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Protein C deficiency
Other names PROC Deficiency
Anesthetic relevance

Medium

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.

Specialty

Hematology

Signs and symptoms

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

Diagnosis

Functional assay for Protein C levels

Treatment

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

Article quality
Editor rating
Comprehensive
User likes
0

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 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]

Pathophysiology

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

or

Recurrent VTE

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

Pregnancy-associated thrombosis

Post-thrombotic syndrome

Severe Homozygous

or

Compound heterozygous

Neonatal period Disseminated intravascular coagulation (DIC)

Purpura fulminans (PF)

Intracranial thromboembolism

Diagnosis

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]

Treatment

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]

Medication

  • 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

Surgery

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

Prognosis

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]

Epidemiology

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]

References

  1. ↑ 1.0 1.1 1.2 1.3 Bauer, Kenneth (2021). "Protein C deficiency". www.uptodate.com. Retrieved 2022-06-20.
  2. ↑ 2.0 2.1 Douketis, James (2022). "Perioperative Management of Patients Receiving Anticoagulants". www.uptodate.com. Retrieved 2022-06-20.
  3. ↑ Douketis, James D.; Johnson, Judith A.; Turpie, Alexander G. (2004-06-28). "Low-Molecular-Weight Heparin as Bridging Anticoagulation During Interruption of Warfarin". Archives of Internal Medicine. 164 (12): 1319. doi:10.1001/archinte.164.12.1319. ISSN 0003-9926.
  4. ↑ Ortel, Thomas L. (2012-12-06). "Perioperative management of patients on chronic antithrombotic therapy". Blood. 120 (24): 4699–4705. doi:10.1182/blood-2012-05-423228. ISSN 0006-4971. PMC 3653565. PMID 22855600.CS1 maint: PMC format (link)
  5. ↑ Thakkar, Savyasachi C.; Streiff, Michael B.; Bruley, Duane F.; Mears, Simon C. (2010). "Case Report: Perioperative Use of Protein C Concentrate for Protein C Deficiency in THA". Clinical Orthopaedics & Related Research. 468 (7): 1986–1990. doi:10.1007/s11999-009-1189-8. ISSN 0009-921X. PMC 2882006. PMID 20012238.CS1 maint: PMC format (link)
  6. ↑ Toupance, Olivier; Nguyen, Philippe; Brandt, Bernard; Dion, Jean-Jacques; Potron, Gérard; Chanard, Jacques (1994). "Prevention of vascular thrombosis by human purified protein C concentrate in a patient with familial PC deficiency undergoing renal transplantation". Transplant International. 7 (2): 144–145. doi:10.1111/j.1432-2277.1994.tb01236.x. ISSN 0934-0874.
  7. ↑ 7.0 7.1 Watanabe, Kentaro; Kato, Motohiro; Ishimaru, Tetsuya; Hiwatari, Mitsuteru; Suzuki, Tomonori; Minosaki, Yoshihiro; Takita, Junko; Fujishiro, Jun; Oka, Akira (2017). "Perioperative management of severe congenital protein C deficiency". Blood Coagulation & Fibrinolysis. 28 (8): 646–649. doi:10.1097/MBC.0000000000000654. ISSN 0957-5235.
  8. ↑ Goldenberg, N. A.; Manco-Johnson, M. J. (2008-10-30). "Protein C deficiency". Haemophilia. 14 (6): 1214–1221. doi:10.1111/j.1365-2516.2008.01838.x.
  9. ↑ Benesch, Curtis; Glance, Laurent G.; Derdeyn, Colin P.; Fleisher, Lee A.; Holloway, Robert G.; Messé, Steven R.; Mijalski, Christina; Nelson, M. Timothy; Power, Martha; Welch, Babu G. (2021-05-11). "Perioperative Neurological Evaluation and Management to Lower the Risk of Acute Stroke in Patients Undergoing Noncardiac, Nonneurological Surgery: A Scientific Statement From the American Heart Association/American Stroke Association". Circulation. 143 (19). doi:10.1161/cir.0000000000000968. ISSN 0009-7322.
  10. ↑ Chiasakul, Thita; De Jesus, Elizabeth; Tong, Jiayi; Chen, Yong; Crowther, Mark; Garcia, David; Chai‐Adisaksopha, Chatree; Messé, Steven R.; Cuker, Adam (2019-10-01). "Inherited Thrombophilia and the Risk of Arterial Ischemic Stroke: A Systematic Review and Meta‐Analysis". Journal of the American Heart Association. 8 (19): e012877. doi:10.1161/JAHA.119.012877. PMC 6806047. PMID 31549567.CS1 maint: PMC format (link)
  11. ↑ van Vlijmen, E. F. W.; Wiewel-Verschueren, S.; Monster, T. B. M.; Meijer, K. (2016). "Combined oral contraceptives, thrombophilia and the risk of venous thromboembolism: a systematic review and meta-analysis". Journal of Thrombosis and Haemostasis. 14 (7): 1393–1403. doi:10.1111/jth.13349.
  12. ↑ "Prevention of Venous Thromboembolism in Gynecologic Surgery". Obstetrics & Gynecology. 138 (1): e1–e15. 2021. doi:10.1097/aog.0000000000004445. ISSN 0029-7844.
  13. ↑ Straczek, Céline; Oger, Emmanuel; Yon de Jonage-Canonico, Marianne Beau; Plu-Bureau, Geneviève; Conard, Jacqueline; Meyer, Guy; Alhenc-Gelas, Martine; Lévesque, Hervé; Trillot, Nathalie; Barrellier, Marie-Thérèse; Wahl, Denis (2005-11-29). "Prothrombotic Mutations, Hormone Therapy, and Venous Thromboembolism Among Postmenopausal Women". Circulation. 112 (22): 3495–3500. doi:10.1161/circulationaha.105.565556. ISSN 0009-7322.
  14. ↑ Watanabe, Kentaro; Kato, Motohiro; Ishimaru, Tetsuya; Hiwatari, Mitsuteru; Suzuki, Tomonori; Minosaki, Yoshihiro; Takita, Junko; Fujishiro, Jun; Oka, Akira (2017). "Perioperative management of severe congenital protein C deficiency". Blood Coagulation & Fibrinolysis. 28 (8): 646–649. doi:10.1097/MBC.0000000000000654. ISSN 0957-5235.
  15. ↑ Sallah, Sabah; Abdallah, Jorge M.; Gagnon, Gregory A. (1998). "Recurrent Warfarin-Induced Skin Necrosis in Kindreds with Protein S Deficiency". Pathophysiology of Haemostasis and Thrombosis. 28 (1): 25–30. doi:10.1159/000022380. ISSN 1424-8832.
  16. ↑ DeFazio, Michael; Economides, James; Anghel, Ersilia; Tefera, Eshetu; Evans, Karen (2019). "Lower Extremity Free Tissue Transfer in the Setting of Thrombophilia: Analysis of Perioperative Anticoagulation Protocols and Predictors of Flap Failure". Journal of Reconstructive Microsurgery. 35 (04): 270–286. doi:10.1055/s-0038-1675145. ISSN 0743-684X.
  17. ↑ Miller's Anesthesia. Ronald D. Miller (7th ed.). Philadelphia, PA: Churchill Livingstone/Elsevier. 2010. ISBN 978-1-4377-2061-7. OCLC 489070622.CS1 maint: others (link)
  18. ↑ 18.0 18.1 18.2 Wypasek E, Undas A. Protein C and protein S deficiency - practical diagnostic issues. Adv Clin Exp Med. 2013;22(4):459-467.
  19. ↑ 19.0 19.1 Franco, Rendrik F.; Reitsma, Pieter H. (2001-09-01). "Genetic risk factors of venous thrombosis". Human Genetics. 109 (4): 369–384. doi:10.1007/s004390100593. ISSN 0340-6717.
  20. ↑ Erbe, Matthias; Rickerts, Volker; Bauersachs, Rupert Martin; Lindhoff-Last, Edelgard (2003). "Acquired Protein C and Protein S Deficiency in HIV-Infected Patients". Clinical and Applied Thrombosis/Hemostasis. 9 (4): 325–331. doi:10.1177/107602960300900408. ISSN 1076-0296.
  21. ↑ Fourrier, F.; Lestavel, P.; Chopin, C.; Marey, A.; Goudemand, J.; Rime, A.; Mangalaboyi, J. (1990). "Meningococcemia and purpura fulminans in adults: acute deficiencies of proteins C and S and early treatment with antithrombin III concentrates". Intensive Care Medicine. 16 (2): 121–124. doi:10.1007/bf02575306. ISSN 0342-4642.
  22. ↑ Goldenberg, N. A.; Manco-Johnson, M. J. (2008-10-30). "Protein C deficiency: PROTEIN C DEFICIENCY". Haemophilia. 14 (6): 1214–1221. doi:10.1111/j.1365-2516.2008.01838.x.
  23. ↑ Labrouche, Sylvie; Reboul, Marie-Pierre; Guérin, Viviane; Vergnes, Christine; Freyburger, Geneviève (2003). "Protein C and protein S assessment in hospital laboratories". Blood Coagulation & Fibrinolysis. 14 (6): 531–538. doi:10.1097/00001721-200309000-00003. ISSN 0957-5235.
  24. ↑ Pabinger, I; Allaart, C F; Hermans, J; Briët, E; Bertina, R M (1992). "Hereditary Protein C-Deficiency: Laboratory Values in Transmitters and Guidelines for the Diagnostic Procedure Report on a Study of the SSC Subcommittee on Protein C and Protein S". Thrombosis and Haemostasis. 68 (04): 470–474. doi:10.1055/s-0038-1646299. ISSN 0340-6245.
  25. ↑ Gupta, Ashish; Gupta, Hari Prabhat; Dutta, Tanima (2021-06-21). "Towards Identifying Internet Applications Using Early Classification of Traffic Flow". 2021 IFIP Networking Conference (IFIP Networking). IEEE. doi:10.23919/ifipnetworking52078.2021.9472804.
  26. ↑ Minuk, Leonard; Lazo-Langner, Alejandro; Kovacs, Judy; Robbins, Melinda; Morrow, Bev; Kovacs, Michael (2010). "Normal levels of protein C and protein S tested in the acute phase of a venous thromboembolic event are not falsely elevated". Thrombosis Journal. 8 (1): 10. doi:10.1186/1477-9560-8-10. ISSN 1477-9560. PMC 2887791. PMID 20482785.CS1 maint: PMC format (link)
  27. ↑ Bock, Margret E.; Bobrowski, Amy E.; Bhat, Rukhmi (2019). "Utility of thrombophilia screening in pediatric renal transplant recipients". Pediatric Transplantation. 23 (1): e13314. doi:10.1111/petr.13314.
  28. ↑ Dhouha, Bahri; Hela, Baccouche; Lilia, Ben Fatma; Sarra, Haddad; Karim, Zouaghi Mohamed; Neila, Ben Romdhane (2021). "Relevance of Inherited Thrombophilia Screening in Adult Kidney Transplant Recipients". Experimental and Clinical Transplantation. 19 (3): 212–216. doi:10.6002/ect.2020.0234.
  29. ↑ 29.0 29.1 Ortel, Thomas L.; Neumann, Ignacio; Ageno, Walter; Beyth, Rebecca; Clark, Nathan P.; Cuker, Adam; Hutten, Barbara A.; Jaff, Michael R.; Manja, Veena; Schulman, Sam; Thurston, Caitlin (2020-10-02). "American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism". Blood Advances. 4 (19): 4693–4738. doi:10.1182/bloodadvances.2020001830. ISSN 2473-9529.
  30. ↑ Lipe, Brea; Ornstein, Deborah L. (2011-10-04). "Deficiencies of Natural Anticoagulants, Protein C, Protein S, and Antithrombin". Circulation. 124 (14): e365–e368. doi:10.1161/CIRCULATIONAHA.111.044412.
  31. ↑ 31.0 31.1 Monagle, Paul; Chan, Anthony K.C.; Goldenberg, Neil A.; Ichord, Rebecca N.; Journeycake, Janna M.; Nowak-Göttl, Ulrike; Vesely, Sara K. (2012). "Antithrombotic Therapy in Neonates and Children". Chest. 141 (2): e737S–e801S. doi:10.1378/chest.11-2308. PMC 3278066. PMID 22315277.CS1 maint: PMC format (link)
  32. ↑ Casella, JamesF.; Bontempo, FrancisA.; Markel, Howard; Lewis, JessicaH.; Zitelli, BasilJ.; Starzl, ThomasE. (1988). "SUCCESSFUL TREATMENT OF HOMOZYGOUS PROTEIN C DEFICIENCY BY HEPATIC TRANSPLANTATION". The Lancet. 331 (8583): 435–438. doi:10.1016/s0140-6736(88)91231-7. ISSN 0140-6736.
  33. ↑ 33.0 33.1 Knoebl, Paul (2008). "Severe congenital protein C deficiency: the use of protein C concentrates (human) as replacement therapy for life-threatening blood-clotting complications". Biologics: Targets & Therapy: 285. doi:10.2147/BTT.S1954. ISSN 1177-5475. PMC 2721356. PMID 19707361.CS1 maint: PMC format (link)
  34. ↑ Ghassemi, Fariba; Abdi, Fatemeh; Esfahani, Mandana (2020-07-13). "Ophthalmic manifestations of congenital protein C deficiency: a case report and mini review". BMC Ophthalmology. 20 (1): 282. doi:10.1186/s12886-020-01424-x. ISSN 1471-2415. PMC 7358193. PMID 32660449.CS1 maint: PMC format (link)
  35. ↑ TEN KATE, M. K.; VAN DER MEER, J. (2008-05-12). "Protein S deficiency: a clinical perspective". Haemophilia. 0 (0): 080512004759292–???. doi:10.1111/j.1365-2516.2008.01775.x. ISSN 1351-8216.
  36. ↑ Pabinger, Ingrid; Kyrle, Paul A; Heistinger, Max; Eichinger, Sabine; Wittmann, Eva; Lechner, Klaus (1994). "The Risk of Thromboembolism in Asymptomatic Patients with Protein C and Protein S Deficiency: A Prospective Cohort Study". Thrombosis and Haemostasis. 71 (04): 441–445. doi:10.1055/s-0038-1642457. ISSN 0340-6245.
  37. ↑ Conard, J; Horellou, M H; Dreden, P Van; Lecompte, T; Samama, M (1990). "Thrombosis and Pregnancy in Congenital Deficiencies in AT III, Protein C or Protein S: Study of 78 Women". Thrombosis and Haemostasis. 63 (02): 319–320. doi:10.1055/s-0038-1645218. ISSN 0340-6245.
  38. ↑ Stefano, V De; Leone, G; Mastrangelo, S; Tripodi, A; Rodeghicro, F; Castaman, G; Barbui, T; Finaazi, G; Bizzi, B; Mannucci, P M (1994). "Thrombosis during Pregnancy and Surgery in Patients with Congenital Deficiency of Antithrombin III, Protein C, Protein S". Thrombosis and Haemostasis. 71 (06): 799–800. doi:10.1055/s-0038-1642528. ISSN 0340-6245.
  39. ↑ Croles, F Nanne; Nasserinejad, Kazem; Duvekot, Johannes J; Kruip, Marieke JHA; Meijer, Karina; Leebeek, Frank WG (2017-10-26). "Pregnancy, thrombophilia, and the risk of a first venous thrombosis: systematic review and bayesian meta-analysis". BMJ: j4452. doi:10.1136/bmj.j4452. ISSN 0959-8138.
  40. ↑ Bates, Shannon M.; Greer, Ian A.; Middeldorp, Saskia; Veenstra, David L.; Prabulos, Anne-Marie; Vandvik, Per Olav (2012). "VTE, Thrombophilia, Antithrombotic Therapy, and Pregnancy". Chest. 141 (2): e691S–e736S. doi:10.1378/chest.11-2300. ISSN 0012-3692.
  41. ↑ Trauscht-Van Horn, Jennifer J.; Capeless, Eleanor L.; Easterling, Thomas R.; Bovill, Edwin G. (1992). "Pregnancy loss and thrombosis with protein C deficiency". American Journal of Obstetrics and Gynecology. 167 (4): 968–972. doi:10.1016/s0002-9378(12)80021-4. ISSN 0002-9378.
  42. ↑ Krabbendam, Ineke; Franx, Arie; Bots, Michiel L.; Fijnheer, Rob; Bruinse, Hein W. (2005). "Thrombophilias and recurrent pregnancy loss: a critical appraisal of the literature". European Journal of Obstetrics & Gynecology and Reproductive Biology. 118 (2): 143–153. doi:10.1016/j.ejogrb.2004.07.019. ISSN 0301-2115.
  43. ↑ Tait, R C; Walker, Isobel D; Reitsma, P H; Islam, S I A M; McCall, Frances; Poort, S R; Conkie, J A; Bertina, R M (1995). "Prevalence of Protein C Deficiency in the Healthy Population". Thrombosis and Haemostasis. 73 (01): 087–093. doi:10.1055/s-0038-1653730. ISSN 0340-6245.
  44. ↑ "ACOG Practice Bulletin No. 197: Inherited Thrombophilias in Pregnancy". Obstetrics & Gynecology. 132 (1): e18–e34. 2018. doi:10.1097/AOG.0000000000002703. ISSN 0029-7844.

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