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Protein C Deficiency

Protein C and S Deficiencies

Protein C deficiency is a disorder of blood related to a disturbance in the anticoagulation mechanism and can precipitate thrombotic complications such as deep vein thrombosis (DVT) and pulmonary embolism. Protein C deficiency can be either congenital or acquired. 


Presentation

Unlike other disorders, protein C deficiency does not present itself clinically. The complications that follow the disorder can be identified by their typical signs and symptoms.

Neonates with severe type I homozygous protein C deficiency typically present with neonatal purpura fulminans (NPF), a life-threatening condition characterized by appearance of purple skin lesions due to generalized microvascular thrombosis occurring shortly after birth [13]. 

Heterozygous protein C deficiency is associated with VTE and warfarin-induced skin necrosis (WISN). WISN is a thrombotic complication characterized by tissue necrosis resulting from infarction of the tissue that is devoid of blood supply. It develops in patients after initial administration of warfarin to control thrombosis [14].

DVT, a commonly developed complication in patients with protein C deficiency, accompanies symptoms such as pain, tenderness, swelling and discoloration of skin on the site where clots are present. If DVT invades circulation and enters the lungs, it can obstruct the pulmonary artery causing pulmonary embolism. Pulmonary embolism is a life-threatening complication that is characterized by shortness of breath (SOB), chest pain, chest tenderness, coughing, increased pulse, slight fever and dizziness

Other less common complications that might accompany protein C deficiency comprise thrombophlebitis, which is presented as redness on the site where the inflamed vein is present and cirrhosis. The classical clinical presentation of cirrhosis includes jaundice, ascites, edema, mental confusion and hematemesis

Splenectomy
  • However, portal vein thrombosis developed after splenectomy. This was a rare case of severe complications of IPH accompanying MCTD and protein C deficiency.[ncbi.nlm.nih.gov]
Facial Skin Lesion
  • Michaela Döring, Karin Melanie Rohrer, Ilias Tsiflikas, Wolfgang Buchenau, Marko Wilke, Rupert Handgretinger, Christian Friedrich Poets and Rangmar Goelz, A newborn with grouped facial skin lesions and subsequent seizures, BMC Pediatrics, 14, 1, (2014[oadoi.org]
Skin Bullae
  • Multiple hemorrhagic skin bullae were found at birth on various parts of the body with bilateral leukocoria, organized vitreous hemorrhage, retinal detachment, and intracranial hemorrhage with undetectable levels of protein C activity.[ncbi.nlm.nih.gov]
Neonate-Onset
  • All but two patients presented within 16 days after birth (three prenatal and six neonatal onsets). Postnatal-onset cases had normal growth at full-term delivery.[ncbi.nlm.nih.gov]
Stroke
  • Radiotherapy-induced carotid stenosis is an exacerbating feature of stroke in patients with protein C deficiency. We suggest early carotid duplex sonography and survey of the coagulation profile to prevent a stroke in patients with NPC.[ncbi.nlm.nih.gov]
  • Disorders of coagulation leading to thrombotic disorders are approximately 1% of all ischemic strokes and 4-8% of young strokes.[dx.doi.org]
  • Most stroke cases do not require evaluation of coagulation, but hypercoagulability is a significant reason for unexplained strokes, especially for youth strokes.[omicsonline.org]

Workup

Diagnosis of protein C is based on identification of complications that follow the disorder, with the most important one being DVT. 

DVT is confirmed by complete medical history, clinical presentation and laboratory test results. The levels of D-dimer are determined while confirming DVT. D-dimer is a product formed by degradation of fibrin clot and its concentration in blood is directly related to DVT, with increased levels indicating DVT. Additional tests used to confirm DVT include venography and ultrasonography which further help in verify the presence of blood clots. In venography technique, detection of blood clots is achieved by injecting a dye in a large body vein and examining it under X-ray where the clot becomes visible [15]. However, ultrasound is a preferred method as it is non-invasive. Computerized tomography (CT) and magnetic resonance imaging (MRI) may also be used to determine the presence and location of blood clots.

Treatment

Treatment is based on dissolving clots by anticoagulation therapy. Heparin and warfarin are commonly used anticoagulants to treat thrombosis that accompanies protein C deficiency [16]. As described earlier, initial administration of warfarin may cause WISN.

Neonatal purpura fulminans must be treated as emergency as it is a life threatening condition. It is typically attended by replacing protein C with normal plasma or purified concentrate and a anticoagulation therapy with heparin [17].

Prognosis

The prognosis is largely affected by the presence of other thrombotic events. The risk of developing VTE in patients with protein C deficiency is increased by about 12.5 folds [6]. In a recent case study, the recurrence rate of VTE was found to be approximately 60% [12]. Furthermore, the risk of worsening VTE has also been documented in pregnant women following birth

Etiology

Protein C is encoded by the PROC gene. Mutations in the PROC gene change the normal structure of protein C and disrupt its anticoagulant function causing protein C deficiency [5] [6]. However, certain non-genetic factors may also increase the risk of developing mild acquired protein C deficiency such as ageing, surgery, pregnancy and immobility particularly in patients with a family history of thrombosis.

Epidemiology

The average incidence of protein C deficiency is found to be 1 in 350 cases [7]. According to another population study, protein C deficiency has been found to be present in roughly 2%-5% of patients suffering from venous thromboembolism (VTE) [8]. 

Sex distribution
Age distribution

Pathophysiology

As described earlier, protein C in its active form (aPC) serves to regulate the blood clotting mechanism by exerting anticoagulant activity through a series of activation and inactivation cycles. Therefore, deficit of protein C in the blood leads to irregulated anticoagulation due to the disturbance in the balance among clotting factors. This results in impediment in blood circulation and thrombophilia. Abnormal blood clots formed this way can cause further complications. Deep vein thrombosis (DVT) is one such complication that arises from deficiency of protein C. DVT is a type of blood clot that is formed in the deep veins of the body such as those of arms and legs. A DVT carries the likelihood for traveling through the blood stream and blocking an artery in the lungs, causing a life threatening condition called pulmonary embolism

The genetic pathogenesis of protein C deficiency lies in mutations in genes of chromosome 2. On the basis of the genetic mutations, protein C deficiency has been classified as type I and type II. Phenotypically, the condition is referred to as homozygous if an identical pair of mutated genes responsible for controlling protein C synthesis is inherited in an individual. Alternatively, when only one mutated gene is inherited, the condition is termed as heterozygous. Most patients with severe congenital protein C deficiency carry a homozygous defective gene and present with clinical symptoms in the initial days of life. In patients displaying a heterozygous cause, symptoms often develop later in life [9] [10].

Type I protein C deficiency is characterized by reduced synthesis of protein C in the blood and serum levels of protein C are found to be lowered by half compared to those of normal patients. Type II protein C deficiency is thought to result from point mutations of the protein C gene and indicates normal levels of protein C with diminished functional activity. Type I is the most common type of deficiency between the two forms [11]. 

Prevention

In patients with a family history of protein C deficiency or thrombosis, appropriate preventive measures must be taken. To prevent the development of a thromboembolic disease in patients with heterozygous protein C deficiency, thromboprophylaxis must be performed before surgery, during trauma and air travel. If the patient is pregnant, estrogen-containing hormonal therapy may also be used. 

Prevention of WISN is not inevitable in individuals with protein C deficiency. WISN can be avoided by administering small doses of warfarin and by concomitant use of another parenteral anticoagulant for a minimum of 5 days. 

Summary

Protein C deficiency is a disorder characterized by insufficient levels of protein C in the blood, a vitamin K-dependent circulating blood glycoprotein involved in the regulation of blood coagulation.

Normally, protein C is synthesized in the liver and released into the blood in its inactive zymogenic form. In the blood, protein C is converted to its active form called activated protein C (aPC) by thrombin. The activation occurs on the vessel endothelium and is catalyzed by a thrombin-thrombomodulin complex [1]. Once activated, the aPC binds and forms a complex with protein S, another vitamin k-dependent protein. In the bound form, the activated protein C inactivates factors Va and VIIIa which further results in inactivation of clotting factor X. As a result, the enzyme thrombin, which is responsible for activating fibrin clot formation, remains inhibited and consequently the anticoagulation mechanism is balanced [1] [2]. Deficiency of protein C leads to unregulated anticoagulation resulting in thrombophilia and increased risk of deep vein thrombosis (DVP) as well as pulmonary embolism [3]. aPC also provides cytoprotective and antiinflammatory functions through protein C receptor and protease-activated receptor-1 (PAR-1) found in the vascular endothelium [2].

Different cases of protein C deficiency vary widely, from very mild to extremely severe. The majority of patients with mild protein C deficiency hardly develop abnormal blood clots and lead a normal life. Infants suffering from severe protein C deficiency develop purpura fulminans shortly after birth [4]. Purpura fulminans is a fatal disorder of the blood clotting mechanism characterized by formation of blood clots inside blood vessels. The presence of numerous blood clots hinders the normal flow of blood through blood vessels and continuous blood clotting uses up all available blood clotting proteins. Consequently, abnormal bleeding ensues from different parts of the body which appears clinically on the skin in the form of purple lesions. 

Protein C deficiency can either be congenital or acquired. The congenital form can be categorized as type I protein C deficiency and type II protein C deficiency. In type I, mutations in the PROC gene result in reduced synthesis of protein C. Type I is the most common type of protein C deficiency. In type II protein C deficiency, mutations in the PROC gene cause formation of an abnormal protein C that is insufficient as a functional protein and fails to regulate blood clotting. 

Protein C deficiency does not present with definite clinical symptoms. However, the complications that ensue the disorder can be recognized and diagnosis can be made accordingly. The patient's disease history, family history and laboratory data analysis can aid in establishing accurate diagnosis and designing appropriate treatment regimen. Treatment is mostly aimed at dissolving clots with anticoagulant therapy. 

Patient Information

Protein C deficiency is a disorder characterized by irregulated blood anticoagulation due to deficiency of protein C or presence of abnormal, non-functional protein C in the blood. 

Protein C is normally found in the blood and plays a vital role in preventing the formation of abnormal blood clots and promoting a smooth blood flow through the blood vessels.

Two types of the disorder have been recognized; congenital and acquired. Congenital protein C deficiency has been further classified as type I and type II. Type I protein C deficiency is characterized by reduced synthesis of protein C by the body which leads to abnormally low levels of protein C in the blood. Type II is associated with the presence of abnormal functional protein C. Acquired protein C deficiency occurs due to other diseases that include severe infection, disseminated intravascular coagulation, liver disease, vitamin K deficiency, warfarin therapy, chemotherapeutic drugs and hemopoietic stem cell transplantation

The disorder itself does not show specific symptoms. However, the complications arising from protein C deficiency are presented clinically. One such complication is purpura fulminans that occurs in neonates few hours after birth with severe congenital protein C deficiency. Purpura fulminans is a fatal condition in which clots are formed throughout the body and are visible as purple skin lesions on the skin. Other manifestations of the disease include deep vein thrombosis (DVT), which is the formation of blood clot in one of the deep veins of the body as well as pulmonary embolism, which is the obstruction of the lung artery caused by DVT. 

The disorder is diagnosed by evaluation of symptoms, medical history and assessment of protein C levels. Accurate diagnosis is highly important as treatment based on incorrect diagnosis can further complicate the illness. Venography, ultrasound, CT scan and MRI scan are commonly used to detect presence and location of blood clots. 

In individuals with a family history of thrombotic diseases, preventive treatment is recommended especially during surgery and in pregnant patients. Treatment of the disorder is based on replacement of protein C with fresh frozen plasma or plasma concentrate and anticoagulant therapy with heparin and warfarin. 

References

Article

  1. Dahlback B. Advances in understanding pathogenic mechanisms of thrombophilic disorders. Blood. 2008;112(1):19-27.
  2. Mosnier LO, Zlokovic BV, Griffin JH. The cytoprotective protein C pathway. Blood. 2007;109(8):3161-3172.
  3. Heit JA. Predicting the risk of venous thromboembolism recurrence. Am J Hematol. 2012;87 Suppl 1:S63-S67.
  4. Dreyfus M, Masterson M, David M, et al. Replacement Therapy with Monoclonal Antibody Purified Protein C Concentrate in Newborns with Severe Congenital Protein C Deficiency. Seminars in Thrombosis and Hemostasis. 1995;21(4):371-381.
  5. Bertina RM, Koeleman C, Koster T, et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature. 1994;369:64–67.
  6. Khan S, Dickerman JD. Hereditary thrombophilia. Thromb J. 2006;12;4:15. 
  7. Tait RC, Walker ID, Reitsma PH, et al. Prevalence of protein C deficiency in the healthy population. Thromb Haemost. 1995;73(1):87-93.
  8. Mateo J, Oliver A, Borrell M, Sala N, Fontcuberta J. Laboratory evaluation and clinical characteristics of 2,132 consecutive unselected patients with venous thromboembolism--results of the Spanish Multicentric Study on Thrombophilia (EMET-Study). Thromb Haemost. 1997;77(3):444-451.
  9. Moritz B, Rogy S, Tonetta S, Schwarz HP, Ehrlich H and the CEPROTIN Study Group. Efficacy and Safety of a High Purity Protein C Concentrate in the Management of Patients with Severe Congenital Protein C Deficiency. In: Scharrer I, Schramm W, ed. 31st Hemophilia Symposium Hamburg 2000. Berlin Heidelburg: Springer-Verlag. 2002;101-109.
  10. Marciniak E, Wilson HD, Marlar RA. Neonatal purpura fulminans: a genetic disorder related to the absence of protein C in blood. Blood. 1985;65(1):15-20.
  11. Reitsma PH, Bernardi F, Doig RG, et al. Protein C deficiency: a database of mutations, 1995 update. Thromb Haemost. 1995;73(5):876-889.
  12. Brouwer JL, Lijfering WM, Ten Kate MK, et al. High long-term absolute risk of recurrent venous thromboembolism in patients with hereditary deficiencies of protein S, protein C or antithrombin. Thromb Haemost. 2009;101(1):93-99.
  13. Marciniak E, Wilson HD, Marlar RA, et al. Neonatal purpura fulminans: a genetic disorder related to the absence of protein C in blood. Blood. 1985; 65(1):15-20.
  14. Faraci PA, Deterling RA Jr, Stein AM, et al. Warfarin induced necrosis of the skin. Surg Gynecol Obstet. 1978;146(5):695-700. 
  15. Michiels JJ, Hamulyak K. Laboratory diagnosis of hereditary thrombophilia. Semin Thromb Hemost. 1998;24(4):309-320.
  16. Schramm W, Spannagl M, Bauer KA, et al. Treatment of coumarin-induced skin necrosis with a monoclonal antibody purified protein C concentrate. Arch Dermatol. 1993;129(6):753-756.
  17. Dreyfus M, Magny JF, Bridey F, et al. Treatment of homozygous protein C deficiency and neonatal purpura fulminans with a purified protein C concentrate. N Engl J Med. 1991;325(22):1565-1568.

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Last updated: 2019-07-11 21:10