Protein C deficiency: Difference between revisions
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Following are the two tests that are performed to reach the absolute diagnosis:<ref name="pmid3511097">{{cite journal |vauthors=Vigano D'Angelo S, Comp PC, Esmon CT, D'Angelo A |title=Relationship between protein C antigen and anticoagulant activity during oral anticoagulation and in selected disease states |journal=J. Clin. Invest. |volume=77 |issue=2 |pages=416–25 |date=February 1986 |pmid=3511097 |pmc=423361 |doi=10.1172/JCI112319 |url=}}</ref> | Following are the two tests that are performed to reach the absolute diagnosis:<ref name="pmid3511097">{{cite journal |vauthors=Vigano D'Angelo S, Comp PC, Esmon CT, D'Angelo A |title=Relationship between protein C antigen and anticoagulant activity during oral anticoagulation and in selected disease states |journal=J. Clin. Invest. |volume=77 |issue=2 |pages=416–25 |date=February 1986 |pmid=3511097 |pmc=423361 |doi=10.1172/JCI112319 |url=}}</ref> | ||
* Functional assays such as [[aPTT]] based assay, [[factor Xa]] based (enzymatic assay that uses a [[chromogenic]] [[substrate]] to check the amidolytic cleavage of a synthetic [[protein]] ([[Snake venoms|snake venom]]) are used to determine function of protein C. | * Functional assays such as [[aPTT]] based assay, [[factor Xa]] based (enzymatic assay that uses a [[chromogenic]] [[substrate]] to check the amidolytic cleavage of a synthetic [[protein]] ([[Snake venoms|snake venom]]) are used to determine function of protein C.<ref name="pmid6547008">{{cite journal |vauthors=Bertina RM, Broekmans AW, Krommenhoek-van Es C, van Wijngaarden A |title=The use of a functional and immunologic assay for plasma protein C in the study of the heterogeneity of congenital protein C deficiency |journal=Thromb. Haemost. |volume=51 |issue=1 |pages=1–5 |date=February 1984 |pmid=6547008 |doi= |url=}}</ref> | ||
*[[Antigenic]] determination of [[protein C]] levels. This can detect low levels of [[protein C]] as well as the [[anticoagulant]] effects. | *[[Antigenic]] determination of [[protein C]] levels. This can detect low levels of [[protein C]] as well as the [[anticoagulant]] effects. | ||
*Clotting based assays ([[aPTT]] and [[Factor X|factor Xa]]) may be used; however, the results may be affected [[heparin]] and other anticoagulants. Hence chromogenic assays are preferred. The only exception is when the patient is using [[vitamin K antagonists]] which lowers the activity of [[protein C]] activity in any assay.<ref name="pmid6317087">{{cite journal |vauthors=Comp PC, Nixon RR, Esmon CT |title=Determination of functional levels of protein C, an antithrombotic protein, using thrombin-thrombomodulin complex |journal=Blood |volume=63 |issue=1 |pages=15–21 |date=January 1984 |pmid=6317087 |doi= |url=}}</ref> | *Clotting based assays ([[aPTT]] and [[Factor X|factor Xa]]) may be used; however, the results may be affected [[heparin]] and other anticoagulants. Hence chromogenic assays are preferred. The only exception is when the patient is using [[vitamin K antagonists]] which lowers the activity of [[protein C]] activity in any assay.<ref name="pmid6317087">{{cite journal |vauthors=Comp PC, Nixon RR, Esmon CT |title=Determination of functional levels of protein C, an antithrombotic protein, using thrombin-thrombomodulin complex |journal=Blood |volume=63 |issue=1 |pages=15–21 |date=January 1984 |pmid=6317087 |doi= |url=}}</ref> | ||
Revision as of 18:58, 1 October 2018
| Protein C deficiency | |
| ICD-9 | 289.81 |
|---|---|
| OMIM | 176860 |
| DiseasesDB | 10807 |
| MedlinePlus | 000559 |
| MeSH | D020151 |
For patient information click here
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Badria Munir M.B.B.S.[2]
Synonyms and keywords: Protein C deficiency disorder
Overview
Protein C deficiency is hyper-coagulopathy in which a person develops increased tendency of forming abnormal blood clots, especially in peripheral extremities (legs and arms). These clots can dislodge and ascend into the lungs, causing a life threatening condition, pulmonary embolism. Protein C is one of vitamin K dependent anticoagulants, which upon activation inactivates the clotting factors Va and factor VIIIa and hence plays role its role as anticoagulant. The manifestations of the disease can be mild which don't develop deep venous thrombosis; however, it has an increased risk of developing warfarin-induced skin necrosis and neonatal purpura fulminans in which widespread clots are formed in the body leading to necrosis and after utilization of all the clotting factors leads to massive bleeding. Protein C deficiency can be hereditary or acquired. Hereditary variant is associated with mutation in PROC gene, which is transmitted in an autosomal dominant pattern. People carrying two alleles of the mutant gene tend to develop more aggressive disease.
Historical Perspective
- Protein C deficiency was first discovered by Stenflo, a Swedish chemist, in 1976.[1]
- In 1982, Bertina was the first to discover the association between thrombosis and protein C deficiency.[2]
- The association between thrombosis and protein C deficiency was again confirmed in 1993 by Dahlbäck et al and 1994 by Bertina et al 1994.[3]
Classification
Protein C deficiency may be classified according to etiology:[4]
- Congential protein C deficiency:[5]
- Heterozygous protein deficiency[6]
- Type I disease: Generally mild form. It has decreased levels of protein C.
- Type II disease: It has normal or near normal levels of protein C but reduced functional activity
- Homozygous protein C deficiency: It is severe form of disease. It presents with neonatal purpura fulminans.[7]
- Acquired protein C deficiency
- Heterozygous protein deficiency[6]
Pathophysiology
- The protein C is a vitamin K dependent glycoprotein, 62 kD, synthesized in the liver.[8]
- It circulates as zymogen and is activated to activated protein C (APC) is catalyzed by thrombine-thrombmomdulin complex when it is bound to endothelial proteoglycan.
- Synthesis of gamma-carboxylic acid on protein C requires vitamin K. The Gla domains bind to calcium leading to structural change that facilitates phospholipid binding which is important for protein function.[9]
Protein C after its activation has following functions:
- The primary role of protein C is to inactivate factor Va and factor VIIIa, both of these factors are essential for activation of thrombin and factor Xa which forms clots. The inhibitory effect of factor protein C is enhanced by protein S. Both perform similar functions. When protein C is deficient or inactive it leads to uncontrolled clot formation.
- Activated protein C indirectly increases the profibrinolytic activity by activating to tissue plasminogen activator (tPA) after binding to plasminogen activator inhibitor (PAI). The reduced thrombin generation thus decreases the activation of TAFI (thrombin activatable fibrinolysis inhibitor) hence resulting in enhanced profibrinolytic potential.[10]
- The other role of protein C is its anti inflammatory effect. The reactions are mediated by epithelial protein cell receptors (EPCR) and protease activated receptor 1 (PAR -1) that play primary role in cytoprotective, anti inflammatory effects and barrier stabilizing effects.<ref name="pmid12004250">{{cite journal |vauthors=Joyce DE, Grinnell BW |title=Recombinant human activated protein C attenuates the inflammatory response in endothelium and monocytes by modulating nuclear factor-kappaB |journal=Crit. Care Med. |volume=30 |issue=5 Suppl |pages=S288–93 |date=May 2002 |pmid=12004250 |doi= |url=}}</ref>[11]
- The deficiency of protein C creates procoagulant effect generally in areas with slow moving venous blood flow, such as extremities leading to thrombosis which manifests as deep venous thrombosis.
Causes
- The cause of protein C deficiency is PROC miss sense or nonsense mutation gene mutation of chromosome 2 at 14q3.[12]
- Other types of mutations have also been described, including promoter mutations, splice site abnormalities, in-frame deletions, frameshift deletions, in-frame insertions, and frameshift insertions.[13]
- Protein C consumption:
- Disseminated intravascular coagulation[14]
- Surgery
- Decreased synthesis of protein C in liver disease[14]
- Vitamin K deficiency
- Nephrotic syndrome[15]
- Infection[16]
- Autoantibodies[17]
- Cancer[17]
Differentiating Protein C deficiency from Other Diseases
Protein C deficiency must be differentiated from other diseases that cause symptoms of DVT and pulmonary embolism such as:
- Factor V Leiden mutation
- Antithrombin III deficiency
- Protein S deficiency
- Prothrombin gene mutation
- Disseminated intravascular coagulation (DIC)
- Antiphospholipid antibody syndrome
For more information on differentiating protein C deficiency, click here.
Epidemiology and Demographics
- The incidence of Protein C deficiency is approximately 142 per 100,000 individuals, worldwide.[18]
- The prevalence of Protein C deficiency was estimated to be 145 per 100,000 annually.[18]
Age
- The median age of a first episode is typically in third to fourth decade with family history; while, individuals without a family history tend develop first episode in their fourth to fifth decade.[19]
Risk Factors
- The most potent risk factor in the development of protein C deficiency is consanguineous marriage.[12]
- Hereditary variant is associated with mutation in PROC gene, which is transmitted in an autosomal dominant pattern.[20]
Screening
- There is insufficient evidence to recommend routine screening for protein C deficiency, however in patients with positive family history, it is recommended to check protein C activity (functional) assay which is either clotting time based or chromogenic.[6]
Natural History, Complications, and Prognosis
- If left untreated, the patients of protein C deficiency manifest as unprovoked episodes of venous thromboembolism.[21] [1]
- The probability of manifestation of disease is enhanced in presence of the precipitating factors such as immobility, prolonged use of oral contraceptives, and pelvic surgery.
Common complications of protein C deficiency include:
- Deep venous thrombosis[22]
- Warfarin-induced skin necrosis[23]
- Neonatal purpura fulminans[24]
- Pulmonary embolism and thrombosis in unusual sites such as cerebral, mesenteric, splenic and hepatic veins.[25]
Less common complications include:
- Impaired fetal growth and miscarriage has also been reported with homozygous protein C deficiency.[26]
- Severe complications such as arterial thrombosis is seen resulting in ischemic stroke in young patient with heterozygous protein C deficiency.
Prognosis
- Prognosis of protein C deficiency is generally good with anticogulation therapy survival rate of patients with protein C deficiency is improved.
Diagnosis
Diagnostic Study of Choice
Following are the two tests that are performed to reach the absolute diagnosis:[28]
- Functional assays such as aPTT based assay, factor Xa based (enzymatic assay that uses a chromogenic substrate to check the amidolytic cleavage of a synthetic protein (snake venom) are used to determine function of protein C.[29]
- Antigenic determination of protein C levels. This can detect low levels of protein C as well as the anticoagulant effects.
- Clotting based assays (aPTT and factor Xa) may be used; however, the results may be affected heparin and other anticoagulants. Hence chromogenic assays are preferred. The only exception is when the patient is using vitamin K antagonists which lowers the activity of protein C activity in any assay.[30]
- If functional assays do not reveal the reduced function of protein C especially when clinical suspicion is high, alternative methods should be considered.
- Some people have normal levels of protein C with reduced or near normal anticoagulant function, but normal or near normal amidolytic activity, this indicates reduced ability of protein C to interact with substrate such as factor V, platelet membrane and factor VIII.
History and Symptoms
- The majority of patients with protein C deficiency are asymptomatic.
- The probability of developing venous thromboembolism is especially increased in patients with protein C deficiency in the presence of risk factors such as, factor V Leiden mutation, prolonged immobility, surgery, and prolonged use of oral contraceptives.[31]
- Initial episode of venous thromboembolism is spontaneous in 2/3rd of cases, however, it tends to be recurrent.
- In deep venous thrombosis, a clot is formed in deep veins of leg with potential to ascend upwards to right heart and pulmonary arteries, if dislodged may manifest as pulmonary embolism.
- The patients with acquired disease tend to develop skin changes after the use of anticoagulants such as warfarin.[32]
- For symptoms of deep venous thrombosis click here.
- For symptoms of pulmonary embolism click here.
- Other symptoms include following:
- Purpura and skin changes[22]
- Abnormal pigmentation
- Neurologic abnormalities[26]
- Superficial [[thrombophlebitis]
Physical Examination
- For physical signs related to deep venous thrombosis click here.
- for physical signsrelated to pulmonary embolism click here.
- Warfarin-induced necrosis can present with erythematous macules which begins on the torso and extremities which can become pupuric and necrotic.
- Homozygous cases may present with more severe disease such as neonatal purpura fulminans which is seen as diffuse ecchymoses, if left untreated it can progress to necrotic bullae.[33]
Laboratory Findings
- The diagnosis of protein C deficiency is based on the clinical presentation in addition to strong familial history.[34]
- Various tests are conducted to document protein C deficiency in addition to baseline clotting profile including:
- It is important to mention that testing should be done after the episode has settled because it can lead to falsely lower protein C measurements.
- The diagnostic tests of choice has been described above.
- Genetic testing for mutations in PROC gene.
Electrocardiogram
- Protein C deficiency may be associated with development of myocardial infarction in young patients.[35]
- Following are the ECG findings:
- ST segment elevations in leads II, III, and aVF with reciprocal ST depression in lead V4–6
- Loss of R wave
X-ray
- There are no specific x-ray findings associated with protein C deficiency.
- For specific x-ray findings seen with pulmonary embolism, click here.
Echocardiography or Ultrasound
- There are no specific echocardiography/ultrasound findings associated with protein C deficiency.
- For ultrasound findings related to deep vein thrombosis, click here.
- For echocardiography findings associated with pulmonary embolism, click here.
CT scan
- There are no specific CT scan findings associated with protein C deficiency.
- For CT scan findings related to pulmonary embolism, click here.
MRI
- There are no MRI findings associated with protein C deficiency.
Other Imaging Findings
- There are no other imaging findings associated with protein C deficiency.
Other Diagnostic Studies
- There are no other diagnostic studies associated with protein C deficiency.
Treatment
Medical Therapy
- Pharmacologic medical therapy is recommended among patients with warfarin-induced skin necrosis, neonatal purpura fulminans, and pulmonary embolism.[36]
Management of venous thromboembolism:
- Anticoagulation is primarily recommended.
- For longer duration, it is suggested to bridge warfarin and heparin.
- However, oral anticoagulants such as factor Xa inhibitors can also be used depending on compliance of patient in addition to severity of disease.
- The duration of anticoagulation varies according to case.
- In case of unprovoked episode of thromboembolism or once the diagnosis of protein C has been established, life long anticoagulation therapy is suggested.[37]
- For provoked episodes and in presence of precipitating factors 6 months of warfarin therapy bridged with heparin is recommended.
- For more information related to management of deep venous thrombosis, click here.
Management of pulmonary embolism:
- Warfarin is suggested for patients with complicated disease such as in case of pulmonary embolism.
- For management of pulmonary embolism click here.
Management of warfarin-induced skin necrosis:
- Once the episode of warfarin induced skin necrosis sets in, it needs immediate therapy to prevent the further complications.[36]
- Stop warfarin.
- Administer vitamin K intravenously.
- Administer unfractionated heparin.
- Administer a source of protein C such as protein C concentrate or fresh frozen plasma.[38]
- For skin lesions consult a Dermatologist.
Surgery
- Surgical consultation is recommended for the complication of protein C deficiency such as management of skin lesions in warfarin-induced skin necrosis.[36]
- Liver transplantation was performed in neonatal purpura fulminans that resulted in permanent cure.
Primary Prevention
- There are no established measures for the primary prevention of protein C deficiency.
Secondary Prevention
- Prophylaxis:[39]
- Start warfarin at a low dose, gradually increase from 2 mg to therapeutic dose.
- Other anticoagulants such as dabigatran, rivaroxaban, apaxaban, or edoxaban may be used.
- Overlapping of warfarin with heparin during the first several days of warfarin administration is recommended.
- Use of warfarin in patients of protein C deficiency: Protein C concentrate should be used unless the required level of anticoagulation is achieved. After which warfarin can be administered again.[36]
- Prophylactic anticoagulation should be considered in patients having risk factors for venous thromboembolism such as recurrent episodes of VTE, prolonged use of oral contraceptives, and surgeries.[37]
Effective measures for secondary prevention of protein C deficiency include:
- Avoid prolonged use of oral contraceptives.
- Avoid immobilization.
- Education concerning signs and symptoms of venous thromboembolic events.
References
- ↑ 1.0 1.1 Goldenberg NA, Manco-Johnson MJ (November 2008). "Protein C deficiency". Haemophilia. 14 (6): 1214–21. doi:10.1111/j.1365-2516.2008.01838.x. PMID 19141162.
- ↑ Bertina RM, Broekmans AW, van der Linden IK, Mertens K (August 1982). "Protein C deficiency in a Dutch family with thrombotic disease". Thromb. Haemost. 48 (1): 1–5. PMID 6897135.
- ↑ Dahlbäck B, Carlsson M, Svensson PJ (February 1993). "Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C". Proc. Natl. Acad. Sci. U.S.A. 90 (3): 1004–8. PMC 45799. PMID 8430067.
- ↑ Greengard JS, Fisher CL, Villoutreix B, Griffin JH (April 1994). "Structural basis for type I and type II deficiencies of antithrombotic plasma protein C: patterns revealed by three-dimensional molecular modelling of mutations of the protease domain". Proteins. 18 (4): 367–80. doi:10.1002/prot.340180407. PMID 8208728.
- ↑ Reitsma PH (July 1997). "Protein C deficiency: from gene defects to disease". Thromb. Haemost. 78 (1): 344–50. PMID 9198177.
- ↑ 6.0 6.1 Bovill EG, Bauer KA, Dickerman JD, Callas P, West B (February 1989). "The clinical spectrum of heterozygous protein C deficiency in a large New England kindred". Blood. 73 (3): 712–7. PMID 2521802.
- ↑ Baliga V, Thwaites R, Tillyer ML, Minford A, Parapia L, Allgrove J (July 1995). "Homozygous protein C deficiency--management with protein C concentrate". Eur. J. Pediatr. 154 (7): 534–8. PMID 7556318.
- ↑ Beckmann RJ, Schmidt RJ, Santerre RF, Plutzky J, Crabtree GR, Long GL (July 1985). "The structure and evolution of a 461 amino acid human protein C precursor and its messenger RNA, based upon the DNA sequence of cloned human liver cDNAs". Nucleic Acids Res. 13 (14): 5233–47. PMC 321861. PMID 2991859.
- ↑ Esmon CT (March 1989). "The roles of protein C and thrombomodulin in the regulation of blood coagulation". J. Biol. Chem. 264 (9): 4743–6. PMID 2538457.
- ↑ de Fouw NJ, de Jong YF, Haverkate F, Bertina RM (October 1988). "Activated protein C increases fibrin clot lysis by neutralization of plasminogen activator inhibitor--no evidence for a cofactor role of protein S". Thromb. Haemost. 60 (2): 328–33. PMID 2975409.
- ↑ Joyce DE, Grinnell BW (May 2002). "Recombinant human activated protein C attenuates the inflammatory response in endothelium and monocytes by modulating nuclear factor-kappaB". Crit. Care Med. 30 (5 Suppl): S288–93. PMID 12004250.
- ↑ 12.0 12.1 Reitsma PH, Bernardi F, Doig RG, Gandrille S, Greengard JS, Ireland H, Krawczak M, Lind B, Long GL, Poort SR (May 1995). "Protein C deficiency: a database of mutations, 1995 update. On behalf of the Subcommittee on Plasma Coagulation Inhibitors of the Scientific and Standardization Committee of the ISTH". Thromb. Haemost. 73 (5): 876–89. PMID 7482420.
- ↑ Reitsma PH, Poort SR, Allaart CF, Briët E, Bertina RM (August 1991). "The spectrum of genetic defects in a panel of 40 Dutch families with symptomatic protein C deficiency type I: heterogeneity and founder effects". Blood. 78 (4): 890–4. PMID 1868249.
- ↑ 14.0 14.1 Tripodi A, Salerno F, Chantarangkul V, Clerici M, Cazzaniga M, Primignani M, Mannuccio Mannucci P (March 2005). "Evidence of normal thrombin generation in cirrhosis despite abnormal conventional coagulation tests". Hepatology. 41 (3): 553–8. doi:10.1002/hep.20569. PMID 15726661.
- ↑ Llach F (September 1985). "Hypercoagulability, renal vein thrombosis, and other thrombotic complications of nephrotic syndrome". Kidney Int. 28 (3): 429–39. PMID 3906225.
- ↑ Smith OP, White B, Vaughan D, Rafferty M, Claffey L, Lyons B, Casey W (November 1997). "Use of protein-C concentrate, heparin, and haemodiafiltration in meningococcus-induced purpura fulminans". Lancet. 350 (9091): 1590–3. PMID 9393338.
- ↑ 17.0 17.1 Mitchell CA, Rowell JA, Hau L, Young JP, Salem HH (December 1987). "A fatal thrombotic disorder associated with an acquired inhibitor of protein C". N. Engl. J. Med. 317 (26): 1638–42. doi:10.1056/NEJM198712243172606. PMID 3683503.
- ↑ 18.0 18.1 Miletich J, Sherman L, Broze G (October 1987). "Absence of thrombosis in subjects with heterozygous protein C deficiency". N. Engl. J. Med. 317 (16): 991–6. doi:10.1056/NEJM198710153171604. PMID 3657866.
- ↑ Mustafa S, Mannhalter C, Rintelen C, Kyrle PA, Knöbl P, Lechner K, Pabinger I (January 1998). "Clinical features of thrombophilia in families with gene defects in protein C or protein S combined with factor V Leiden". Blood Coagul. Fibrinolysis. 9 (1): 85–9. PMID 9607123.
- ↑
- ↑
- ↑ 22.0 22.1 Broekmans AW, Veltkamp JJ, Bertina RM (August 1983). "Congenital protein C deficiency and venous thromboembolism. A study of three Dutch families". N. Engl. J. Med. 309 (6): 340–4. doi:10.1056/NEJM198308113090604. PMID 6688122.
- ↑ McGehee WG, Klotz TA, Epstein DJ, Rapaport SI (July 1984). "Coumarin necrosis associated with hereditary protein C deficiency". Ann. Intern. Med. 101 (1): 59–60. PMID 6547283.
- ↑
- ↑ Wysokinski W, Verhaeghe R, Arnout J, Vermylen J (1990). "Protein C deficiency associated with venous thromboembolism". Acta Clin Belg. 45 (2): 78–84. PMID 2164313.
- ↑ 26.0 26.1 Preston FE, Rosendaal FR, Walker ID, Briët E, Berntorp E, Conard J, Fontcuberta J, Makris M, Mariani G, Noteboom W, Pabinger I, Legnani C, Scharrer I, Schulman S, van der Meer FJ (October 1996). "Increased fetal loss in women with heritable thrombophilia". Lancet. 348 (9032): 913–6. PMID 8843809.
- ↑ Douay X, Lucas C, Caron C, Goudemand J, Leys D (August 1998). "Antithrombin, protein C and protein S levels in 127 consecutive young adults with ischemic stroke". Acta Neurol. Scand. 98 (2): 124–7. PMID 9724011.
- ↑ Vigano D'Angelo S, Comp PC, Esmon CT, D'Angelo A (February 1986). "Relationship between protein C antigen and anticoagulant activity during oral anticoagulation and in selected disease states". J. Clin. Invest. 77 (2): 416–25. doi:10.1172/JCI112319. PMC 423361. PMID 3511097.
- ↑ Bertina RM, Broekmans AW, Krommenhoek-van Es C, van Wijngaarden A (February 1984). "The use of a functional and immunologic assay for plasma protein C in the study of the heterogeneity of congenital protein C deficiency". Thromb. Haemost. 51 (1): 1–5. PMID 6547008.
- ↑ Comp PC, Nixon RR, Esmon CT (January 1984). "Determination of functional levels of protein C, an antithrombotic protein, using thrombin-thrombomodulin complex". Blood. 63 (1): 15–21. PMID 6317087.
- ↑
- ↑
- ↑ Seligsohn U, Berger A, Abend M, Rubin L, Attias D, Zivelin A, Rapaport SI (March 1984). "Homozygous protein C deficiency manifested by massive venous thrombosis in the newborn". N. Engl. J. Med. 310 (9): 559–62. doi:10.1056/NEJM198403013100904. PMID 6546411.
- ↑
- ↑ Bux-Gewehr I, Nacke A, Feurle GE (March 1999). "Recurring myocardial infarction in a 35 year old woman". Heart. 81 (3): 316–7. PMC 1728956. PMID 10026361.
- ↑ 36.0 36.1 36.2 36.3 Zauber NP, Stark MW (May 1986). "Successful warfarin anticoagulation despite protein C deficiency and a history of warfarin necrosis". Ann. Intern. Med. 104 (5): 659–60. PMID 3754407.
- ↑ 37.0 37.1
- ↑ Stenflo J (January 1976). "A new vitamin K-dependent protein. Purification from bovine plasma and preliminary characterization". J. Biol. Chem. 251 (2): 355–63. PMID 1245477.
- ↑ Schramm W, Spannagl M, Bauer KA, Rosenberg RD, Birkner B, Linnau Y, Schwarz HP (June 1993). "Treatment of coumarin-induced skin necrosis with a monoclonal antibody purified protein C concentrate". Arch Dermatol. 129 (6): 753–6. PMID 8507079.