clinical scenario.

Although the concentrate is intended for IV use, reports of effective management with SC protein C concentrate have been documented in several cases of homozygous deficiency.

Ceprotin is indicated for prevention and treatment of life-threatening venous thrombosis and purpura fulminans caused by severe congenital protein C deficiency. Off-label use in the treatment of warfarin-induced skin necrosis in patients with heterozygous protein C deficiency has also been reported.

Dosing

Adult

Dose, administration frequency, and treatment duration depend on the severity of the protein C deficiency and are adjusted to individual pharmacokinetic profile (see Precautions, below).

For severe congenital protein C deficiency:

Acute episode or short-term prophylaxis: 100-120 IU/kg IV once as initial dose; then, 60-80 IU/kg IV q6h for next 3 doses (adjust to maintain a peak protein C activity of 100%); then, 45-60 IU/kg IV q6-12h as maintenance (adjusted to trough of >25%)

Long-term prophylaxis: 45-60 IU/kg IV q12h (adjust to trough of >25% protein C activity)

Pediatric

Severe congenital protein C deficiency: Administer as in adults.

Interactions

Data are limited; the bleeding risk may increase when coadministered with thrombolytic agents or anticoagulants.

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Common adverse effects include rash, itching, and lightheadedness; contains heparin and human albumin; acquired from pooled human plasma (risk of infectious transmission); hemothorax and hypotension have been reported; discontinue if allergic reaction occurs; after the initial dose for acute episodes and short-term prophylaxis, subsequent doses should maintain a target peak protein C activity of 100% (chromogenic assay recommended); target dosage for maintenance after acute episode resolves or for long-term prophylaxis should maintain protein C activity level >25%; if switching to oral anticoagulant (eg, warfarin), continue protein C replacement therapy until stable anticoagulation has been obtained

Fresh frozen plasma

Contains plasma components of whole blood.

Dosing

Adult

10-15 mL/kg IV q12h (equates to 3-5 250 mL units in most adults)

Pediatric

10-15 cc/kg IV q12h

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Risk of transfusion-transmitted infection; volume overload

Follow-up

Deterrence/Prevention

Venous thromboembolism prevention

Thromboprophylaxis should be considered for surgery, pregnancy and the puerperium, trauma, and prolonged air travel in individuals with heterozygous protein C deficiency, particularly if there is a strong family history of thrombosis. Similarly, estrogen-containing hormonal therapy should only be used in such patients after careful consideration of the thrombotic risk.

Warfarin-induced skin necrosis prevention

For patients with heterozygous protein C deficiency, the following is recommended in order to avoid the development of WISN:

• When warfarin is initiated, it should be overlapped with a parenteral anticoagulant such as unfractionated or low molecular weight heparin.
• The parenteral anticoagulant should be continued for at least 5 days and until the international normalized ratio (INR) measurement has been 2.0 or greater for at least 2 days. 

Patient Education

• Patients with protein C deficiency should be advised of the presenting signs and symptoms of VTE.
• Patients who are not maintained on anticoagulation should speak with their physician about thromboprophylaxis during events associated with an elevated risk of thrombosis such as surgery, trauma, immobilization, pregnancy, the postpartum period, and estrogen-containing hormonal therapy.
• Patients on warfarin should be advised of the importance of maintaining a regular diet and notifying their physician when changes to their medications have been made.

Miscellaneous

Medicolegal Pitfalls

Anticoagulant therapy carries a risk of major hemorrhage. A number of factors influence this risk including age, concomitant use of antiplatelet agents, and certain comorbid conditions. Among patients who have experienced a previous VTE, this risk must be balanced against the risk of recurrent VTE in determining the optimal duration of anticoagulation therapy. Because the risks and benefits of anticoagulation for a given individual may change over time, they should be reassessed on a regular basis. 

Multimedia

Media file 1: The protein C pathway. APC = activated protein C; PC = protein C; S= protein S; T = thrombin; TM = thrombomodulin; Va = factor Va; VIII = factor VIIIa.

Media file 2: A patient with warfarin-induced skin necrosis.

Media file 3: A patient with neonatal purpura fulminans.

References

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Keywords

protein C deficiency, thrombophilia, hypercoagulability, venous thromboembolism, VTE, acquired protein C deficiency, warfarin-induced skin necrosis, WISN, neonatal purpura fulminans, NPF, activated protein C resistance, aPC, inherited blood coagulation disorders, inherited blood protein disorders

Contributor Information and Disclosures

Author

Adam Cuker, MD, Fellowship in Hematology/Oncology, Hospital of the University of Pennsylvania
Adam Cuker, MD is a member of the following medical societies: American Society of Hematology, Hemophilia and Thrombosis Research Society, International Society on Thrombosis and Haemostasis, and National Hemophilia Foundation
Disclosure: Nothing to disclose.

Coauthor(s)

Eleanor S Pollak, MD, Associate Director of Special Coagulation, Associate Professor, Department of Pathology and Laboratory Medicine, Section of Hematology and Coagulation, University of Pennsylvania
Eleanor S Pollak, MD is a member of the following medical societies: American Society of Hematology, College of American Pathologists, and National Multiple Sclerosis Society
Disclosure: Nothing to disclose.

Medical Editor

David Aboulafia, MD, Medical Director, Bailey-Boushay House; Clinical Professor, Department of Medicine, Division of Hematology, University of Washington
David Aboulafia, MD is a member of the following medical societies: American College of Physicians, American Medical Association, American Medical Directors Association, American Society of Hematology, Infectious Diseases Society of America, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Troy H Guthrie, Jr, MD, Director of Cancer Institute, Baptist Medical Center
Troy H Guthrie, Jr, MD is a member of the following medical societies: American Federation for Medical Research, American Medical Association, American Society of Hematology, Florida Medical Association, Medical Association of Georgia, and Southern Medical Association
Disclosure: Nothing to disclose.

CME Editor

Rajalaxmi McKenna, MD, FACP, Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Thomas Jefferson University
Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, and New York Academy of Sciences
Disclosure: Nothing to disclose.

Related eMedicine Topics

• Antithrombin Deficiency
• Cerebral Venous Thrombosis [in the Neurology section]
• Deep Venous Thrombosis and Thrombophlebitis [in the Emergency Medicine section]
• Dysfibrinogenemia  
• Hypercoagulability: Hereditary Thrombophilia and Lupus Anticoagulants Associated With Venous Thrombosis and Emboli
• Mesenteric Venous Thrombosis [in the General Surgery section]
• Miscarriages Caused by Blood Coagulation Protein or Platelet Deficits
• Protein S Deficiency
• Pulmonary Embolism [in the Emergency Medicine section]

• Activated Protein C and Corticosteroids for Human Septic Shock
• Activated Protein C in Acute Stroke Trial
• Evaluate Protein C levels in Severe Sepsis Patients on Drotrecogin Alfa (Activated)

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