Clinical and genetic analysis of a rare fetus with Protein C deficiency due to compound heterozygous variants of PROC gene / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic etiology for a fetus with hydrocephalus and intraventricular hemorrhage.@*METHODS@#Trio whole exome sequencing was carried out. Candidate variants were verified by Sanger sequencing of the fetus and its parents.@*RESULTS@#The fetus was found to harbor c.818G>A (p.W273X) and c.833T>C (p.L278P) compound heterozygous variants of the PROC gene, which were respectively inherited from its mother and father. Based on the guidelines of the American College of Medical Genetics and Genomics (ACMG), both variants were predicted to be likely pathogenic (PVS1_Strong+PM2_Supporting+PP4; PM2_Supporting+PM3+PP1+PP3+PP4).@*CONCLUSION@#The fetus was diagnosed with Protein C deficiency due to the c.818G>A (p.W273X) and c.833T>C (p.L278P) compound heterozygous variants of the PROC gene. Above finding has enriched the spectrum of PROC gene variants and enabled genetic counseling and prenatal diagnosis for the family.

Clinical phenotype and gene mutation analysis of 12 patients with hereditary protein C deficiency in different families / 中华血液学杂志

Objective: To investigate the molecular pathogenesis and clinical features of unrelated 12 patients with inherited coagulation protein C (PC) deficiency in Chinese population. Methods: The PC activity (PC:A) and PC antigen (PC:Ag) were detected by chromogenic substrate and enzyme linked immunosorbent assay, respectively. The nine exons and flanking sequences of the protein C (PROC) gene were amplified by polymerase chain reaction with direct sequencing, and the suspected mutations were validated by reverse sequencing (clone sequencing for deletion mutations) . Results: The PC:A of the 12 probands decreased significantly, ranging from 18% to 55%, and the PC:Ag of the 10 probands decreased significantly. Eleven mutations were found, out of which four mutations [c.383G>A (p.Gly128Asp) , c.997G>A (p.Ala291Thr) , c.1318C>T (p.Arg398Cys) , and c.532G>C (p.Leu278Pro) ] were discovered for the first time. Six mutations were in the serine protease domain, four mutations were located in epidermal growth factor (EGF) -like domains, and one mutation was located in activation peptide. There were two deletion mutations (p.Met364Trp fsX15 and p.Lys192del) , and the rest were missense mutations. Mutations p.Phe181Val and p.Arg189Trp were identified in three unrelated families. All mutations may be inherited, and consanguineous marriages were reported in two families. Among the probands, nine cases had venous thrombosis, two cases had poor pregnancy manifestations, and one case had purpura. Conclusion: Patients with PC deficiency caused by PROC gene defects are prone to venous thrombosis, especially when there are other thrombotic factors present at the same time.

Phenotypic and genotypic analysis of a pedigree affected with hereditary protein C deficiency / 中华医学遗传学杂志

OBJECTIVE@#To analyze the phenotype and genetic variant in a pedigree affected with inherited protein C (PC) deficiency.@*METHODS@#The proband and her family members (7 individuals from 3 generations) were tested for plasma protein C activity (PC:A), protein C antigen (PC:Ag) content and other coagulation indicators. All of the 9 exons and flanking sequences of the proband's PROC gene were amplified by PCR and sequenced. Suspected variants were verified by reverse sequencing of the proband and her family members. Bioinformatic software was used to analyze the pathogenicity and conservation of the variant site. Swiss-PdbViewer was used to analyze the three-dimensional model and the interaction with the mutant amino acid.@*RESULTS@#The PC:A and PC:Ag of the proband, her grandmother, father and elder brother were decreased to 55%, 52%, 48%, 51% and 53%, 55%, 50%, 56%, respectively. Genetic analysis showed that the four individuals have all carried heterozygous c.1318C>T (p.Arg398Cys) missense mutation in exon 9 of the PROC gene. The score of MutationTaster was 0.991, PROVEAN was -3.72, and FATHMM was -2.49, all predicted it to be a harmful mutation. Phylogenetic analysis also showed that Arg398 was weakly conservative among homologous species. Protein model analysis showed that, in the wild type, Arg398 can form a hydrogen bond with Glu341 and Lys395 respectively, when it was mutated to Cys398, the hydrogen bond with Glu341 disappears and an additional hydrogen bond was formed with Lys395, which has changed the spatial structure of the protein.@*CONCLUSION@#The heterozygous missense mutation c.1318C>T (p.Arg398Cys) of the PROC gene probably underlay the decreased PC:A and PC:Ag in this pedigree.

Trombosis y su relación con la deficiencia de proteínas C y S / Thrombosis and its relationship to protein C and S deficiency

La trombosis se puede definir como un trastorno vascular que se presenta cuando se desarrolla un trombo que bloquea de forma total o parcial el interior de un vaso sanguíneo, ya sea una vena o una arteria. La trombofilia define a una alteración de la hemostasia que predispone al desarrollo de trombosis; sin embargo, la presencia de una trombofilia no implica necesariamente la aparición de un evento trombótico. La deficiencia de los inhibidores fisiológicos, como las proteínas C y S, constituyen factores de riesgo hereditarios y adquiridos que favorecen al desarrollo de trombosis. Se determinó la incidencia de deficiencia de estas proteínas de la coagulación en pacientes con historia obstétrica adversa, eventos de trombosis y otros eventos asociados. Se realizó un estudio longitudinal prospectivo en el período comprendido del 2011 al 2018, en un grupo de pacientes remitidos al Instituto de Hematología e Inmunología, a los que se les realizó la medición de los niveles plasmáticos de las proteínas C y S. En 133 pacientes (52,17 por ciento) se detectó deficiencia de proteína C (n=50), proteína S (n=66) o ambas (n=17). Las principales causas de realización de estos estudios fueron la historia obstétrica adversa y los eventos trombóticos y coincidieron con los eventos clínicos donde predominó alguna deficiencia. La deficiencia de proteína S tuvo mayor incidencia(AU)

Thrombosis is a vascular disorder appearing when a thrombus totally or partially blocks the inside of a blood vessel, be it a vein or an artery. Thrombophilia is a hemostatic alteration leading to thrombosis. However, the presence of thrombophilia does not necessarily imply the appearance of a thrombotic event. Deficiency in physiological inhibitors such as proteins C and S is a hereditary or acquired risk factor fostering thrombosis. Determination was made of the incidence of deficiency in these coagulation proteins in patients with an adverse obstetric history, thrombotic events and other associated disorders. A prospective longitudinal study was conducted in the period 2011-2018 of a group of patients referred to the Institute of Hematology and Immunology, who underwent measurement of their plasma levels of proteins C and S. A total 133 patients (52.17 percent) were found to be deficient in protein C (n=50), protein S (n=66) or both (n=17). The main reasons for the conduct of these studies were an adverse obstetric history and thrombotic events, which coincided with clinical disorders in which some sort of deficiency prevailed. Protein S deficiency was the most common(AU)

Nefrolitotomía percutánea en pacientes con trastornos de la coagulación / Percutaneous Nephrolithotomy in Patients with Bleeding Disorders

Objetivo Reportar un caso de nefrolitotomía percutánea en paciente con deficiencia de proteína C y S. Introducción Los pacientes con déficit de proteína C y S tienen un riesgo alto de eventos tromboembólicos reportándose tasas de hasta el 6% y 8,4% respectivamente. Reporte de Caso Paciente femenina de 43 años con antecedente de deficiencia de proteína C y S, anticoagulación crónica con warfarina por trombosis venosa profunda (TVP), clínicamente con cuadro de cólico reno ureteral derecho y hematuria, la tomografía de vías urinarias mostró un cálculo coraliforme completo derecho. Fue llevada a nefrolitotomía percutánea derecha previa terapia puente con enoxaparina, el acceso percutáneo fue a través del cáliz inferior. Debido a que no fue posible acceder a los cálculos del cáliz medio y superior y que en la institución donde se realizó el procedimiento no se cuenta con nefroscopio flexible, se decidió realizar una segunda punción en cáliz superior, dejando a la paciente libre de cálculos. Se reinició la anticoagulación plena a las 12 horas del postoperatorio sin presentar sangrado asociado. Discusión Los pacientes con déficit de proteína C y S tienen un riesgo alto para eventos tromboembólicos. Kefer y col., realizaron un estudio en el que evaluaron la eficacia de la terapia puente en pacientes llevados a NLP, encontrando que la anticoagulación con warfarina puede suspenderse 5 días antes y reiniciarse 5 días después del procedimiento quirúrgico sin necesidad de terapia puente con enoxaparina. En la actualidad, las recomendaciones dadas por la Sociedad Americana de Urología, indican realizar la terapia puente mediante un grupo multidisciplinario. Resultados El déficit de proteína C y S corresponde a una entidad, con una prevalencia muy baja y condiciona el requerimiento de anticoagulantes orales de forma indefinida. Fue posible realizar una intervención quirúrgica sin complicaciones hemorrágicas ni tromboembólicas con el uso de terapia puente prequirúrgica.

Objective To report a case of percutaneous nephrolithotomy in patients with protein C and S deficiency. Introduction Patients with protein C and S deficiency have a high risk of thromboembolic events reporting rates of 6% and 8.4%, respectively. Case Report A 43-year-old female patient with a history of protein C and S deficiency with chronic warfarin anticoagulation for deep venous thrombosis (DVT). CT scan with full right staghorn calculi. Enoxaparin was administered bridge therapy. She was taken to right percutaneous nephrolithotomy, access was through the lower calyx. Because it was not possible to access the calculus of the middle and upper calyx it was necessary to perform a second puncture in the upper calyx, leaving the patient free of calculus. Full anticoagulation was resumed at 12 hours postoperatively without associated bleeding. Discussion Patients with protein C and S deficits are at high risk for thromboembolic events. Kefer et al. conducted a study evaluating the efficacy of bridge therapy in patients on NLP, finding that warfarin anticoagulation can be discontinued 5 days earlier and restarted 5 days after the surgical procedure without the need for enoxaparin bridging therapy. Results The protein C and S deficiency corresponds to an entity, with a very low prevalence and conditions the requirement of oral anticoagulants indefinitely. It was possible to perform a surgical procedure without hemorrhagic or thromboembolic complications.

Cerebral Palsy due to Intracranial Hemorrhage Caused by Consumptive Coagulopathy in Protein C Deficiency: A Case Report / 대한소아신경학회지

Protein C (PROC) is a potent anticoagulant inactivating coagulation factors Va and VIIIa. PROC deficiency is very rare condition inherited as an autosomal dominant or recessive trait, and associated with various thromboembolic and ischemic conditions. Moreover, severe form of PROC deficiency can cause fatal hemorrhagic complications due to consumptive coagulopathy. We reported two children with hemorrhagic stroke who were diagnosed as severe PROC deficiency caused by two different types of compound heterozygous PROC gene mutations. We described results of laboratory tests, genetic analysis, brain magnetic resonance images, and functional outcomes. Both children received prophylactic anticoagulation therapy and presented with purple-colored skin lesions during rehabilitation. Purpura fulminans caused by insufficient anticoagulation should be differentiated from hematoma caused by excessive anticoagulation therapy in these children.

Cerebral Palsy due to Intracranial Hemorrhage Caused by Consumptive Coagulopathy in Protein C Deficiency: A Case Report / 대한소아신경학회지

Protein C (PROC) is a potent anticoagulant inactivating coagulation factors Va and VIIIa. PROC deficiency is very rare condition inherited as an autosomal dominant or recessive trait, and associated with various thromboembolic and ischemic conditions. Moreover, severe form of PROC deficiency can cause fatal hemorrhagic complications due to consumptive coagulopathy. We reported two children with hemorrhagic stroke who were diagnosed as severe PROC deficiency caused by two different types of compound heterozygous PROC gene mutations. We described results of laboratory tests, genetic analysis, brain magnetic resonance images, and functional outcomes. Both children received prophylactic anticoagulation therapy and presented with purple-colored skin lesions during rehabilitation. Purpura fulminans caused by insufficient anticoagulation should be differentiated from hematoma caused by excessive anticoagulation therapy in these children.

Analysis of phenotypes and genetic mutations in two pedigrees affected with hereditary protein C deficiency / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To explore the pathogenesis of protein C deficiency in two pedigrees through mutation detection and model analysis.</p><p><b>METHODS</b>Chromogenic substrate method and enzyme linked immunosorbent assay (ELISA) were used to determine the plasma protein C activity (PC: A) and protein C antigen (PC: Ag) in the two probands and their family members. All of the 9 exons and intron-exon boundaries of the PROC gene were amplified by PCR and analyzed with Sanger sequencing after purification. Corresponding mutate sites of the family members were also amplified and sequenced. The PolyPhen-2 software was used to analyze the perniciousness of the mutations and Clustal X was to analyze the conservatism. The protein model and amino acids interaction of the mutations were analyzed by Swiss-PdbViewer software.</p><p><b>RESULTS</b>The PC: A and PC: Ag of proband 1 was 30% and 35%, while PC:A of his father, mother and aunt were all slightly under the reference range. Two heterozygous missense mutations were found in exons 7 and 5 of the PROC gene, namely c.565 C>T (p.Arg147Trp) and c.383 G>A (p.Gly86Asp). His father and aunt were carriers for c.565 C>T, while his mother had carried c.383 G>A. The PC: A of proband 2 and his son were 50% and 64%, respectively. And they were both positive for p.Arg147Trp. Analysis of PolyPhen-2 indicated that p.Arg147Trp was benign, while p.Gly86Asp was damaging. Clustal X analysis indicated that the p.Arg147Trp was non-conservative, while the p.Gly86Asp was highly conservative. Modeling for the mutant proteins revealed that the simple aromatic ring of Trp147 in p.Arg147Trp destroyed the two hydrogen bonds between Arg147-Lys146 and Arg147-Lys151, and steric hindranted with Arg178. The side chain of Asp86 extended and generated steric clash with Gln90 with the occurrence of p.Gly86Asp. The change of hydrogen bonds and steric effects has altered the spatial configuration of amino acids, which led to unstable mutate proteins and interfered with the secretion.</p><p><b>CONCLUSION</b>Both probands had hereditary protein C deficiencies, for which their parents were all carriers. The heterozygous mutations p.Arg147Trp and p.Gly86Asp were the main cause for PC: A activity decrease. Among these, p.Gly86Asp was discovered for the first time.</p>

Central Retinal Vein Occlusion in Young Healthy Patients and the Role of Thrombophilia in Pathogenesis

PURPOSE: We report two young patients who developed central retinal vein occlusion (CRVO) without any systemic disease, and various thrombophilia tests were performed to determine the etiology. CASE SUMMARY: Two young patients, a 22-year-old female and a 23-year-old male, who had acute vision loss were diagnosed with nonischemic CRVO via fluorescein angiography. They had no other disease and no common risk factors for CRVO. We performed various tests to determine the thrombophilic risk factors and discovered a transient decrease in protein S antigen and protein C antigen in the female and male patients, respectively. CONCLUSIONS: CRVO in young patients without systemic disorders may have different mechanisms in the pathology and thus additional laboratory tests to determine thrombophilic disorders are necessary.

Trombosis en el recién nacido / Thrombosis in newborn infants

La probabilidad de padecer trombosis es mucho mayor en el período neonatal que en cualquier otra etapa pediátrica. La labilidad del particular sistema hemostático del neonato, sumada a los múltiples factores de riesgo a que está expuesto y la presencia casi constante de catéteres, son responsables de este hecho. Las trombosis venosas son más frecuentes que las arteriales y ocurren principalmente en los miembros, la aurícula derecha y las venas renales. El accidente cerebrovascular puede ser causado por la oclusión del flujo arterial que llega al cerebro o del sistema de drenaje venoso de este. La púrpura fulminans es una patología de altísima gravedad, que debe ser considerada una emergencia médica y se debe a la deficiencia grave de proteína C o, menos frecuentemente, de proteína S o antitrombina. La mayoría de los episodios trombóticos tienen indicación de tratamiento anticoagulante, que se puede realizar con heparina no fraccionada y/o con heparina de bajo peso molecular. La púrpura fulminans requiere terapia de sustitución con proteína C y/o plasma fresco. El tratamiento trombolítico se realiza con activador tisular del plasminógeno y debe quedar reservado solo para aquellas trombosis cuya localización implique compromiso de vida o pérdida de un órgano o de un miembro.

The incidence of thrombosis is higher among newborn infants than in any other stage of pediatric development. This fact is the consequence of labile characteristics of the neonatal hemostatic system, in addition to exposure to multiple risk factors and the wide use of vascular catheters. Venous thromboses, which mainly affect the limbs, the right atrium and renal veins, are more frequently seen than arterial thromboses. A stroke may be caused by the occlusion of the arterial flow entering the brain or by occlusion of its venous drainage system. Purpura fulminans is a very severe condition that should be treated as a medical emergency, and is secondary to severe protein C deficiency or, less frequently, protein S or antithrombin deficiency. Most thrombotic events should be managed with antithrombotic therapy, which is done with unfractionated and/or low molecular weight heparins. Purpura fulminans requires protein C replacement and/or fresh frozen plasma infusion. Thrombolytic therapy is done using tissue plasminogen activator and should only be used for life-, or limb-, or organ-threatening thrombosis.

Deficiencia congénita de proteína C en un recién nacido con trombosis y necrosis de tejidos extensa / Congenital C protein deficiency in a newborn with extensive thrombosis and necrosis of tissues

Uno de los trastornos hematológicos más graves del período neonatal es la deficiencia congénita de proteína C, de presentación muy rara, y causa de enfermedad tromboembólica severa y púrpura fulminante en recién nacidos. Se puede sintetizar como una entidad clínico-patológica, de aparición aguda, con trombosis de la vasculatura de la dermis, lo cual conduce a necrosis hemorrágica y progresiva de la piel, asociada a coagulación intravascular diseminada y hemorragia perivascular, que ocurre en el período neonatal. El paciente presentado exhibe los elementos clínico-patológicos que caracterizan la púrpura fulminante, cuyo origen se debe a una deficiencia hereditaria de proteína C, lo cual condujo a la aparición de complicaciones trombóticas severas(AU)

One of the most serious hematological disorders of the neonatal period is congenital C protein deficiency of very rare occurrence and the main cause of severe thromboembolic disease and purpura fulminans in newborns. It may be summarized as a clinical and pathological entity of acute occurrence, with dermis vasculature thrombosis that leads to progressive hemorrhagic necrosis of the skin, associated to disseminate intravascular coagulation and perivascular hemorrhage in the neonatal period. The patient of this report showed the clinical and pathological elements characterizing purpura fulminans the origin of which is due to hereditary C protein deficiency that led to onset of severe thrombotic complications in this patient(AU)

A Case of Cerebral Venous Thrombosis in a Patient with Graves' Disease / 고신대학교의과대학학술지

Superior sagittal sinus thrombosis is an uncommon disease, and 25% of cases are considered to be idiopathic. Hypercoagulability, local bloodstream stasis, and vessel wall abnormalities may contribute to the development of this condition. The thyrotoxic phase of Graves’ disease is associated with venous thrombosis caused by hypercoagulability, which is in turn induced by increased levels of homocysteine and factor VIII and decreased fibrinolytic activity. Here, we report the case of a 39-year-old male who presented with superior sagittal sinus thrombosis and concomitant hyperthyroidism.

Diagnosis of Severe Protein C Deficiency Confirmed by Presence of Rare PROC Gene Mutation

Protein C (PROC) deficiency is caused by mutations in the PROC gene on chromosome 2q14.3. Patients with PROC deficiency typically present distinguished purpura, intracerebral and intravascular coagulopathy, and ophthalmologic complications. Here, we report a rare severe form of PROC deficiency resulting from a compound heterozygosity in PROC. The patient was a 5-day-old female neonate born at 39 weeks of gestation with a birth weight of 2,960 g. She was transferred to our hospital with running a fever at 38.5℃ and with dark red patches on her feet. At admission, a complete blood count showed no specific findings, but levels of PROC and protein S were abnormally low (1% and 68%, respectively). Magnetic resonance imaging revealed intracerebral hemorrhaging and parenchymal damage with dysplasia of the brain. Ophthalmologic examination revealed vitreous hemorrhaging with retinal detachment. Genetic testing revealed a missense mutation (Arg211Trp) and a frameshift mutation (Gly239Serfs*8) in PROC, inherited from the father and mother, respectively. The patient recovered from purpura after undergoing ventriculoperitoneal shunting and treatment with fresh frozen plasma, warfarin sodium, and PROC concentrate. This is the first report of severe neonatal PROC deficiency with purpura fulminans, vitreous hemorrhage, and intracerebral hemorrhage confirmed via PROC genetic testing, which identified a rare compound heterozygosity of PROC.

Thrombophilia in Korean patients with arterial or venous thromboembolisms

PURPOSE: To determine the prevalence of thrombophilia in Korean patients with an arterial thromboembolism (ATE) or a venous thromboembolism (VTE), and to evaluate the characteristic of VTE in patients with thrombophilia. METHODS: Hospital records of 294 patients (228 with VTE, 66 with ATE) including two foreign ones (mean age, 51.4 years) who underwent thrombophilia testing between August 2006 and March 2015 were reviewed retrospectively. In general, such screening was performed according to the guidelines of the international consensus statement for VTE. Thrombophilia testing included evaluations of the factor V Leiden and prothrombin G20210A mutations, levels of proteins C and S and antithrombin, and antiphospholipid antibody syndrome (APLS). RESULTS: A factor V Leiden mutation was not found in the 292 Korean patients. A prothrombin G21210A mutation was investigated in 33 patients but none was found. Among 226 Korean patients with VTE, 130 demonstrated no thrombophilia and 55 patients did after exclusion of 41 patients without confirmatory test. The most common form was protein S deficiency (31 of 55, 56%) followed by protein C deficiency, antithrombin deficiency, and APLS. When comparing patients with a VTE or deep vein thrombosis (DVT) according to the presence of thrombophilia, thrombophilia was associated with younger age (P = 0.001 for VTE; P < 0.001 for DVT) and a family history (P < 0.001 for VTE and DVT). CONCLUSION: We did not find any factor V Leiden mutation in Korean subjects at high risk for thrombophilia. Therefore, this testing is not warranted. Thrombophilia was associated with VTE in younger age and a family history.

Unexpected Multiple Organ Infarctions in a Poisoned Patient / 대한중환자의학회지

Predisposing factors for venous thrombosis can be identified in the majority of patients with established venous thromboembolism (VTE). However, an obvious precipitant may not be identified during the initial evaluation of such patients. In the present case, a 47-year-old female presented to the emergency department of our hospital after ingesting multiple drugs. She had no VTE-related risk factors or previous episodes, nor any family history of VTE. After admission to the intensive care unit sudden hypoxemia developed, and during the evaluation cerebral, renal, and splenic infarctions with pulmonary embolisms were diagnosed. However, the sources of the emboli could not be identified by transthoracic echocardiography or computed tomography angiography. Protein C deficiency was identified several days later. We recommend that hypercoagulable states be taken into consideration, especially when unexplained thromboembolic events develop in multiple or unusual venous sites.

Unexpected Multiple Organ Infarctions in a Poisoned Patient / 대한구급학회지

Predisposing factors for venous thrombosis can be identified in the majority of patients with established venous thromboembolism (VTE). However, an obvious precipitant may not be identified during the initial evaluation of such patients. In the present case, a 47-year-old female presented to the emergency department of our hospital after ingesting multiple drugs. She had no VTE-related risk factors or previous episodes, nor any family history of VTE. After admission to the intensive care unit sudden hypoxemia developed, and during the evaluation cerebral, renal, and splenic infarctions with pulmonary embolisms were diagnosed. However, the sources of the emboli could not be identified by transthoracic echocardiography or computed tomography angiography. Protein C deficiency was identified several days later. We recommend that hypercoagulable states be taken into consideration, especially when unexplained thromboembolic events develop in multiple or unusual venous sites.

High prevalence of protein C, protein S, antithrombin deficiency, and factor V Leiden mutation as a cause of hereditary thrombophilia in patients of venous thromboembolism and cerebrovascular accident

To determine the frequency of Protein C, Protein S [PC and PS], antithrombin deficiency [AT III] and Factor V Leiden mutation [FVL] as a cause of thrombophilia in the patients with venous thromboembolism [VTE] and cerebrovascular accident [CVA]. It was an observational study conducted at Department of Haematology, Armed Forces Institute of Pathology [AFIP], Rawalpindi, Pakistan. All patients referred for thrombophilia screening from July 2009 to June 2012 were screened. Patients with evidence of VTE or CVA were screened for PC and PS, AT III deficiency, and FVL. Total 404 patients of age between 1-71 years mean 33 +/- 14 with male to female ratio of 2.4:1 had evidence of thrombophilia. Two hundred eighteen [54%] patients presented with CVA, 116 [29%] with deep vein thrombosis [DVT], 42 [10.5%] with pulmonary embolism [PE], and 28 [7.5%] with portal or mesenteric vein thrombosis [PV]. Protein C and S deficiency was detected in 35/404 [8.7%], AT III in 9/404 [2%], and FVL in 25/173 patients [14.5%]. The findings were suggestive of a significant association of FVL mutation for developing DVT [OR=11.0, 95% C I 4.6-26.3], CVA [OR=5.7, 95% C I 2.1-15.1], and PV [OR=5.4, 95% C I 1.3-21.9]. PC and PS deficiency was a significant risk factor for developing PE [OR=3, 95% C I 0.8-11.4]. FVL mutation and Protein C and S are the leading causes of thrombophilia with strong association of Factor V Leiden mutation as risk for developing DVT

Deficiencia de proteínas C y S: marcadores de riesgo trombótico / Deficiency of proteins C and S: trombotic risk markers

Desde hace varios siglos se conoce que los defectos de la coagulación causan enfermedades hemorrágicas, pero el estudio de su contraparte, las enfermedades trombóticas, se ha desarrollado con mayor profundidad hace solo algunas décadas. Son estos trastornos del sistema de la coagulación los que constituyen una de las causas más comunes de muerte en el mundo de hoy donde cada año mueren alrededor de 2 millones de personas por trombosis, ya sea arterial o venosa. Además, se consideran una fuente importante de morbilidad en las personas que las padecen y sobreviven. Los estados de hipercoagulabilidad o trombofilias son condiciones clínicas que afectan a una serie de pacientes con tendencia anormal a presentar eventos trombóticos. La deficiencia de proteína C (PC) y proteína S (PS) constituyen causas de trombofilias congénitas o adquiridas que predisponen a la aparición de trastornos tromboembólicos, pérdidas recurrentes de embarazos, trombosis venosas recurrentes, entre otros. Su diagnóstico es de gran importancia porque permite realizar profilaxis para evitar el riesgo de recurrencia e informa sobre la posibilidad de un estado de portador en cualquier otro miembro de la familia

For several centuries it has been known that coagulation defects cause hemorrhagic disease, but the study of its counterpart, thrombotic diseases, has been developed in more depth just a few decades ago. These disorders of coagulation system are one of the most common causes of death in the world today, where about two million people die every year from thrombosis, either arterial or venous. They are also considered an important source of morbidity in people who suffer it and survive. Hypercoagulable state or thrombophilia are clinical conditions that affect a number of patients with abnormal tendency to thrombotic events. Deficiency of protein C (PC) and protein S (PS) are causes of congenital or acquired thrombophilias that predispose to thromboembolic disorders, recurrent pregnancy loss, recurrent venous thrombosis, among others. Its diagnosis is very important it provides tools for its prophylaxis in order to reduce the risk of recurrence and the possibility of identify a carrier state in any other family member

Déficit de proteína C en un paciente con coagulación intravascular diseminada asociada a sepsis y trombosis venosa profunda: Case report / Protein C deficiency in patient with sepsis-associated disseminated intravascular coagulation and deep vein thrombosis

La coagulación intravascular diseminada es un síndrome clinicopatológico que complica a varias enfermedades graves; la sepsis es la causa más común en los pacientes pediátricos. Resulta de una anormal activación del sistema de coagulación, que conduce a la formación de trombos en la microcirculación, y al consumo de plaquetas y factores de la coagulación. Los hallazgos clínicos son variables; las hemorragias son la presentación más frecuente, seguidas de la púrpura y la gangrena de las extremidades (púrpura fulminante). Se presenta el caso de un paciente con coagulación intravascular diseminada asociada a sepsis, con trombosis venosa profunda concomitante. Los estudios permitieron diagnosticar una trombofilia hereditaria asociada a déficit hereditario de proteína C.

Disseminate intravascular coagulation (DIC) is a clinical pathological syndrome associated to several diseases. Sepsis is the most common cause in infants and children. DIC results from the anomalous activation of blood coagulation, widespread formation of thrombi in the microcirculation, and consumption of clotting factors and platelets. Clinical findings are variable; the most common is bleeding, followed by purpura and acral gangrene (purpura fulminans). We report a patient with sepsis associated-DIC and concurrent deep venous thrombosis. The diagnostic evaluation allowed to discover inherited thrombophilia associated to protein C deficiency.

Analysis of a hereditary protein C deficient consanguineous pedigree caused by Phe139Val homozygous mutation / 中华血液学杂志

<p><b>OBJECTIVE</b>To analyze genetic mutation and explore its molecular pathogenesis for an hereditary protein C (PC) deficient consanguineous pedigree.</p><p><b>METHODS</b>The pedigree included three generations and contained eight members. PC activity (PC:A), PC antigen (PC:Ag) and other coagulant parameters were detected for all family members. Protein C gene (PROC) include all the exons and intron exon boundaries were amplified by PCR for the proband, then analyzed by direct sequencing. Mutation sites were detected for the other family members.</p><p><b>RESULTS</b>The PC:A and PC:Ag in the proband plasma were 20% (normal range 70% -140%) and 13.2% (normal range 70%-130%). A homozygous missense mutation g.6128T>G in exon 7 resulting in Phe139Val was identified in the proband. The PC:A and PC:Ag in her younger brother were 31% and 18.90%, Phe139Val homozygous was also found. The left family members were heterozygous for Phe139Val.</p><p><b>CONCLUSION</b>Phe139Val homozygous missense mutation in exon 7 of PROC caused serious hereditary protein C deficiency. We speculated that homozygous mutation might be resulted from this consanguineous marriage.</p>