Liver transplantation for congenital protein C deficiency with initial poor graft function: a case report with literature review.

Congenital deficiency of protein C (PC) is a rare disease that causes thrombophilia during the neonatal and infantile periods. Despite anticoagulative treatments, purpura fulminans and major vessel thrombosis often occur. We report a 7-year-old girl with congenital PC deficiency who underwent deceased donor liver transplantation (LT) and experienced complications accompanied by initial poor graft function (IPGF). Before LT, she had cerebral and ophthalmic hemorrhage, and seven episodes of purpura fulminans. The operation was successfully performed; however, the liver graft developed IPGF. Hyperammonemia and coagulopathy required continuous hemodiafiltration and infusion of fresh frozen plasma. It took 22 days for PC activity to reach reference levels. The changes in clotting and anticlotting activities in the patient's plasma were revealed using clot waveform analysis and the HemosIL ThromboPath® assay. PC activity remained normal for 5 years after LT. Even when IPGF occurs, liver function including PC activity can remain normal for a long time after recovery from IPGF. LT can be a curative treatment for congenital PC deficiency.

Protein C Deficiency.

Protein C (PC) deficiency is a heritable or acquired risk factor for thrombophilia, with presentations varying from asymptomatic to venous thromboembolism to neonatal purpura fulminans, a life-threatening disorder. Hereditary PC deficiency is caused by mutation in the PC (PROC) gene located on chromosome 2q14.3. Heterozygous and acquired PC deficiencies are more common than homozygous deficiency. The recommended initial laboratory test measures PC activity using either clot-based or chromogenic methods. There are numerous potential interferences in PC activity testing that may result in either false-positive (falsely low activity) or false-negative (falsely normal or elevated activity) results. In the present review, we discuss common clinical presentations; laboratory testing, with a focus on potential assay interferences; treatment options; and prognosis in patients with PC deficiency.

Cerebral Sinus Venous Thrombosis and Prothrombotic Risk Factors in Children: A Single-Center Experience From Turkey.

BACKGROUND: Cerebral sinus venous thrombosis (CSVT) is a rare cerebrovascular disease that may be life-threatening, especially in children. OBJECTIVE: The purpose of this study was to assess the clinical presentation, radiologic imaging, underlying conditions, treatment, and outcomes of children with CSVT. PATIENTS AND METHODS: In total, 23 consecutive children aged between 1 month to 18 years with CSVT, who were followed-up in Erciyes University Children's Hospital, were retrospectively enrolled in the study from January 2000 to December 2016. RESULTS: The median age of the 23 children (13 female patients, 10 male patients) at initial diagnosis was 60 months (1 to 204 mo). The most common clinical manifestation was headache/irritability (n=9). The most common site of the CSVT was the transverse sinus (n=16). The most common prothrombotic risk factor was protein C deficiency (n=4). Underlying risk factors were detected in 15 patients. Genetic risk factors such as protein C deficiency, infections, trauma, malignancies, autoimmune hemolytic anemia, neurometabolic disorders, asphyxia, and cardiac malformations were common risk factors. Six children died. Multiple sinus involvement and parenchymal hemorrhages were seen in 4 and in 3 of the 6 children who died, respectively. CONCLUSIONS: Protein C deficiency seemed to be relatively high in the presented children. Multiple sinus involvement and additional parenchymal hemorrhages represent poor prognostic features.

The prevalence and clinical manifestation of hereditary thrombophilia in Korean patients with unprovoked venous thromboembolisms.

BACKGROUND: Hereditary thrombophilia (HT) is a genetic predisposition to thrombosis. Asian mutation spectrum of HT is different from Western ones. We investigated the incidence and clinical characteristics of HT in Korean patients with unprovoked venous thromboembolism (VTE). METHODS: Among 369 consecutive patients with thromboembolic event who underwent thrombophilia tests, we enrolled 222 patients diagnosed with unprovoked VTE. The presence of HT was confirmed by DNA sequencing of the genes that cause deficits in natural anticoagulants (NAs). Median follow-up duration was 40±38 months. RESULTS: Among the 222 patients with unprovoked VTE, 66 (29.7%) demonstrated decreased NA level, and 33 (14.9%) were finally confirmed to have HT in a genetic molecular test. Antithrombin III deficiency (6.3%) was most frequently detected, followed by protein C deficiency (5.4%), protein S deficiency (1.8%), and dysplasminogenemia (1.4%). The HT group was significantly younger (37 [32-50] vs. 52 [43-65] years; P < 0.001) and had a higher proportion of male (69.7% vs. 47%; P = 0.013), more previous VTE events (57.6% vs. 31.7%; P = 0.004), and a greater family history of VTE (43.8% vs. 1.9%; P < 0.001) than the non-HT group. Age <45 years and a family history of VTE were independent predictors for unprovoked VTE with HT (odds ratio, 9.435 [2.45-36.35]; P = 0.001 and 92.667 [14.95-574.29]; P < 0.001). CONCLUSIONS: About 15% of patients with unprovoked VTE had HT. A positive family history of VTE and age <45 years were independent predictors for unprovoked VTE caused by HT.

Disseminated intravascular coagulation.

Disseminated intravascular coagulation (DIC) is an acquired syndrome characterized by widespread intravascular activation of coagulation that can be caused by infectious insults (such as sepsis) and non-infectious insults (such as trauma). The main pathophysiological mechanisms of DIC are inflammatory cytokine-initiated activation of tissue factor-dependent coagulation, insufficient control of anticoagulant pathways and plasminogen activator inhibitor 1-mediated suppression of fibrinolysis. Together, these changes give rise to endothelial dysfunction and microvascular thrombosis, which can cause organ dysfunction and seriously affect patient prognosis. Recent observations have pointed to an important role for extracellular DNA and DNA-binding proteins, such as histones, in the pathogenesis of DIC. The International Society on Thrombosis and Haemostasis (ISTH) established a DIC diagnostic scoring system consisting of global haemostatic test parameters. This scoring system has now been well validated in diverse clinical settings. The theoretical cornerstone of DIC management is the specific and vigorous treatment of the underlying conditions, and DIC should be simultaneously managed to improve patient outcomes. The ISTH guidance for the treatment of DIC recommends treatment strategies that are based on current evidence. In this Primer, we provide an updated overview of the pathophysiology, diagnosis and management of DIC and discuss the future directions of basic and clinical research in this field.

Fetal hydrocephalus and neonatal stroke as the first presentation of protein C deficiency.

Severe protein C-deficiency is a rare heritable thrombophilia of the newborn. Infants with biallelic PROC mutations present purpura fulminans and intracranial thromboembolism, while the prenatal onset of mutated heterozygotes remains unclear. We herewith present the first case of fetal ventriculomegaly and neonatal stroke associated with heterozygous PROC mutation. The infant was born to a healthy mother at 38 gestational weeks. The fetal growth had been normal, but the routine ultrasound screening had indicated mild hydrocephalus at 28 weeks of gestation. He developed convulsions two days after birth. Computed tomography of the brain revealed multiple hemorrhagic infarctions and ventriculomegaly. Dissociated levels of the plasma activity between protein C (21%) and protein S (42%) reached to determine the heterozygote of PROC c.574_576delAAG, a common thrombophilic predisposition in Asian ancestries. PC-mutant heterozygotes may have a limited high risk of cerebral thromboembolism during the perinatal course.

Neonatal asphyxia and renal failure as the presentation of non-inherited protein C deficiency.

Inherited or acquired protein C (PC) deficiency leads to thromboembolic events. Plasma PC activity in infancy is physiologically lower than in adults. We describe a case of neonatal asphyxia and acute renal failure associated with isolated PC deficiency. A full-term male infant was born to a healthy mother by caesarean section because of fetal distress. The small-for-gestational age infant showed 2 and 7 of Apgar scores at 1 and 5 minutes, respectively. Hypercoagulability required repeated infusions of fresh frozen plasma. Coagulation study revealed PC activity, 6%, protein S activity, 61%, and high D-dimer levels, along with normal factor VII activity and absent vitamin K deficiency. Anticoagulant and activated PC therapy improved coagulopathy and nephropathy. Imaging analyses indicated no visceral infarctions. Renal function and PC activity have been slowly normalized until 6 months of age. He had no PROC mutation or PC-deficient parents. Selective PC deficiency may occur as an acquired cause of hypercoagulable crisis in the stressed newborn.

Severe protein C deficiency is associated with organ dysfunction in patients with severe sepsis.

PURPOSE: The aim of this study was to assess the relationship between protein C levels and temporal changes in organ dysfunction. MATERIALS AND METHODS: Using data from the placebo arm of Recombinant Human Activated PROtein C Worldwide Evaluation in Severe Sepsis trial (N = 775), we compared the development of organ dysfunction over time, in adult severe sepsis patients with and without severe protein C deficiency. RESULTS: At study enrollment (baseline), patients with and without severe protein C deficiency were similar in age and likelihood of comorbidities. Patients with severe protein C deficiency had lower arterial blood pressure (P = .0006), greater serum creatinine concentration (P < .0001), elevated markers of thrombosis and inflammation, and impairment of fibrinolysis (P < .0001). The baseline PaO(2)/FiO(2) ratio was not significantly different between the 2 groups. Seven days after study enrollment, cardiovascular and renal function remained significantly worse in patients with severe protein C deficiency (P < .0001), and respiratory dysfunction was greater (P < .0001). Baseline protein C deficiency was seen to be associated with subsequent pulmonary, renal, and hematologic organ failure. CONCLUSIONS: Severe protein C deficiency in patients with severe sepsis is associated with both the incidence and severity of organ dysfunction and subsequent worsening of organ function and may be a useful predictor of organ failure in severe sepsis.

Protein C deficiency: a case review.

Protein C (PC) deficiency is a rare but life-threatening bleeding disorder that can present in the immediate neonatal period. This article presents the case of a baby girl with acute and progressive neonatal purpura fulminans as the presenting feature of PC deficiency. Other common complications of this disease include ophthalmic problems and central nervous system (CNS) changes. Management consists of correcting the coagulopathy, intensive wound care including negative-pressure dressings and skin grafting, and supportive care for the ophthalmic and CNS issues. Long-term follow-up consists of lifelong anticoagulant therapy to avoid recurrence of these complications.

Genome scan of clot lysis time and its association with thrombosis in a protein C-deficient kindred.

BACKGROUND: Previously, we found increased clot-lysis time (CLT), as measured with a plasma-based assay, to increase the risk of venous thrombosis in two population-based case-control studies. The genes influencing CLT are as yet unknown. PATIENTS/METHODS: We tested CLT as risk factor for venous thrombosis in Kindred Vermont II (n = 346), a pedigree suffering from a high thrombosis risk, partially attributable to a type I protein C deficiency. Furthermore, we tested for quantitative trait loci (QTLs) for CLT, using variance component linkage analysis. RESULTS: Protein C-deficient family members had shorter CLTs than non-deficient members (median CLT 67 min vs. 75 min). One standard deviation increase in CLT increased the risk of venous thrombosis 2.4-fold in non-deficient family members. Protein C deficiency without elevated CLT increased the risk 6.9-fold. Combining both risk factors yielded a 27.8-fold increased risk. The heritability of CLT was 42-52%. We found suggestive evidence of linkage on chromosome 11 (62 cM), partly explained by the prothrombin 20210A mutation, and on chromosome 13 (52 cM). Thrombin-activatable fibrinolysis inhibitor genotypes did not explain the variation in CLT. CONCLUSION: Hypofibrinolysis appears to increase thrombosis risk in this family, especially in combination with protein C deficiency. Protein C deficiency is associated with short CLT. CLT is partly genetically regulated. Suggestive QTLs were found on chromosomes 11 and 13.

Protein C and protein S deficiencies: similarities and differences between two brothers playing in the same game.

Protein C (PC) and protein S (PS) are vitamin K-dependent glycoproteins that play an important role in the regulation of blood coagulation as natural anticoagulants. PC is activated by thrombin and the resulting activated PC (APC) inactivates membrane-bound activated factor VIII and factor V. The free form of PS is an important cofactor of APC. Deficiencies in these proteins lead to an increased risk of venous thromboembolism; a few reports have also associated these deficiencies with arterial diseases. The degree of risk and the prevalence of PC and PS deficiency among patients with thrombosis and in those in the general population have been examined by several population studies with conflicting results, primarily due to methodological variability. The molecular genetic background of PC and PS deficiencies is heterogeneous. Most of the mutations cause type I deficiency (quantitative disorder). Type II deficiency (dysfunctional molecule) is diagnosed in approximately 5%-15% of cases. The diagnosis of PC and PS deficiencies is challenging; functional tests are influenced by several pre-analytical and analytical factors, and the diagnosis using molecular genetics also has special difficulties. Large gene segment deletions often remain undetected by DNA sequencing methods. The presence of the PS pseudogene makes genetic diagnosis even more complicated.

Trombosis de la arteria cerebral media en un neonato afectado de déficit de proteína C / Perinatal stroke associated with protein-C deficiency

Los accidentes cerebrovasculares (ACV) son una causa frecuente de mortalidad y morbilidad neurológica crónica en niños. El ACV perinatal se define como aquel que ocurre entre la semana 28 de gestación y los 28 días de vida. Se suele manifestar en forma de convulsiones en las primeras semanas de vida, aunque puede permanecer asintomático hasta meses después del parto, cuando aparecen alteraciones en la lateralidad de la función motora fina, fallo al alcanzar los hitos del desarrollo o convulsiones. Gracias a la mejora de los métodos diagnósticos de imagen, esta patología se ha incluido como diagnóstico diferencial en los recién nacidos con sintomatología neurológica. Los obstetras se encargan del seguimiento de los embarazos de alto riesgo trombótico, pero rara vez tienen en cuenta el efecto de este riesgo en el feto o en el recién nacido. Se presenta un caso de ACV perinatal asociado a déficit de proteína C (AU)

Stroke is an important cause of mortality and chronic neurological morbidity in children. Perinatal stroke has been defined as a cerebrovascular event occurring between 28 weeks of fetal life and the 28th postnatal day. The most common manifestation of stroke is neonatal seizures but this entity may also be asymptomatic until months after birth when asymmetry of reach and grasp, failure to reach developmental milestones, or postnatal seizures can develop. Improvements in neuroimaging and its availability have increased the diagnosis and awareness of perinatal stroke in newborns and infants with neurological symptoms. Obstetricians are responsible for monitoring pregnancies at high thromboembolic risk, but rarely consider the effect this has on the fetus or newborn. We present the case of a newborn with perinatal stroke associated with protein-C deficiency (AU)

A neonate with homozygous protein C deficiency with a homozygous Arg178Trp mutation.

Homozygous protein C deficiency affects approximately 1/400,000 to 1/1,000,000 live births. Homozygous protein C deficiency is associated with catastrophic and fatal purpura fulminans-like or thrombotic complications and disseminated intravascular coagulation. In the present patient, genetic study revealed Arg178Trp, a mutation found widely in European population; but this is the first case of homozygous Arg178Trp mutation who suffered from catastrophic purpura fulminans phenotype.

Human protein C concentrates for replacement therapy in congenital and acquired protein C deficiency.

The protein C pathway has an important function in regulating and modulating blood coagulation and ensuring patency of the microcirculation. Protein C deficiency leads to macro- or microvascular thrombosis. Hereditary severe protein C deficiency is a life-threatening state with neonatal purpura fulminans. Patients with heterozygous protein C deficiency have an increased risk for thromboembolic events or coumarin-induced skin necrosis. Secondary protein C deficiency occurs during disseminated intravascular coagulation (DIC), sepsis (especially meningococcal sepsis with purpura fulminans), liver failure and vitamin K deficiency. Replacement with protein C concentrates is an established treatment for congenital protein C deficiency. The high-purity, plasma-derived protein C concentrate Ceprotin (Baxter AG, Vienna, Austria) is approved for this indication, but its use in acquired deficiency states is not approved. Several case series demonstrated beneficial effects in infectious purpura fulminans and DIC, but no controlled studies for these indications exist. Protein C concentrate may therefore be given off-label in such cases. Protein C concentrate has an excellent safety profile: no drug interactions, overdose or bloodborne infections, bleeding or prothrombotic complications have been observed. As with all protein preparations, a potential risk of hypersensitivity reactions exists.

[Hemostatic disorders in liver disease]. / Anomaliile hemostazei in suferintele hepatice.

Hemorrhagic complications are common in patients with liver diseases and contribute to the morbidity and mortality associated to this condition. The liver plays a central role in the hemostatic process as here all clotting factors and their inhibitors are synthetized. Liver damage is commonly associated with variable impairment of hemostasis due to multiple causes: decreased synthesis of clotting and inhibitor factors, decreased clearance of activated factors, hyperfibrinolysis, accelerated intravascular coagulation, quantitative and qualitative platelet defects. Their clinical implications remain to be elucidated, so further studies addressing this issue are needed.

Protein C deficiency.

Severe protein C deficiency (i.e. protein C activity <1 IU dL(-1)) is a rare autosomal recessive disorder that usually presents in the neonatal period with purpura fulminans (PF) and severe disseminated intravascular coagulation (DIC), often with concomitant venous thromboembolism (VTE). Recurrent thrombotic episodes (PF, DIC, or VTE) are common. Homozygotes and compound heterozygotes often possess a similar phenotype of severe protein C deficiency. Mild (i.e. simple heterozygous) protein C deficiency, by contrast, is often asymptomatic but may involve recurrent VTE episodes, most often triggered by clinical risk factors. The coagulopathy in protein C deficiency is caused by impaired inactivation of factors Va and VIIIa by activated protein C after the propagation phase of coagulation activation. Mutational analysis of symptomatic patients shows a wide range of genetic mutations. Management of acute thrombotic events in severe protein C deficiency typically requires replacement with protein C concentrate while maintaining therapeutic anticoagulation; protein C replacement is also used for prevention of these complications around surgery. Long-term management in severe protein C deficiency involves anticoagulation with or without a protein C replacement regimen. Although many patients with severe protein C deficiency are born with evidence of in utero thrombosis and experience multiple further events, intensive treatment and monitoring can enable these individuals to thrive. Further research is needed to better delineate optimal preventive and therapeutic strategies.

[The numerous properties of the anticoagulant protein C]. / La proteina C anticoagulante ed i suoi molteplici ruoli.

The systemic inflammation associated to the simultaneous activation of blood coagulation and the alterated blood fibrinolysis, leads to microvascular endothelial injury, acute organ dysfunction and possibly death. Activated Protein C, a natural, multifunctional protein, has demonstrated antithrombotic, anti-inflammatory, and profibrinolitic properties and may be an important modulator of the vicious cycle whereby inflammation initiates coagulation and coagulation amplifies inflammation. Protein C couples with its receptor, EPCR (endothelial-cell protein-C receptor), and the ligand-receptor complex then interact with thrombin-thrombomodulin on endothelial surface to produce activated protein C (APC). Once activated, protein C then interact with its cofactor, protein S, to catalyze the inactivation of factors Va and VIIILa, two important accelerators of the clotting cascade, reducing thrombin generation and microvascular thrombosis. In addiction to its anticoagulant activity APC promotes profibrinolytic activity through the inhibition of plasminogen activator inhibitor-1, which is upregulated during inflammation. Inhibition of thrombin generation by APC decreases inflammation by inhibiting platelet activation, neutrophil recruitment, and mast-cell degranulation. APC also shows direct antiinflammatory properties, including blocking of cytokines production by monocytes and blocking cell adhesion. Moreover, APC has antiapoptotic properties that may contribute to its efficacy. In conclusion, APC, besides its physiologic role in the coagulation cascade, plays a key role in the pathophysiology of systemic inflammation justifying its potential therapeutic role in sepsis and systemic inflammatory responses.

Early experience of Budd-Chiari syndrome treatment with transjugular intrahepatic portosystemic shunt.

The Budd-Chiari syndrome is a heterogeneous group of disorders characterized by obstruction of hepatic venous outflow at any level from the small hepatic veins to the junction of the inferior vena cava with the right atrium. We present two cases of Budd- Chiari syndrome with severe ascites associated with polycythemia vera in first case and protein C deficiency in the second, in both cases transjugular intrahepatic portosystemic shunt were placed, with excellent control of symptoms, no mortality were observed, and just one episode of pulmonary venous thrombosis was observed. To our knowledge this is the first time that transjugular intrahepatic portosystemic shunt are used and reported in Budd-Chiari syndrome in Mexico.

Technique of anaesthesia in pulmonary hypertension and thrombophilia in early pregnancy.

Pulmonary hypertension in pregnancy is a rare condition but is associated with a high mortality. We report the case of a 29 year old female in early pregnancy with Protein C and S deficiency with recurrent deep venous thrombosis and pulmonary embolism and subsequent secondary pulmonary hypertension. The patient was counselled and consented for termination of pregnancy with tubal sterilization. She was administered continuous spinal anaesthesia with invasive monitoring. The successful anaesthetic management of this condition is described.