Protein C deficiency
Other names PROC Deficiency
Anesthetic relevance


Anesthetic management

Weigh patient's thrombotic risk against surgical bleeding risk to determine timing of perioperative anticoagulation. Bridging therapy if using warfarin due to increased risk of skin necrosis. Replacement protein C for severe congenital manifestations.



Signs and symptoms

Recurrent VTE. DIC and purpura fulminans in neonates with severe presentation.


Functional assay for Protein C levels


Therapeutic anticoagulation for VTE. Replacement protein C or fresh frozen plasma for severe congenital presentation.

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Protein C deficiency is a rare thrombophilic disease that may be inherited or acquired. There is significant variability in the severity of Protein C deficiency, ranging from initial life-threatening manifestations in neonates with DIC and purpura fulminans to milder asymptomatic cases of adults at increased risk for VTE.

Anesthetic implications

Preoperative optimization

Achieving an acceptable perioperative risk of thrombosis balanced with an appropriate risk of bleeding is the primary goal of optimization before surgery. The patient's baseline increased thrombotic risk and timeline of past manifestations of thrombotic sequelae will influence (1) whether preoperative anticoagulation is needed (2) when to discontinue preoperative anticoagulation (3) whether to use bridging anticoagulation. There are not standardized guidelines for appropriate anticoagulation metrics prior to surgery due to the rarity of protein C deficiency and the variability in severity of the disorder. Consequently, it is important to take a history regarding past personal and family thrombotic events to characterize the patient's risk for thrombosis[1]:

  • Personal history of VTE
    • Delineation between provoked and unprovoked VTEs (higher risk associated with unprovoked)
    • Site of past VTEs (as atypical sites indicate higher thrombotic risk, e.g. mesenteric, portal, cerebral veins)
    • Determination of whether past VTE was life-threatening (e.g. large pulmonary embolus or extensive proximal DVT)
  • Active VTE (prompting consideration of preoperative IVC filter)
  • Family history of VTE (more relevant to risk stratification if patient lacks personal history of VTE)
  • History of other inherited thrombophilias (with potential for further heightened baseline risk for VTE)

Other factors that impact risk stratification for perioperative thromboembolic events include the presence of atrial fibrillation, prosthetic cardiac valves, recent stroke/TIA, and use of estrogen-containing medications.[2] Ultimately these factors must be weighed against the bleeding risks associated with the surgery and discussed with the surgical team and potentially a hematology consultant to determine the optimal course of preoperative anticoagulation.

Related Preoperative Considerations

Preoperative Bridging Anticoagulation

Patients on warfarin therapy who have protein C deficiency may be considered from bridging anticoagulation with unfractionated heparin or LMWH for the period of time before surgery during which warfarin is being held. By decreasing the amount of time that the patient is not anticoagulated, there is a theoretical benefit of reduced thromboembolic risk prior to surgery.[3] Still, there is not high quality data regarding the use of preoperative bridging anticoagulation, and it comes with the tradeoff of increased risk of bleeding.[4]

Preoperative Protein C Replacement Therapy

Protein C replacement therapy prior to surgery is not common practice but has been documented in case studies with the aim of reducing risk of perioperative VTE. One case study documents a man with heterozygous protein C deficiency in his 70s with history of idiopathic PE who underwent total hip arthroplasty without evidence of excessive bleeding after receiving replacement protein C therapy from the night before surgery through several days post-op.[5] Protein C replacement therapy has also been used preoperatively to reduce the thrombotic risk for a patient undergoing renal transplantation.[6] In young patients with severe protein C deficiency, surgeries have been successfully performed after preoperative administration of replacement protein C and fresh frozen plasma.[7] Measurement of protein C activity may be done to evaluate the efficacy of protein C replacement therapy prior to surgery.[8]

Active VTE

Delaying surgery in patients with a VTE within the three months following diagnosis is likely beneficial due to the heightened risk thromboembolic risk following diagnosis of a VTE, although there is not clear data on when thromboembolic risk returns to baseline. Patients with a VTE diagnosed within the prior 4 weeks who require stopping anticoagulation for surgery may be considered for IVC filter placement to reduce risk of pulmonary embolus. Diagnosis of hereditary thrombophilia without presence of active VTE is not an indication for temporary IVC filter placement.[2]

Recent Stroke

The American Heart Association and American Stroke Association recommend delaying elective surgery 6-9 months following stroke, largely due to impaired cerebral autoregulation following stroke.[9] Adults with protein C deficiency are at heightened risk for ischemic stroke.[10]

Active Use of Estrogen-Containing Medications

Use of combined oral contraceptives or oral estrogen by a patient with protein C deficiency places the patient at significantly heightened VTE risk prior to surgery. Due to increased risk of VTE with use of combined oral contraceptives, the WHO disrecommends combined oral contraceptive use in women with hereditary thrombophilias.[11] The American College of Obstetricians and Gynecology (ACOG) recommends that combined OCPs be stopped at least 4 weeks before a major surgery with prolonged immobilization due to increased risk of VTE, regardless of whether or not a patient has protein C deficiency.[12] Women with a hereditary thrombophilia taking oral estrogen are at 25-fold increased risk of VTE compared to women without genetic predisposition for thrombosis who do not take hormone replacement therapy.[13]

Intraoperative management

Pneumatic compression devices are universally recommended for DVT prophylaxis. Fresh frozen plasma or replacement protein C may be administered intraoperatively. Thromboelastography may be of value in quickly checking coagulation status in the perioperative space, but there is not good available data on use of this for protein C deficiency, especially in neonates.[14]

Postoperative management

Postoperative management is focused on monitoring for thrombotic complications and bleeding complications. Timing of restarting anticoagulation for patients on chronic therapy must be determined on an individualized basis, weighing the patient's increased risk for VTE against the risk of postoperative bleeding. For individuals with protein C deficiency who restart warfarin, particular attention must be given to the heightened risk for warfarin-induced skin necrosis in this population. Warfarin-induced skin necrosis typically occurs between days 3 and 10 after initiating warfarin.[15]

For patients with inherited thrombophilias who undergo free tissue transfer, there is a heightened risk of microvascular thrombosis and flap failure.[16]

Lengthened observation times for infants with severe protein C deficiency who undergo surgery may be of value, as they are at heightened risk for purpura fulminans and post-operative bleeding due to the lack of standardized guidelines for timing and dosing of anticoagulation and protein C replacement therapy. A two-year-old who underwent laprascopic fundoplication and gastrotomy was observed to have two episodes of abdominal hemorrhage and two episodes of purpura fulminans 2-4 weeks postoperatively.[7]


Role of Protein C in Coagulation Cascade

Protein C is an anticoagulant protein synthesized by the liver in a Vitamin K-dependent fashion. Protein C circulates in plasma in low levels as a zymogen. Conversion from Protein C to activated Protein C (aPC) occurs via interactions with thrombin. aPC is a protease that cleaves and inactivates two coagulation factors:

  • Va (needed for thrombin generation)
  • VIIIa (needed for Xa activation)

When Protein C is deficient, its role in thrombin downregulation is dysfunctional, resulting in a hypercoaguable state.[17]

Inheritance of Protein C Deficiency

Protein C Deficiency is inherited as an autosomal dominant disorder on chromosome 2.[18] Patient with heterozygous, heterozygous combined (both chromosomes impacted but by different mutations), or homozygous fashion. Over 160 mutations in the protein C gene (located on chromosome 2) have been documented.[19]

Acquisition of Protein C Deficiency

Protein C levels may be reduced due to noninherited conditions, including liver disease (reduced synthesis of Protein C), disseminated intravascular coagulation (consumption of Protein C), severe infection like meningococcemia, infection in HIV patients, uremia, cancer, cancer therapies like asparaginase.[1][20][21]

Signs and symptoms

The presentation of Protein C Deficiency ranges from asymptomatic to mild presentation with recurrent thromboses in adulthood to severe with presentation in the neonatal period with purpura fulminans and disseminated intravascular coagulation.[22] The severity of presentation is related to the level of activity of protein C, with lower levels leading to more severe presentations.

Severity Inheritance Typical Age at Presentation Presenting Symptoms and History
Mild Heterozygous Adulthood, if at all Asymptomatic


Recurrent VTE

Moderate Heterozygous Adolescence Recurrent VTE (DVT, PE, parenchymal thrombi, ischemic atrerial stroke)

Pregnancy-associated thrombosis

Post-thrombotic syndrome

Severe Homozygous


Compound heterozygous

Neonatal period Disseminated intravascular coagulation (DIC)

Purpura fulminans (PF)

Intracranial thromboembolism


Quantitative protein C levels are needed to diagnose protein C deficiency. Diagnostic testing is performed with a functional assay (chromogenic test, ELISA, or clotting assay) in order to report a plasma concentration of protein C or a percentage of functional protein C.[23] However, no definitive diagnostic cutoff exists, as there is significant variability in protein C levels among patients with known familial protein C mutations.[24] There is overlap between low normal protein C levels and low levels consistent with a heterozygous gene mutation, and so hematology consultation can aid in interpretation of borderline protein C levels.

There are two categorizations of protein C deficiency based on the mechanism of protein C dysfunction:

  • Type I: quantitative defect in protein C (75% of patients)
  • Type II: qualitative defect in protein C
    • Type IIa: normal antigen concentrations, reduced activity in both amidolytic and clotting functional assays (23.75% of patients)
    • Type IIb: normal antigen concentrations, reduced clotting activity (rarest, 1.25% of patients)[18]

Diagnostic Considerations

Protein C levels must be interpreted according to the age of the patient, as levels are lowest as a neonate and continually increase through puberty.[25] Protein C activity level is not necessarily reliable as a diagnostic test during acute thrombosis or while on warfarin therapy.

Ongoing Acute Thrombosis

Patients who undergo protein C level assays during the acute phase of a VTE and have abnormally low protein C levels must undergo repeat testing at least 3 months after initiating treatment and at least 14 days after stopping warfarin therapy. Individuals may falsely appear to be deficient in protein C if in the initial phase of a VTE due to consumption of protein C. However, a normal protein C level during the acute phase of a VTE does not require repeat testing, as protein C deficiency is effectively excluded.[26] Ultimately protein C testing should not be performed during an active clotting event, as the patient will likely be therapeutically anticoagulated regardless of the result.

Ongoing Warfarin Therapy

While a patient is taking warfarin, a vitamin K antagonist, synthesis of Protein C is significantly reduced. Patients should wait at least two weeks from their last dose of warfarin or other vitamin K antagonists until undergoing testing for protein C deficiency. However, if warfarin therapy cannot be discontinued and a protein C level is taken while on therapy, a normal protein C assay effectively excludes protein C deficiency, while an abnormally low result cannot be used to diagnose protein C deficiency.[1]

Ongoing Non-Warfarin Anticoagulant Therapy

Heparin, fondaparinux, direct thrombin inhibitors, and direct Xa inhibitors may interfere specifically with clotting-based Protein C assays.[1]

Low Utility of Universal Screening for Inherited Thrombophilia Before Surgery

Screening for inherited thrombophilias in the population of patients planning to undergo elective surgery is not recommended, even in surgeries with high risk of thrombotic complications.

Renal Transplant Surgery

Universal thombophilia screening prior to transplant surgery is not currently recommended for transplant recipients. A single center retrospective study of 100 pediatric renal graft recipients who underwent comprehensive thrombophilia evaluation found no association between preoperative screening abnormalities and post-transplant thrombotic events.[27] Similarly, a prospective single center longitudinal study looking at 46 adult renal transplant recipients who underwent universal thrombophilia screening found no association between preoperative thrombophilia and posttransplant thrombotic events for 2 years after renal transplant.[28]


Standardized guidelines are lacking for treatment of Protein C deficiency, with most management based on case studies and clinical experience, rather than large randomized studies. The goal is to appropriately reduce thrombotic risk through medical therapy for at-risk patients. Management of protein C deficiency focuses on acute treatment of thromboembolic events, long-term anticoagulation for some patients, and treatment of severe neonatal manifestations like purpura fulminans.

Acute Thromboembolic Event

Individuals with protein C deficiency and a newly diagnosed VTE are treated similarly to those who do not carry the diagnosis.[29] Patients undergo anticoagulation for at least 3-6 months. If warfarin is used for anticoagulation, special consideration is given to prevention of warfarin-induced skin necrosis due to predisposition for the complication among protein C deficient patients. Typically patients receive at least 5 days of concurrent treatment with heparin, LMWH, or fondaparinux before taking warfarin alone.[30]

Long-Term Anticoagulation

The American Society of Hematology recommends indefinite anticoagulation (with DOACs, vitamin K antagonists, or LMWH) for the majority of patients with history of unprovoked DVT, especially those with chronic risk factors like inherited thrombophilias. The society recommends that these patients be evaluated annually to reassess the continued clinical indication for indefinite anticoagulation.[29]

Indefinite anticoagulation is also required of individuals with severe neonatal manifestations of protein C deficiency and may be accomplished with subcutaneous protein C concentrate in addition to a DOAC, vitamin K antagonist, or LMWH.[31]

Purpura Fulminans

Purpura fulminans is life-threatening and must be treated initially with exogenous protein C, either protein C concentrate or fresh frozen plasma. Empiric therapy is recommended regardless of whether low protein C levels have yet been detected.[31]


  • Anticoagulation therapy for acute VTE management and long-term anticoagulation
    • Direct-acting Oral Anticoagulants
    • LMWH
    • Warfarin
  • Replacement therapy (given for patients with purpura fulminans or warfarin-induced skin necrosis)
    • Protein C Concentrate (human plasma-derived, viral inactivated)
    • Fresh frozen plasma


Individuals with homozygous protein C deficiency have been successfully treated with liver transplantation.[32]


In individuals with neonatal manifestations of protein C deficiency, prognosis is poor. Mortality without therapy in homozygotes with severe manifestations nears 100%.[33] Patients may be blind due to in utero retinal thrombosis.[34] These patients almost invariably require lifelong anticoagulation.

Some heterozygote patients with protein C deficiency remain asymptomatic throughout their lifetime. Among protein C and protein S deficient individuals, about half will have a symptomatic manifestation by age 55.[35] Asymptomatic individuals with inherited protein C deficiency and symptomatic protein C deficient relatives are at significantly increased risk of developing thrombosis compared to asymptomatic individuals who lack protein C deficiency but have family history of symptomatic protein C deficient relatives.[36]

Women with Protein C deficiency are at increased risk of VTE in pregnancy. For those with personal or family history of VTE and Protein C deficiency, the risk of VTE in pregnancy is estimated at 2-8%.[37][38][39] Women with Protein C deficiency but no personal or family history have a 0.7% risk of VTE during pregnancy.[40] There is little evidence suggesting that Protein C deficiency leads to recurrent pregnancy loss.[41][42]


The prevalence of Protein C deficiency in the general population is 0.2-0.4%.[19][43] There is not strong evidence regarding differences in prevalence of protein C deficiency among racial or ethnic groups.[44] Patients most commonly present with heterozygous protein C deficiency, whereas homozygous protein C deficiency occurs in 1 per 500,000-750,000 live births.[33] Heterozygous Protein C deficiency is found in 3% of patients with a first-time DVT.[18]


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