In patients who are heterozygous for the mutation, a somewhat milder clinical presentation may be seen due to the fact that the plasma levels of protein C are between 35-65% of normal [5]. High incidence of deep venous thrombosis and pulmonary embolism, arising either spontaneously or associated with certain events (trauma, pregnancy or surgical procedures), are main symptoms in patients between 15 and 40 years of age who exhibit heterozygous deficiency [3] [5]. On the other hand, homozygous individuals develop severe hypercoagulatory states such as DIC, PF and profound venous thrombosis in utero or in early neonatal period [4] [5]. Skin lesions may be encountered in homozygous forms and consist of irregularly formed necrotic areas that are hypoperfused and contain an erythematous inflammatory border [3]. Retinal thrombosis and bleeding that leads to blindness may also be found in some patients [3]. Because mortality rates in this form reach 100% if untreated on time [3], immediate diagnostic and therapeutic actions should be taken in the attempt to save the life of the neonate.

• Pain

  The first patient presented with continuous right upper quadrant pain and high fever. The abdominal sonography revealed normal liver parenchyma but portal vein and superior mesenteric vein thrombosis. [ncbi.nlm.nih.gov]

  People should seek medical help immediately if any of the following symptoms appear: cramps, pain, or tenderness in the arms or legs a red or purple color on the skin swelling warmth in the painful area Blood clots occur in 900,000 people in the United [medicalnewstoday.com]

  If you have a Deep Vein Thrombosis or DVT you will notice: Pain or tenderness in your arm or leg – often described as a cramp or Charley horse – with one or more of the following: Swelling Red or purple skin color Warm to the touch If a piece of a DVT [stoptheclot.org]

• Swelling

  Call your provider if you have symptoms of clotting in a vein (swelling and redness of the leg). If your provider diagnoses you with this disorder, you should be careful to prevent clots from forming. [medlineplus.gov]

  This means that the skin in the area becomes discolored, and the swelling grows more serious. Pulmonary embolism This dangerous condition may develop after DVT. A pulmonary embolism blocks blood flow to the lungs. [medicalnewstoday.com]

  If you have a Deep Vein Thrombosis or DVT you will notice: Pain or tenderness in your arm or leg – often described as a cramp or Charley horse – with one or more of the following: Swelling Red or purple skin color Warm to the touch If a piece of a DVT [stoptheclot.org]

• Protein S Deficiency

  Etiology Protein S deficiency is caused by mutations in the PROS1 gene (3q11-q11.2). Diagnostic methods Diagnosis is based on the measurement of protein S antigen levels (total protein S or free protein S) and anticoagulant activity. [orpha.net]

  Mild protein S deficiency is estimated to occur in approximately 1 in 500 individuals. Severe protein S deficiency is rare; however, its exact prevalence is unknown. Protein S deficiency is caused by mutations in the PROS1 gene. [ghr.nlm.nih.gov]

  […] disease, protein C deficiency disorder, protein C resistance, protein S deficiency disease, protein S deficiency disorder, prothrombin G20210A mutation, prothrombin gene mutation, resistance to activated protein C due to Factor V Leiden, thrombophilia [healthresearchfunding.org]

  C deficiency disease Protein C deficiency disorder Protein C resistance Protein S deficiency disease Protein S deficiency disorder Prothrombin G20210A mutation Prothrombin gene mutation Resistance to activated protein C due to Factor V Leiden Thrombophilia [icd9data.com]

  lupus kontra l- koagulazzjoni) English (APC-) resistance, antithrombin-III deficiency, protein C deficiency, protein S deficiency, hyperhomocysteinemia, and antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant) Last Update: 2012 [mymemory.translated.net]

• Venous Insufficiency

  The clinical phenotype of simple heterozygous protein C deficiency, characterized by mild deficiency in measured protein C activity, can range from asymptomatic to a potent thrombophilic state with recurrent thromboses resulting in severe venous insufficiency [stoptheclot.org]

  Less usual presentations of venous thromboembolic disease include abdominal and cerebral vein thrombosis, along with pregnancy loss or other complications due to placental vascular insufficiency and thrombosis. [medtextfree.wordpress.com]

• Osteoporosis

  The roles of vitamins D and K in bone health and osteoporosis prevention. Proc Nutr Soc. 1997;56(3):915-937. (PubMed) 58. O'Connor E, Molgaard C, Michaelsen KF, Jakobsen J, Cashman KD. [lpi.oregonstate.edu]

  It is worthy of note that osteoporosis has developed in the 20-year-old woman described earlier, maintained on life-long intensive oral anticoagulation with warfarin. [stoptheclot.org]

  Koga R, Tsuda H, Imai K, Abe S, Masuda T, Iwamoto M, Nakazono E, Kamohara T, Kinukawa N, Sakata T Experimental biology and medicine (Maywood, N.J.) 232(8) 1064-1070 2007年09月 [査読有り] 中年女性の骨密度、骨吸収マーカーと身体状況、生活習慣との関連 境美樹、鳥実泰江、原田知香、中園栄里、進藤直子、松尾尚、高柳涼一、津田博子 Osteoporosis [soran.nakamura-u.ac.jp]

  Three cases of tamoxifen-associated venous thrombosis associated with factor V Leiden have been reported.121 Given the increasing use of selective estrogen receptor modulators for treating or preventing breast cancer and osteoporosis, it will be important [medtextfree.wordpress.com]

• Purpura

  The purpura fulminans syndrome can be treated with either replacement therapy or with coumarin therapy. Heparin appears to be ineffective in the prevention of both the purpura fulminans syndrome and the coumarin-induced skin necrosis. [ncbi.nlm.nih.gov]

  Purpura fulminans is a life-threatening condition involving severe clotting throughout the body and causing necrosis of tissues. [orpha.net]

  The purpura fulminans syndrome can be treated with either replacement therapy or with coumarin therapy. Heparin appears to be ineffective in the prevention of both the purpura fulminans syndrome and the coumarin-induced skin necrosis. © 1985 S. [karger.com]

  Protein C Deficiency and Purpura Fulminans Purpura fulminans are caused by the leakage of small blood vessels throughout the body that produce skin lesions and bruises. [www-personal.umd.umich.edu]

• Skin Lesion

  Protein C Deficiency and Purpura Fulminans Purpura fulminans are caused by the leakage of small blood vessels throughout the body that produce skin lesions and bruises. [www-personal.umd.umich.edu]

  Often associated with ecchymotic skin lesions which can turn necrotic called purpura fulminans, this disorder is very rare. [genecards.org]

  As a result, abnormal bleeding occurs in various parts of the body and is often noticeable as large, purple skin lesions. Individuals who survive the newborn period may experience recurrent episodes of purpura fulminans. [ghr.nlm.nih.gov]

  Symptoms appear within 12 hours after birth and include skin lesions that start out dark red and then become purple-black. Thrombophlebitis: This condition causes inflammation and redness along the affected part of the vein. [healthline.com]

  Skin lesions may be encountered in homozygous forms and consist of irregularly formed necrotic areas that are hypoperfused and contain an erythematous inflammatory border. [symptoma.com]

• Warm Skin

  Warning signs of DVT include: pain, swelling and tenderness in your leg (usually in your calf) a heavy ache in the affected area warm skin in the area of the clot red skin, particularly at the back of your leg below the knee DVT usually only affects one [nhs.uk]

• Stroke

  Stroke 1990, 21(7):1077-1080. 10.1161/01.STR.21.7.1077 View Article PubMed Google Scholar Camerlingo M, Finazzi G, Casto L, et al .: Inherited protein C deficiency and non-hemorrhagic arterial stroke in young adults. [thrombosisjournal.biomedcentral.com]

  Ischemic stroke due to protein C deficiency. Stroke. 1990 Jul. 21(7):1077-80. [Medline]. [Full Text]. Camerlingo M, Finazzi G, Casto L, et al. Inherited protein C deficiency and nonhemorrhagic arterial stroke in young adults. [emedicine.medscape.com]

  Complications may include: Childhood stroke More than one pregnancy loss (recurrent miscarriage) Recurrent clots in the veins Pulmonary embolism (blood clot in a lung artery) In rare cases, using warfarin to thin the blood and prevent clots can cause [medlineplus.gov]

  Arterial thrombosis (stroke, myocardial infarction, etc) may occur. Some individuals with hereditary heterozygous protein C deficiency may have no personal or family history of thrombosis and may or may not be at increased risk. [mayomedicallaboratories.com]

Clinical signs and symptoms immediately point to a disorder involving the vascular system and coagulation, suggesting a prompt evaluation of clotting factors and other parameters of coagulation (fibrinogen, D-dimer, thrombocyte count). If a high clinical suspicion toward HPCD exists, it is necessary to perform protein C assays - activity and antigen (or immunoassay), which will determine both quantitative and qualitative changes of this protein (and thus determine whether type I or type II deficiency is present) [6]. As mentioned, heterozygous forms will have protein C values between 35-65% of normal, whereas patients with homozygous mutations will have much lower values [5]. If possible, genetic testing to determine the exact mutation should be done to confirm the diagnosis [6].

Treatment principles somewhat vary depending on the type of mutation and severity of symptoms and includes several anticoagulant drugs. In heterozygous patients, oral intake of coumarin-derived drugs or parenteral heparin is recommended, whereas homozygous patients that suffer from purpura fulminans or DIC should receive fresh frozen plasma (FFP) and activated protein C concentrate, the cornerstone of treatment [7] [8]. Use of low-molecular weight heparin (LMWH) and liver transplantation are other viable options in therapy and the optimal regimen may significantly differ from patient to patient. Also, skin necrosis may occur when using warfarin (which may be a diagnostic sign for heterozygous HPCD), while thrombocytopenia and bleeding are potential side effects of heparin [5]. For these reasons, a careful evaluation of presenting symptoms and additional factors should be made prior to initiation of therapy. Once treatment is started, long-term monitoring is vital due to the life-threatening nature of the disease, especially in patients with homozygous mutations [3].

The prognosis depends on the underlying subtype. Homozygous forms are incompatible with life without adequate supplementation of protein C and numerous complications during the neonatal period (but also in utero) may occur. Heterozygous deficiency, on the other hand, presents as a milder disease, but in general, protein C deficiency increases the risk for thrombotic events by several times [6].

HPCD occurs as a result of various mutations of the PROC gene located on chromosome 2 (q13-14) and it is stated that these mutations are transmitted through an autosomal dominant pattern of inheritance [1]. Depending on the presence of different mutations, HPCD may be classified into heterozygous, homozygous and mixed heterozygous form [3] [8]. Specifically, a heterozygous mutation implies that only one chromosome 2 is affected, whereas the PROC gene is mutated on both chromosomes in homozygous mutations [3]. A mixed heterozygous mutation occurs if of both chromosomes but with different mutations and so far, more than 160 mutations involving the human protein C gene (PROC) have been described [3] [6]. Missense mutations are by far the most common cause of this condition [3]. Additionally, on the basis of the activity and its concentration in plasma, two main subtypes are described: type I, in which parallel reduction of activity and concentration in plasma occurs and Type II, characterized by approximately normal antigen concentrations, but reduced activity of the protein is observed [3]. Large deletions,insertions or frameshifts in the hydrophobic core of the protein are the main cause of type I, while mutations affecting the active site of the enzyme and also its ability to bind to receptors are the main mechanisms of protein C inactivity [3].

The heterozygous type of deficiency is shown to be present in approximately 0.1-0.5% of the general population [6], while homozygous forms are considered to be very rare, appearing in 1 per 500,000-750,000 live births [3]. Isolated studies have estimated that protein C deficiency is responsible for approximately 3% of all venous thrombosis cases [9] [10]. Additionally, HPCD is presumed to be responsible for 9% of all deep venous thromboses in DVT patients younger than 70 years [6].

Protein C is a vitamin K-dependent zymogen that circulates in the plasma as an inactive substance [11]. It is primarily synthesized in the liver, but the epididymis, the kidneys, lungs,brain and male reproductive tissue have also been determined as additional sites of its production [12]. Under physiological conditions, protein C acts as a natural anticoagulant through a cascade of events that start at the endothelial cells [2] [4]. Namely, when thrombin binds to two receptors found on the surface of endothelial cells, thrombomodulin and endothelial protein C receptors (EPCR), protein C binds to EPCR and, under the effects of thrombin, transforms into its active form, the serine protease activated protein C [2]. Its anticoagulant properties include inactivation of factors Va and VIIIa, together with its cofactors protein S, factor V, HDL and various phospholipids [2] [4]. Degradation of fibrin is an additional mechanism of maintaining adequate coagulation, as activated protein C is able to down-regulate thrombin and thus promote fibrinolysis [12]. But in addition to its role in coagulation, activated protein C also possesses various cytoprotective effects, including anti-inflammatory and anti-apoptotic activity, stabilization of the endothelial barrier, but also regulation of gene expression [2] [12]. In the setting of protein C deficiency (regardless of the type of mutation), a hypercoagulable state ensues that may significantly endanger the individuals life. It is still not known why patients with homozygous mutations are able to survive through the initial fetal period and the presumable theory is that transplacental passage of protein C occurs during pregnancy, thus limiting the impact of genetic mutations on organogenesis and fetal maturation [3].

Due to the autosomal dominant nature of the disease [1], genetic counselling of families with known protein C deficiencies may be advised, but the exact cause of these mutations remains to be discovered.

Hereditary protein C deficiency (HPCD) is a rare autosomal dominant genetic disease of hypercoagulation in which various types of mutations lead to inability of protein C to play its role in the coagulation cascade [1]. Protein C is a natural anticoagulant synthesized primarily in the liver and acts by inhibiting factors Va and VIIIa, but also by promoting fibrinolysis [2]. However, different genetic mutations in the human protein C (PROC) gene located on chromosome 2 create a hypercoagulable state, as protein C is either insufficiently produced (type I deficiency) or improperly synthesized (type II deficiency) [3]. Depending on the type of mutation, three genetic forms are recognized:

• Homozygous, in which the PROC gene is affected on both chromosomes and causes a severe clinical presentation characterized by disseminated intravascular coagulation (DIC), purpura fulminans (PF) and severe arterial and venous thrombosis in early neonatal period or even in utero during the final stages of fetal life [4]. This type is considered to be rare, with estimated incidence rates of 1 in 500,000-750,000 live births [3].
• Heterozygous, distinguished by the appearance of mutations on only one chromosome, has a somewhat delayed onset of complaints consisting of extensive venous thrombosis and pulmonary embolism developing either spontaneously or as a result of trauma or surgery [5]. Heterozygous protein C deficiency is assumed to affect between 0.1-0.5% of the general population [6].
• Mixed heterozygous, developing in a very small number of cases, is comprised of mutations that appear on both chromosomes but are of different type [3].

Observation of clinical signs and symptoms should be sufficient to suspect a disorder of blood vessels and coagulation, but to confirm HPCD, two protein C assays need to be performed in order to determine the concentrations and the subtype of deficiency [6]. In heterozygous PCD, protein C values range between 35-65% of normal, whereas markedly lower values are seen in homozygous individuals, but until the diagnosis is confirmed, immediate administration of anticoagulant drugs is vital, as mortality rates are 100% for homozygous forms if not treated on time [3] [5]. Warfarin, heparin and fresh frozen plasma (FFP) are used in management of milder forms of the disease, while activated protein C concentrate is the mainstay of HPCD treatment and it is not uncommon for treatment to be life-long [7] [8]. Despite the fact that the condition is often life-threatening, early recognition and proper treatment may significantly reduce overall mortality rates, but it is important to consider this genetic disease in unexplained hypercoagulable states, especially in newborns.

Hereditary protein C deficiency (HPCD) is a genetic disease that occurs as a result of mutations of the gene that codes for protein C, one of the proteins involved in blood coagulation, but also several other functions in the body related to the vascular system. The human protein C (PROC) gene is located on chromosome 2 and mutations in HPCD may either cause insufficient production of protein C (also known as type I deficiency) or improper synthesis (type II deficiency), universally leading to a markedly reduced ability to perform its respective function. Under physiological conditions, protein C is synthesized primarily in the liver and exists as a nonactive substance in the circulation. When coagulation of blood occurs for any reason, protein C binds to specific receptors and is cleaved into its active form, which enables it to inhibit several molecules that promote coagulation. However, in the setting of protein C deficiency, blood coagulates abnormally and causes conditions that may be severe or even life-threatening. On the basis of different types of genetic mutations and clinical presentation, two main forms of the disease are described:

• The homozygous forms (mutations appear on both chromosomes) is encountered in approximately 1 per 500,000-750,000 live births and is characterized by a severe and life-threatening disease that appears in very early life, most commonly during neonatal period. Excessive coagulation leads to the development of systemic syndromes such as disseminated intravascular coagulation (DIC) and purpura fulminans (PF), pathological states that are 100% fatal without immediate treatment.
• The heterozygous form (mutations appear on only one chromosome) has a somewhat milder clinical presentation consisting of venous thrombosis that develops in adolescence and adulthood. In general, HPCD increases the risk for venous thrombosis by several times.

The signs and symptoms seen in HPCD point to a disease of vascular origin and a diagnostic workup is immediately directed to diagnose coagulation disorders. To confirm HPCD, however, specific tests to determine the concentrations of protein C are available. In patients with heterozygous forms of the disease, circulating protein C levels will be between 35-65% of normal, whereas patients suffering from homozygous HPCD will have much lower values. Immediate administration of anticoagulant drugs, either heparin or warfarin, are vital in preventing early death, but the mainstay of therapy is the use of protein C concentrate. Although therapy may be life-long, adequate levels of protein C in plasma can be achieved and a normal life may be expected,if the diagnosis is made early. Therefore this condition must be taken into consideration in neonates who suffer from severe coagulation abnormalities or in adults with severe venous thrombosis without an identifiable cause.

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