Protein C deficiency: Difference between revisions
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==Natural History, Complications, and Prognosis== | ==Natural History, Complications, and Prognosis== | ||
If left untreated, | If left untreated, the patients of Protein C deficiency menifest unprovoked episodes of venous thromboembolism, thrombus formation in cerebral, mesenteric, splenic and hepatic veins. The probability of menifestation of disease is ehnanced in the presence of precipitating factors such as immobility, prolonged use of oral contraceptives and pelvic surgery. | ||
Common complications of Protein C deficiency include deep venous thrombosis, warfarin induced skin necrosis, neonatal purpura fulminans, pulmonary embolism and thrombosis in unusual sites such as cerebral, hepatic, mesenteric and splenic veins. Severe complications such as arterial thrombosis is seen resulting in ischemic stroke in young patient with heterozygous protein C deficiency. <ref name="pmid2195715">{{cite journal |vauthors=Kohler J, Kasper J, Witt I, von Reutern GM |title=Ischemic stroke due to protein C deficiency |journal=Stroke |volume=21 |issue=7 |pages=1077–80 |date=July 1990 |pmid=2195715 |doi= |url=}}</ref><ref name="pmid2220892">{{cite journal |vauthors=Grewal RP, Goldberg MA |title=Stroke in protein C deficiency |journal=Am. J. Med. |volume=89 |issue=4 |pages=538–9 |date=October 1990 |pmid=2220892 |doi= |url=}}</ref> | Common complications of Protein C deficiency include deep venous thrombosis, warfarin induced skin necrosis, neonatal purpura fulminans, pulmonary embolism and thrombosis in unusual sites such as cerebral, hepatic, mesenteric and splenic veins. Severe complications such as arterial thrombosis is seen resulting in ischemic stroke in young patient with heterozygous protein C deficiency. <ref name="pmid2195715">{{cite journal |vauthors=Kohler J, Kasper J, Witt I, von Reutern GM |title=Ischemic stroke due to protein C deficiency |journal=Stroke |volume=21 |issue=7 |pages=1077–80 |date=July 1990 |pmid=2195715 |doi= |url=}}</ref><ref name="pmid2220892">{{cite journal |vauthors=Grewal RP, Goldberg MA |title=Stroke in protein C deficiency |journal=Am. J. Med. |volume=89 |issue=4 |pages=538–9 |date=October 1990 |pmid=2220892 |doi= |url=}}</ref> | ||
*Impaired fetal growth and fetal loss has also been reported with homozygous Protein C deficiency.<ref name="pmid8843809">{{cite journal |vauthors=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 |title=Increased fetal loss in women with heritable thrombophilia |journal=Lancet |volume=348 |issue=9032 |pages=913–6 |date=October 1996 |pmid=8843809 |doi= |url=}}</ref> | *Impaired fetal growth and fetal loss has also been reported with homozygous Protein C deficiency.<ref name="pmid8843809">{{cite journal |vauthors=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 |title=Increased fetal loss in women with heritable thrombophilia |journal=Lancet |volume=348 |issue=9032 |pages=913–6 |date=October 1996 |pmid=8843809 |doi= |url=}}</ref> | ||
Revision as of 14:22, 26 September 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: Template loop detected: Template:BM
Synonyms and keywords:
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 VIIIa and hence plays role its role in anticoagulation. The manifestations of the disease can be mild which don't develop Deep Venous thrombosis, however it has increased risk of developing Warfarin Induced 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 can cause 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.
- In 1982, Bertina was the first to discover the association between Thrombosis and Protein C deficiency.
- The association between thrombosis and Protein C Deficiency was made in 1993 and 1994 (Dahlbäcket al 1993; Bertina et al 1994)[1][2][3] .
Classification
Protein C deficiency may be classified according to etiology.
- Congential Protein C Deficiency.[4]
- Heterozygous Protein Deficiency
- Type I Disease: Generally mild form. It has decreased levels of protein C.
- Type II Disease: It has normal or near noraml levels of Protein c but reduced functional activity.[5]
- Homozygous Protein C Deficiency: It is severe form of disease. It presents with Neonatal Purpura Fulminans.
- Heterozygous Protein Deficiency
- Acquired Protein C Deficiency.[6]
Pathophysiology
The Protein C is a vitamin K dependent glycoprotein, 62 kD, synthesized in the liver,. 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 it vit K.The Gla domains bind to calcium leading to structural change that facilitates phospholipid binding which is important for protein.
Protein C after its activation has two main 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.
- The other role of Protein C is its anti inflammatory effect.[7] 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.[8]
- The deficiency of protein C results by creating a procoagulant effect generally in areas with slow moving venous blood flow, i.e extremities leading to thrombosis which manifests as Deep Venous Thrombosis.[9]
- 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 causes decreased the activation of TAFI (thrombin activatable fibrinolysis inhibitor) hence resulting in enhanced profibrinolytic potential.
Causes
The cause of Protein C deficiency is PROC gene mutation in long arm (q) of chromosome 2 at position 14.3. [6]
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.[10]
- In prevalence of Protein C deficiency was estimated to be 1.45 per 1000 (95% CI, 0.79/1000 to 2.43/1000.[11]
Risk Factors
The most potent risk factor in the development of Protein C deficiency is consanguineous marriage.
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.[12]
Natural History, Complications, and Prognosis
If left untreated, the patients of Protein C deficiency menifest unprovoked episodes of venous thromboembolism, thrombus formation in cerebral, mesenteric, splenic and hepatic veins. The probability of menifestation of disease is ehnanced in the presence of precipitating factors such as immobility, prolonged use of oral contraceptives and pelvic surgery. Common complications of Protein C deficiency include deep venous thrombosis, warfarin induced skin necrosis, neonatal purpura fulminans, pulmonary embolism and thrombosis in unusual sites such as cerebral, hepatic, mesenteric and splenic veins. Severe complications such as arterial thrombosis is seen resulting in ischemic stroke in young patient with heterozygous protein C deficiency. [13][14]
- Impaired fetal growth and fetal loss has also been reported with homozygous Protein C deficiency.[15]
Prognosis is generally good with anticoagulation 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.
- Functional assays such as apTT based assay, Factor Xa based (enzymaic 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.
- 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) can be interfered by Heparin and other anticoagulants. Hence chromogenic assays are preffered. The only exception is when the patient is using Vit K antagonists lowers the activity of Protein C activity in any assay.[16]
- If functional assays do not reveal the reduced function of protein C especially when clinical suscpision then alternative methods should be considered.Some people have normal levels of Proteins 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. [17][18]
History and Symptoms
The majority of patients with Protein C deficiency are asymptomatic. However the patients are at increased risk of developing abnormal blood clots in unusual sites such as cerebral,hepatic,mesenteric and splenic veins. The patients with acquired disease tend to develop skin skin after the use of anticoagulants such as warfarin. 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.
- Initial episode of venous thrombolism 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 ( popletial and femoral veins).
OR
The hallmark of [disease name] is [finding]. A positive history of [finding 1] and [finding 2] is suggestive of [disease name]. The most common symptoms of [disease name] include [symptom 1], [symptom 2], and [symptom 3]. Common symptoms of [disease] include [symptom 1], [symptom 2], and [symptom 3]. Less common symptoms of [disease name] include [symptom 1], [symptom 2], and [symptom 3].
Physical Examination
Patients with Protein C deficiency usually present with deep venous thrombosis in extremities. Physical examination may show
- Swelling
- Redness
- Tenderness
Other cases can present with erythematous macules which begins on the torso and extremities which can become pupuric and necrotic in case of Warfarin induced Necrosis.[19][20][21] Homozygous cases may be present with more severe disease i.e Neonatal purpura fulminans which is seen as diffuse ecchymoses, if left untreated these can progress to necrotic bullae.
Laboratory Findings
The diagnosis of Protein C deficiency is based on the clinical presentation i.e history of recurrent venous thrombosis , thrombosis in unusual site such as hepatic, mesenteric, splenic and cerebral veins or with strong family history. Various tests are conducted to document Protein C deficiency in addition to baseline clotting profile. i.e Bleeting time(BT),Clotting time(CT), Prothrombin time(PT), activated prothrombin time(apTT).It is important to mention that testing should be done after the episode has settled because it can lead to false low Protein C measurements.[22]
- 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.
- 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) can be interfered by Heparin and other anticoagulants. Hence chromogenic assays are preffered. The only exception is when the patient is using Vit K antagonists lowers the activity of Protein C activity in any assay.[16]
- If functional assays do not reveal the reduced function of protein C especially when clinical suscpision then alternative methods should be considered.Some people have normal levels of Proteins 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. [17][18]
- Genetic testing for mutations in PROC gene.
Electrocardiogram
Protein C deficiency may be associated with development of Myocardial Infarction in young patients. Following are the ECG findings
- ST segment elevation
- T wave inversion
X-ray
The x-ray findings associated with complications of Protein C deficiency i.e pulmonary embolism are here.
Echocardiography or Ultrasound
There are no echocardiography/ultrasound findings associated with Protein C deficiency.
CT scan
A clot may be seen in hepatic, cerebral, mesenteric, cerebral veins is suggestive of Protein C deficiency. Subsequent area of necrosis is seen as hypoluscent area on CT scan.
MRI
There are no MRI findings associated with Protien 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, pulmonary embolism.
- Management of Venous Thromboembolism: Anticoagulation is primarily used. 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.Warfarin is suggested for patients with complicated disease e.g in case of pulmonary embolism.
- The duration of anticoagulation varie 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.
Once the episode of warfarin induced skin necrosis happens, it needs immediate therapy to prevent the further complications.
- Stop warfarin.
- Administer vitamin K intravenously.
- Administer unfractionated heparin.
- Administer a source of protein C such as protein C concentrate or Fresh Frozen Plasma.[23]
- For skin lesions consult dermatologist.
- prophylaxis: Start warfarin at a low dose,gradually increase from 2 mg to therapeutic dose.
- other anticoagulants such as dabigatran, rivaroxaban, apaxaban, or edoxaban[24]
- Overlapping of warfarin with heparin during the first several days of warfarin administration.
- 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.[23]
- Prophylactic anticoagulation should be considered in patients having risk factors for venous thromboembolism such as recurrent episodes of VTE, prolonged use of oral contraceptives, surgeries.
Surgery
Surgical consultation is recommended for the management of skin lesions in warfarin induced skin necrosis i.e complication of Protein C Deficiency.
Primary Prevention
Effective measures for the primary prevention of warfarin induced skin necrosis are described above.
Secondary Prevention
Ptolonged anticoagulation with Direct oral anticoagulants and warfarin bridged with heparin is recommended to prevent secondary complications of Protein C deficiency.
References
- ↑ 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.
- ↑ 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.
- ↑ Troiano R, Boehme C, Siegel A (January 1978). "A corthicothalamic projection involving the midline septum in the cat". Brain Res. 139 (2): 348–53. PMID 304753.
- ↑ Lind B, Johnsen AH, Thorsen S (April 1997). "Naturally occurring Arg(-1) to His mutation in human protein C leads to aberrant propeptide processing and secretion of dysfunctional protein C". Blood. 89 (8): 2807–16. PMID 9108399.
- ↑ 6.0 6.1 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.
- ↑ Okajima K (December 2001). "Regulation of inflammatory responses by natural anticoagulants". Immunol. Rev. 184: 258–74. PMID 11918684.
- ↑ 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.
- ↑ Fourrier F, Chopin C, Goudemand J, Hendrycx S, Caron C, Rime A, Marey A, Lestavel P (March 1992). "Septic shock, multiple organ failure, and disseminated intravascular coagulation. Compared patterns of antithrombin III, protein C, and protein S deficiencies". Chest. 101 (3): 816–23. PMID 1531791.
- ↑ 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.
- ↑ Tait RC, Walker ID, Reitsma PH, Islam SI, McCall F, Poort SR, Conkie JA, Bertina RM (January 1995). "Prevalence of protein C deficiency in the healthy population". Thromb. Haemost. 73 (1): 87–93. PMID 7740502.
- ↑ Khor B, Van Cott EM (June 2010). "Laboratory tests for protein C deficiency". Am. J. Hematol. 85 (6): 440–2. doi:10.1002/ajh.21679. PMID 20309856.
- ↑ Kohler J, Kasper J, Witt I, von Reutern GM (July 1990). "Ischemic stroke due to protein C deficiency". Stroke. 21 (7): 1077–80. PMID 2195715.
- ↑ Grewal RP, Goldberg MA (October 1990). "Stroke in protein C deficiency". Am. J. Med. 89 (4): 538–9. PMID 2220892.
- ↑ 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.
- ↑ 16.0 16.1 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.
- ↑ 17.0 17.1 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.
- ↑ 18.0 18.1 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.
- ↑ 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.
- ↑ Martinelli I, Mannucci PM, De Stefano V, Taioli E, Rossi V, Crosti F, Paciaroni K, Leone G, Faioni EM (October 1998). "Different risks of thrombosis in four coagulation defects associated with inherited thrombophilia: a study of 150 families". Blood. 92 (7): 2353–8. PMID 9746774.
- ↑ Nazarian RM, Van Cott EM, Zembowicz A, Duncan LM (August 2009). "Warfarin-induced skin necrosis". J. Am. Acad. Dermatol. 61 (2): 325–32. doi:10.1016/j.jaad.2008.12.039. PMID 19615543.
- ↑ Bovill EG, Tomczak JA, Grant B, Bhushan F, Pillemer E, Rainville IR, Long GL (March 1992). "Protein CVermont: symptomatic type II protein C deficiency associated with two GLA domain mutations". Blood. 79 (6): 1456–65. PMID 1347706.
- ↑ 23.0 23.1 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.
- ↑ 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.