Protein C Deficiency 

Updated: Jan 04, 2019
Author: Shamudheen Rafiyath, MD; Chief Editor: Perumal Thiagarajan, MD 

Overview

Practice Essentials

Protein C deficiency is a congenital or acquired condition that leads to increased risk for thrombosis. Congenital protein C deficiency is one of several inherited thrombophilias, which are a heterogeneous group of genetic disorders associated with an elevated risk of venous thromboembolism.[1] Other inherited thrombophilias include the following:

See also Hereditary and Acquired Hypercoagulability.

This article focuses on the pathophysiology, prevalence, clinical manifestations, diagnosis, and treatment of hereditary protein C deficiency. Causes of acquired protein C deficiency are also addressed.

For patient education information, see the Deep Vein Thrombosis Health Center, as well as 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, 3] The protein C pathway is illustrated in the image below.

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

aPC exerts its anticoagulant activity primarily through inactivation of coagulation factors Va and VIIIa, which are required for factor X activation and thrombin generation. The catalytic activity of aPC is greatly enhanced by the vitamin K–dependent cofactor protein S.[4]

Aside from its role in coagulation, aPC subserves anti-inflammatory and cytoprotective functions, which are mediated through the endothelial protein C receptor and the protease-activated receptor–1 (PAR-1).[5, 6]

A deficiency of aPC disturbs the delicate balance between procoagulant and anticoagulant proteins and engenders a prothrombotic environment. The role of aPC and other anticoagulant proteins in this balance appears to be especially important in the slow-flowing venous circulation, in which procoagulant proteins and platelet phospholipids have  prolonged exposure to the vessel wall. This may explain, in part, why protein C deficiency appears to be associated primarily with venous thrombosis.

Genetics of protein C deficiency

Heterozygous protein C deficiency is inherited in an autosomal dominant fashion. The gene for protein C is located on the long arm of chromosome 2 and nearly 200 pathogenic mutations of this gene have been described.[7] These mutations are divided into 2 types—type I and type II—on the basis of whether they cause a quantitative (type I) or functional (type II) deficiency of protein C.

Type I deficiency

Type I protein C deficiency refers to a quantitative deficiency in the plasma protein C concentration. Heterozygous individuals typically demonstrate protein C antigen and activity levels that are approximately one half that of normal patient plasma. A range of causative genetic alterations within the protein C promoter region and splice sites as well as in the coding sequence of the protein C gene itself have been reported.[7]

There is marked phenotypic variation among families with heterozygous type I protein C deficiency. Some families exhibit a severe thrombotic tendency, whereas others remain asymptomatic.[8, 9, 10] Interestingly, this variability is seen even among different pedigrees that harbor the same protein C mutation, suggesting that the mutation itself does not fully explain the phenotypic variability.[11] The presence of a second thrombophilic mutation such as factor V Leiden has been associated with a more severe phenotype in some protein C–deficient kindreds.[12]

Type II deficiency

Type II protein C deficiency is less common than type I disease and is associated with decreased functional activity and normal immunologic levels of protein C. A number of point mutations within the protein C gene giving rise to this disorder have been described.[7] .

Individuals who are homozygous or compound heterozygous for a mutation or other genetic defect affecting the protein C, typically due to the inheritance of abnormal alleles from both parents, can experience neonatal purpura fulminans, intracranial thromboembolism, and thrombosis.[13]

Epidemiology

Frequency

Studies in cohorts with no clinical history of venous thromboembolism (VTE) have found protein C deficiency in 1 in 200 to 1 in 500 persons.[14, 15]  In patients presenting with VTE, approximately 3-5% may have protein C deficiency.[16, 17, 18] Severe homozygous or compound heterozygous protein C deficiency occurs in approximately 1 in 500,000 to 1 in 750,000 live births.[14, 15, 16, 17, 18]

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. Heterozygous protein C deficiency does not appear to be associated with an elevated risk of arterial thrombosis.

Homozygous and compound heterozygous protein C deficiency are classically associated with neonatal purpura fulminans (NPF); intracranial thromboembolism may also occur in neonates.[19] 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 higher than that of the general population.[20, 21] 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.[22] 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.[23, 24, 25] Approximately 40% of patients with protein C deficiency present with evidence of pulmonary embolism, and roughly 60% suffer recurrent thrombosis if anticoagulation is discontinued.[22]

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.[26]

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.[27, 28]

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 below). Dermal biopsy demonstrates ischemic necrosis of the cutaneous tissue with cutaneous vessel thrombosis and surrounding interstitial hemorrhage.[29]

A patient with warfarin-induced skin necrosis. A patient with warfarin-induced skin necrosis.

Although protein C deficiency is a strong risk factor for the development of WISN, approximately two thirds of patients with WISN do not have underlying hereditary protein C deficiency.[30] Other conditions reported in association with WISN include acquired protein C deficiency (see Causes)[31] and heterozygous protein S deficiency.[32]

See Deterrence/Prevention for the discussion of prevention and treatment of WISN.

Pregnancy loss

Protein C deficiency may be weakly associated with late and recurrent pregnancy loss. In the European Prospective Cohort on Thrombophilia, the odds ratio (OR) for stillbirth (defined as pregnancy loss at > 28 weeks' gestation) among women with an inherited thrombophilia was 3.6 (95% confidence interval [CI] 1.4-9.4), whereas the risk of miscarriage before 28 weeks' gestation in this cohort was not significantly different than that of nonthrombophilic women.[33] Among the subgroup of thrombophilia subjects with congenital protein C deficiency, the OR of stillbirth was 2.3 (95% CI 0.6-8.3).[34, 33] In a meta-analysis of 633 subjects with hereditary protein C deficiency, the association with recurrent fetal loss was likewise nonsignificant (OR 1.57; 95% CI 0.23-10.54).[35]

Arterial thrombosis

There are several case reports of arterial stroke[36, 37] and myocardial infarction[38] occurring in young adults with congenital protein C deficiency. However, the results of larger studies are conflicting[39, 40, 41, 42, 43] and the existence of an association between protein C deficiency and arterial thrombosis remains controversial.

Peripheral arterial disease

In a study of 106 patients with peripheral arterial disease (PAD) and 44 with abdominal aortic aneurysm (AAA), Komai and colleagues found that the incidences of protein C deficiency was 4.7% in patients with PAD and 4.% in patients with AAA — higher rates than those observed in the general population. Protein C activity levels were significantly lower in PAD patients with critical limb ischemia than in those with intermittent claudication. In multivariate logistic regression analysis, lower protein C activity and female gender were determinant factors of critical limb ischemia.[44]

Neonatal purpura fulminans

NPF is a life-threatening condition that occurs in newborns with homozygous or compound heterozygous protein C deficiency, usually during the first several days of life. Affected neonates present with diffuse ecchymoses (see image below). Skin biopsy demonstrates extensive thrombosis of cutaneous venous and arterial channels, much as is observed in WISN.[45, 46] Laboratory testing reveals severe deficiency (< 1% of normal) of immunologic protein C levels.[47] Expeditious treatment with an exogenous source of protein C, (discussed in Treatment, Medical Care, is paramount.

A patient with neonatal purpura fulminans. 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.[48, 49] In contrast, the factor V Leiden and prothrombin gene mutations (see Hereditary and Acquired Hypercoagulability) 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[50, 51] ; 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.[52]

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.[26, 53]

 

Presentation

History

Individuals with hereditary protein C deficiency can present with venous thromboembolism (VTE), warfarin-induced skin necrosis in adults, and neonatal purpura fulminans in newborns who are homozygous or compound heterozygous for protein C mutation. Obtaining a detailed history that focuses on personal history—including previous history of thrombosis and any abnormal laboratory results—fmailiy history, and obstetric history is paramount.             

Venous Thromboembolism

The most common sites of VTE are the deep veins of the leg (DVT), mesenteric veins, and pulmonary veins. Other sites, including cerebral veins, portal veins, superficial veins, or other unusual sites are also reported.[54, 55]

In patients who present with VTE or warfarin-induced skin necrosis, family history is the best predictor for congenital thrombophilia. The initial episode of VTE in individuals with protein C deficiency is apparently spontaneous in approximately two-thirds of cases, and the other third usually have typical risk factors such as pregnancy, oral contraceptives, surgery, or trauma. Among patients with a positive family history, the risk is as high as 75% in those with severely affected families and closer to 30% in members of other families.[55]

Warfarin-induced skin necrosis

Wafarin-induced skin necrosis (WISN) typically develops in the first few days of warfarin therapy, often in patients given large loading doses of 10 mg or more per day. If the patient is on warfarin and heparin, the lesions may appear upon discontinuation of the heparin. If a product containing protein C is not rapidly administered, the affected cutaneous area typically becomes edematous, develops central purpura, and eventually becomes necrotic.

WISN is not pathognomonic for protein C deficiency. It has been described in individuals with other inherited thrombophilias (factor V Leiden mutation, protein S deficiency) and transient reduction of protein C levels.[27, 28]

Neonatal purpura fulminans

Purpura fulminans is a rare life-threatening condition in newborns characterized by disseminated intravascular coagulation (DIC), extensive venous and arterial thrombosis, and hemorrhagic skin necrosis. Laboratory testing reveals evidence of DIC and extremely low protein levels of less than 1% of normal.

Physical

Patients with symptomatic hereditary protein C deficiency may present with VTE or WISN. Homozygotes and compound heterozygotes frequently present with neonatal purpura fulminans 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. See image below.

A patient with warfarin-induced skin necrosis. A patient with warfarin-induced skin necrosis.

Neonatal purpura fulminans

Affected neonates present with diffuse ecchymoses that, like the lesions of WISN, progress to form necrotic bullae if appropriate therapy is not rapidly instituted. See image below.

A patient with neonatal purpura fulminans. 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.

Acquired Protein C Deficiency

Causes of acquired protein C deficiency include the following:

  • Acute thrombosis
  • Warfarin therapy
  • Liver disease (eg, liver fibrosis from chronic hepatitis C [53]
  • Vitamin K deficiency
  • Sepsis
  • Certain chemotherapeutic agents (eg, L-asparaginase)
  • Uremia - Uremic patients may have a normal levels of protein C with low levels of protein C anticoagulant activity due to a antibodies against protein C [56]

Cases of acquired protein C deficiency in association with the development of a protein C autoantibody[57] and hematopoietic stem cell transplantation[58] 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.[59]

Causes of increased protein C include the following:

  • Nephrotic syndrome [60]
  • Hyperlipidemia [61]
  • Normal aging
 

DDx

Diagnostic Considerations

Patients who develop venous thromboembolism (VTE) in the absence of acquired risk factors may have protein C deficiency or some other congenital thrombophilia, or may have protein C deficiency together with one or more other congenital risk factors for VTE. In a retrospective analysis of prospectively gathered data on 58 outpatients with VTE (approximate mean age 39 years) without major acquired risk factors, 45 had at least one hereditary risk factor for VTE. Diagnoses in these patients were as follows[62] :

  • Protein C deficiency - 18 patients
  • Protein S deficiency - 17 patients
  • Factor V Leiden mutation - 30 patients (25 heterozygous and five 5 homozygous)
  • Prothrombin gene mutation - 16 patients
  • Methylenetetrahydrofolate reductase C677T mutation - 24 patients (19 heterozygous, 5 homozygous)
  • Antithrombin III deficiency - 14 patients
  • Hyperhomocysteinemia - 13 patients

Of the 18 patients with protein C deficiency, four also had protein S deficiency, two also had hyperhomocystinemia, and one had both protein S deficiency and hyperhomocysteinemia.

These authors concluded that thrombophilia testing should be performed in younger VTE patients without known acquired risk factors. Testing for protein C, protein S, and prothrombin gene mutations should be followed by additional molecular assessment in patients with suspicious findings.[62]

Skin necrosis (eg, warfarin-induced skin necrosis) can occur not only in patients with protein C deficiency, but as a result of any of the following: 

Differential Diagnoses

 

Workup

Laboratory Studies

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.[63] Logarithms of protein C antigen levels in the healthy, nonpregnant, adult population show a Gaussian distribution.[64] 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.[15] 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.[51]

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 produce activated protein C (aPC).[65]  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.[15] 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, a number of conditions may result in acquired protein C deficiency. To the extent possible, laboratory testing should be performed in patients without a history 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 assessed 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, protein C testing is not recommended 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.[66, 67] However, such methods have not been broadly validated.

The clotting-based assays may be affected by anticoagulants, including heparin and direct oral anticoagulants (DOAC), whereas the chromogenic assay generally is unaffected by anticoagulants. Vitamin K antagonists can lower the activity of any assay.[68]

The direct thrombin inhibitors (DTIs; argatroban, dabigatran) do not impact the results of functional assays using snake venom to activated protein C and a chromogenic substrate to measure enzymatic activity.  DTIs may interfere with the functional assays that use a clotting-based endpoint.  DTIs do not interfere with antigenic assays of protein C.[68]

 

 

Treatment

Medical Care

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

A case report by Milleret and colleagues describes 2 years of successful prophylaxis in a patient with neonatal severe protein C deficiency, using warfarin oral suspension. The international normalized ratio (INR) was measured by home monitoring, with a target INR of 2.5 to 3.5.[69]

For those patients who do develop clinical manifestations of hereditary protein C deficiency, treatment depends on the particular clinical syndrome: venous thromboembolism (VTE), warfarin-induced skin necrosis (WISN), or neonatal purpura fulminans (NPF).

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. Because the risk of recurrent VTE in protein C–deficient patients may be as high as 60%,[22] long-term anticoagulation is often recommended, particularly following a spontaneous thromboembolic event.

In protein C deficiency, caution should be taken to reduce the risk of warfarin-induced skin necrosis while choosing the anticoagulant agent. Preventive measures include the use of an oral anticoagulant other than warfarin, use of warfarin with a lower starting dose, and longer duration of overlapping heparin or low molecular weight heparin (LMWH) administration.

Because of the availability of and familiarity with the use of direct oral anticoagulants (DOACs), the preference is to use DOACs for anticoagulation in patients with a typical VTE presentation. However, in massive pulmonary embolism and other severe clinical presentations such as hypoxemia/shock, or deep vein thrombosis with a proximal clot burden and in patients with concerns about adherence, the preference would be to administer heparin or an LMWH and then transition to warfarin, with the goal of keeping the international normalized ratio (INR) in the high end of the therapeutic range.

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, exogenous protein C should be administered, either in the form of fresh frozen plasma or, preferably, as purified protein C concentrate (Ceprotin) with the goal of expeditiously normalizing plasma protein C activity.[70]

In adult patients with protein C deficiency who have experienced WISN, dabigatran, rivaroxaban apixaban, or edoxaban have been used successfully for subsequent anticoagulation. A case report describes the effective and safe use of rivaroxaban in a teenage patient, with thrombin generation assays used to adjust the dosage.[71]

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 dosing is required to maintain adequate plasma levels, thereby limiting its usefulness in this setting. Highly purified protein C concentrate represents an attractive alternative that does not subject patients to the high volume and protein load of fresh frozen plasma.[72, 73, 74]

After treatment of the acute phase of NPF, patients are transitioned to anticoagulation therapy, which they must remain on 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.[75] 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.[76]

Living donor liver transplantations have been successfully performed in NPF, resulting in a permanent cure.[77]  

Consultations

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

Diet and Activity

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–containing foods (ie, dark green leafy vegetables) they ingest.

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 trauma and major bleeding.

 

Medication

Medication Summary

A range of anticoagulants is used for prevention and treatment of patients with protein C deficiency. Fresh frozen plasma or protein C concentrate are used in select patients with severe clinical manifestations.

Anticoagulant Agents

Class Summary

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

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.

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.

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.

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.

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.

Rivaroxaban (Xarelto)

Rivaroxaban is an oral factor Xa inhibitor that inhibits coagulation by selectively blocking the active site of factor Xa without requiring a cofactor (eg, antithrombin III) for activity. It is indicated for treatment of DVT or PE, and to reduce risk of recurrent DVT and PE following initial treatment. It is also indicated for prophylaxis of DVT in patients undergoing knee or hip replacement surgery.

Dabigatran (Pradaxa)

Dabigatran is an oral anticoagulant agent that inhibits thrombus development through direct, competitive inhibition of thrombin (thrombin enables fibrinogen conversion to fibrin during the coagulation cascade). It inhibits free and clot-bound thrombin and thrombin-induced platelet aggregation. It is indicated for the treatment of DVT or PE in patients who have been treated with a parenteral anticoagulant for 5 to 10 days. It is also used to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation and prophylaxis of  DVT and PE in patients who have undergone total hip arthroplasty.

Apixaban (Eliquis)

Apixaban is an oral anticoagulant that inhibits platelet activation and fibrin clot formation via direct, selective and reversible inhibition of free and clot-bound factor Xa (FXa). FXa, as part of the prothrombinase complex consisting also of factor Va, calcium ions, and phospholipid, catalyzes the conversion of prothrombin to thrombin. Thrombin both activates platelets and catalyzes the conversion of fibrinogen to fibrin. It is indicated for the treatment of DVT and PE, to reduce the risk of recurrent DVT following initial therapy. It is also indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, and for prophylaxis of DVT and PE in patients who have undergone hip or knee replacement surgery.

Edoxaban (Savaysa)

 Edoxaban, a selective factor Xa inhibitor, inhibits free factor Xa and prothrombinase activity and inhibits thrombin-induced platelet aggregation. Inhibition of factor Xa in the coagulation cascade reduces thrombin generation and thrombus formation. It is indicated for the treatment of DVT and PE, to reduce the risk of recurrent DVT following initial therapy. It is also indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

 

Sources of Exogenous Protein C

Class Summary

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.

Fresh frozen plasma

Contains plasma components of whole blood.

 

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 they have 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 warfarin-induced skin necrosis:

  • Large loading doses of warfarin (>5 mg/d) should be avoided.

  • 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

See the list below:

  • 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, and the postpartum period.

  • 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.

 

Questions & Answers

Overview

What is protein C deficiency?

What is the pathophysiology of protein C deficiency?

What is the role of genetics in the pathophysiology of protein C deficiency?

What is the pathophysiology of type I protein C deficiency?

What is the pathophysiology of type II protein C deficiency?

What is the prevalence of protein C deficiency?

What is the morbidity associated with protein C deficiency?

What is the morbidity associated with VTE in protein C deficiency?

What is the morbidity associated with WISN in protein C deficiency?

What is the effect of protein C deficiency on pregnancy outcome?

What is the morbidity associated with arterial thrombosis in protein C deficiency?

What is the morbidity associated with peripheral arterial disease in protein C deficiency?

What is the morbidity associated with NPF in protein C deficiency?

What are the racial predilections of protein C deficiency?

What are the sexual predilections of protein C deficiency?

Which age groups have the highest prevalence of protein C deficiency?

Presentation

Which clinical history findings are characteristic of protein C deficiency?

Which clinical history findings are characteristic of VTE in protein C deficiency?

Which clinical history findings are characteristic of WISN in protein C deficiency?

Which clinical history findings are characteristic of NPF in protein C deficiency?

Which physical findings are characteristic of protein C deficiency?

Which physical findings are characteristic of VTE in protein C deficiency?

Which physical findings are characteristic of WISN in protein C deficiency?

Which physical findings are characteristic of NPF in protein C deficiency?

What causes protein C deficiency?

What causes acquired protein C deficiency?

DDX

Which conditions are included in the differential diagnoses of protein C deficiency with VTE?

Which conditions are included in the differential diagnoses of protein C deficiency with WISN?

What are the differential diagnoses for Protein C Deficiency?

Workup

What types of lab tests are performed in the workup of protein C deficiency?

What is the role of immunologic assays in the workup of protein C deficiency?

What is the role of functional assays in the role of the workup of protein C deficiency?

How is the diagnosis of protein C deficiency confirmed?

How is protein C deficiency diagnosed in patients with acute thrombosis?

How is protein C deficiency diagnosed in patients taking warfarin?

Treatment

How is protein C deficiency treated?

How is venous thromboembolism in protein C deficiency treated?

How is WISN in protein C deficiency treated?

How is NPF in protein C deficiency treated?

Which specialist consultations are beneficial to protein C deficiency?

Which dietary and activity modification are used in the treatment of protein C deficiency?

Medications

What is the role of medications in the treatment of protein C deficiency?

Which medications in the drug class Sources of Exogenous Protein C are used in the treatment of Protein C Deficiency?

Which medications in the drug class Anticoagulant Agents are used in the treatment of Protein C Deficiency?

Follow-up

When is thromboprophylaxis indicated in the treatment of protein C deficiency?

How is WISN prevented in protein C deficiency?

What should patients with protein C deficiency be educated about?