eMedicine Specialties > Hematology > Coagulation, Hemostasis, and Disorders

Protein C Deficiency: Treatment & Medication

Author: Adam Cuker, MD, Fellowship in Hematology/Oncology, Hospital of the University of Pennsylvania
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
Contributor Information and Disclosures

Updated: Jun 11, 2009

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.

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

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

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

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.

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

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

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

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.

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

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

Documented hypersensitivity; major bleeding, thrombocytopenia; regional anesthesia

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.

Adult

DVT treatment:
175 units/kg SC qd

Pediatric

Not established

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

Documented hypersensitivity; major bleeding, thrombocytopenia

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.

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

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

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

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.

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

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.

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

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.

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.

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

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.

Adult

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

Pediatric

10-15 cc/kg IV q12h

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

More on Protein C Deficiency

Overview: Protein C Deficiency
Differential Diagnoses & Workup: Protein C Deficiency
Treatment & Medication: Protein C Deficiency
Follow-up: Protein C Deficiency
Multimedia: Protein C Deficiency
References
Further Reading
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Further Reading

Related eMedicine Topics

Clinical Trials
National Guideline Clearinghouse

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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

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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.

 
 
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