Changing Concepts of Cirrhotic Coagulopathy.

The state of clinical art of the coagulopathy of cirrhosis changed considerably over the last decade. Until 2005, cirrhosis was considered as the epitome of the hemorrhagic coagulopathies and the abnormal hemostasis tests associated with the disease were corrected with infusion of fresh frozen plasma or platelets to minimize the risk of bleeding. Since that time, a great deal of work has been done and there is now a change of paradigm. The prothrombin time once considered as an isolated measure of bleeding risk was rejected, and cirrhosis shifted from a purely hemorrhagic construct to a mixed and thrombosis-prone paradigm. In this article we examine the interesting history of how these conceptual changes came about.

Low levels of plasma protein S, protein C and coagulation factor XII during early pregnancy and adverse pregnancy outcome.

It was the study objective to evaluate whether low levels of plasma protein S (PS) activity, free PS, protein C (PC) activity and coagulation factor XII (FXII) during early pregnancy are related to adverse pregnancy outcomes. Peripheral blood samples were obtained at 8-14 gestational weeks (GW) from a consecutive series of 1,220 women. The levels of plasma PS activity, free PS, PC activity, and FXII were measured. Cut-off values were defined as < 1st, < 5th, and < 10th percentiles of values obtained from 933 women whose pregnancies ended in normal deliveries without complications. PS activity of < 10th percentile yielded risks of pregnancy-induced hypertension (PIH) and severe PIH, while free PS level of < 5th percentile yielded a risk of pre-eclampsia. FXII level of < 1st percentile yielded a risk of premature delivery (PD) at < 34 GW. None was associated with PD at < 37 GW, fetal growth restriction or fetal loss. A multivariate analysis demonstrated that PS activity of < 10th percentile (odds ratio 5.9, 95 % confidence interval 1.7-18.1) and body mass index (BMI) ≥ 25 kg/m² (4.3, 1.1-13.3) were independent risk factors for severe PIH. Similarly, free PS level of < 5th percentile (4.4, 1.0-14.3) and BMI ≥ 25 kg/m² (4.0, 1.3-10.9) were independent risk factors for pre-eclampsia. In conclusion, women with low levels of plasma PS activity and free PS during early pregnancy might have increased risks of PIH, severe PIH or pre-eclampsia. Women with low FXII level might have an increased risk of PD at < 34 GW.

Sepsis Causing Acquired Protein C and Protein S Deficiency.

Warfarin Induced Skin Necrosis is a well-known and dreaded complication in patients who is being started on warfarin without adequate bridging with other anticoagulants. The mechanism is thought to be due to protein C deficiency acquired after initial exposure to warfarin. We present a rather unusual cause of protein C deficiency due to sepsis resulting in warfarin induced skin necrosis. 43 year old lady who has been on chronic warfarin therapy secondary to anti phospholipid syndrome was admitted to the hospital for acute ischemic cerebellar stroke. Warfarin was held due to acute thrombocytopenia. She was discharged after restarting the warfarin. She presented back with septic shock due to pneumonia. She was found to have multiple necrotic areas consistent with skin necrosis. Unfortunately, patient died due to multi organ failure despite goal directed therapy. This case demonstrates the importance of recognizing the sepsis as an acquired cause of protein C deficiency.

[Analysis of a hereditary protein C deficient consanguineous pedigree caused by Phe139Val homozygous mutation].

OBJECTIVE: To analyze genetic mutation and explore its molecular pathogenesis for an hereditary protein C (PC) deficient consanguineous pedigree. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

[Acute illness following chicken pox: spleen infarction as a complication of varicella zoster infection]. / Acuut ziek na waterpokken: miltinfarcten als complicatie van varicella-zosterinfectie.

BACKGROUND: Varicella zoster virus (VZV) infection can cause temporary acquired protein S or C deficiency via cross reacting antibodies and consequently inducing a hypercoagulable state. CASE DESCRIPTION: A 6-year-old girl with a history of congenital cardiac disease was seen at an Emergency Department with acute chest pain, dyspnoea and fever, seven days after developing chicken pox. Diagnostic tests revealed massive infarction of the spleen, and a protein S and C deficiency. In addition, blood cultures revealed a Lancefield group A ß-haemolytic streptococcus (GABHS). The patient recovered fully after treatment with low molecular weight heparin and antibiotics. CONCLUSION: In this patient, septic emboli caused splenic infarction. Thromboembolic complications should be suspected in children with VZV who present with acute symptoms, in particular if bacterial superinfection is found.

Zymogen Protein C to prevent clotting without bleeding during invasive medical procedures.

Thrombophilic disorders that predispose patients to develop blood clots can be life-threatening and result in a large economic burden on healthcare expenditures. Venous Thromboembolism(VTE) (deep vein thrombosis and pulmonary embolism) are the third leading cause of death in the United States. Protein C deficiency is a common thrombophilic condition that affects an estimated 1 in 400 Americans. Zymogen Protein C (ZPC) is the precursor to Activated Protein C (APC), a pivotal endogenous anticoagulant in human blood. Patients with protein C deficiency who have roughly half the normal level of protein C are estimated to be at 10-fold increased risk of VTE. We describe the use of protein C concentrate (Ceprotin®, Baxter, Deerfield, IL) in a patient with protein C deficiency and with a previous pulmonary embolism who developed a life-threatening gastrointestinal bleed after polypectomy. The patient is a 75-year-old male at very high risk for deep vein thrombosis and possible lung emboli. He has heterozygous Protein C deficiency (50%) and heterozygosity for the prothrombin gene G20210A mutation. During a routine colonoscopy, a large 3 cm cecal polyp was identified and resected. Eight days post-procedure while performing abdominal exercise he developed a life-threatening GI bleed originating from the polypectomy site as his warfarin was becoming therapeutic on a Low Molecular Weight Heparin (LMWH) periprocedural bridge. The patient's warfarin was reversed with vitamin K, and LMWH and warfarin were discontinued. To prevent thrombosis, he was started on ZPC until anticoagulation could be safely restarted. During endoscopy, the bleeding site was treated with an injection of 1:10,000 dilution of epinephrine, followed by cauterization and placement of endoclips (4 metal staples). Three days after endoscopic repair LMWH was restarted with warfarin. Sixteen months post-bleed, the patient remains on life-long warfarin without further episodes of bleeding or thrombosis. Zymogen Protein C concentrate (Ceprotin®, Baxter Deerfield, IL) should be strongly considered for peri-procedural management of any patient with protein C deficiency and previous thromboembolism.

An accompanying genetic severe deficiency of tissue factor protects mice with a protein C deficiency from lethal endotoxemia.

Mice with a severe genetic deficiency of protein C (PC), PC(-/-)PC(tg4), display enhanced susceptibility to lethal effects of gram-negative endotoxemia induced by lipopolysaccharide (LPS), whereas mice severely deficient in tissue factor (TF), TF(-/-)hTF(tg), are protected from LPS-mediated lethality. In this study, we show that a simultaneous severe deficiency of TF protected low-PC mice from LPS-induced death, resulting in a survival profile similar to that experienced by wild-type (WT) mice. Plasma and whole blood coagulation assays, the latter measured by thromboelastography, demonstrated development of coagulopathies in LPS-treated mice, which were more severe in the case of the doubly deficient TF(-/-)hTF(tg)/PC(-/-)PC(tg4) mice, mainly reflecting earlier signs of disseminated intravascular coagulation in this latter cohort. Markers of inflammation were also elevated in response to LPS in both groups of mice at times just preceding death. We conclude that whereas coagulopathies are more exacerbated in LPS-treated TF(-/-)hTF(tg)/PC(-/-)PC(tg4) mice, the lowering of TF levels in mice with an accompanying severe PC deficiency confers protection against death compared with mice with a single severe PC deficiency. This suggests that proteases generated as a result of factor VIIa/TF-mediated thrombin generation play a mechanistic role in the enhanced lethality seen under very low PC conditions in an endotoxemia model in mice.

Use of protein C concentrate in neonatal period.

Levels of protein C, low at birth, physiologically Increase until six months of age and achieve the adult range after puberty. Protein C deficiency may be congenital or acquired. Severe protein C deficiency is a rare autosomal recessive disorder that usually presents in neonatal period with purpura fulminans. Acquired protein C deficiency may be caused by increased consumption (e.g., asphyxia, overt DIC, severe infection without overt DIC, acute VTE) or by decreased synthesis of the active carboxylated protein (e.g. administration of vitamin K antagonists, severe hepatic synthetic disfunction). Two different formulations of protein C are available: recombinant human activated protein C (rhAPC) and human plasma-derived viral-inactivated protein C. It is known that in septic patients replacement therapy with rhAPC reduces mortality but is associated with an increased risk of bleeding. During the neonatal period, when a higher risk of bleeding exists, the human plasma-derived viral-inactivated protein C concentrate may represent an effective therapeutic option. In fact, its administration results effective both in severe congenital and acquired forms of protein C deficiency.

Treatment of sepsis-induced acquired protein C deficiency reverses Angiotensin-converting enzyme-2 inhibition and decreases pulmonary inflammatory response.

The protein C (PC) pathway plays an important role in vascular and immune function, and acquired deficiency during sepsis is associated with increased mortality in both animal models and in clinical studies. However, the association of acquired PC deficiency with the pathophysiology of lung injury is unclear. We hypothesized that low PC induced by sepsis would associate with increased pulmonary injury and that replacement with activated protein C (APC) would reverse the activation of pathways associated with injury. Using a cecal ligation and puncture (CLP) model of polymicrobial sepsis, we examined the role of acquired PC deficiency on acute lung injury assessed by analyzing changes in pulmonary pathology, chemokine response, inducible nitric-oxide synthase (iNOS), and the angiotensin pathway. Acquired PC deficiency was strongly associated with an increase in lung inflammation and drivers of pulmonary injury, including angiotensin (Ang) II, thymus and activation-regulated chemokine, plasminogen activator inhibitor (PAI)-1, and iNOS. In contrast, the protective factor angiotensin-converting enzyme (ACE)-2 was significantly suppressed in animals with acquired PC deficiency. The endothelial protein C receptor, required for the cytoprotective signaling of APC, was significantly increased post-CLP, suggesting a compensatory up-regulation of the signaling receptor. Treatment of septic animals with APC reduced pulmonary pathology, suppressed the macrophage inflammatory protein family chemokine response, iNOS expression, and PAI-1 activity and up-regulated ACE-2 expression with concomitant reduction in AngII peptide. These data demonstrate a clear link between acquired PC deficiency and pulmonary inflammatory response in the rat sepsis model and provide support for the concept of APC as a replacement therapy in acute lung injury associated with acquired PC deficiency.

Protein-c deficiency presenting with subacute intestinal obstruction due to mesenteric vein thrombosis.

We describe a patient with protein C deficiency who presented with subacute intestinal obstruction due to ischaemic small bowel stricture. The patient also had left sided ileofemoral thrombosis. Venous thrombosis at unusual sites especially if associated with deep vein thrombosis of lower limb warrants a thorough screen for underlying thrombophilia. This, however, is a rare cause for ischaemic small bowel stricture.

Human extrahepatic portal vein obstruction correlates with decreased factor VII and protein C transcription but increased hepatocyte proliferation.

PURPOSE: A 3-year-old girl developed extrahepatic portal vein obstruction (EHPVO) after a liver transplant. She had sequelae of portal hypertension that required another transplantation. The circumstances allowed for comparison of liver-dependent coagulation factor production between the second donor liver and the explanted liver with EHPVO. METHODS: Liver samples from the explanted first graft and the second transplant were obtained. Fresh tissue was used to perform reverse transcription-polymerase chain reaction with primers against factors V, VII, as well as VIII, protein C, and paraffin-embedded sections for hepatocyte proliferation using Ki-67 antibody as well as for apoptosis using TUNEL assay. RESULTS: The transcription of factor VII and that of protein C were decreased in the explant as compared with the newly transplanted liver (factor VII, 77% of the donor; protein C, 88% of the donor). The transcription of factor V and that of factor VIII were unchanged. The explant had a greater percentage of proliferating hepatocytes than the new organ (0.85% +/- 0.75% vs 0.11% +/- 0.21%). The percentage of apoptotic cells was similar between the 2 livers (0.09% +/- 0.13% vs 0.09% +/- 0.13%). CONCLUSIONS: Idiopathic EHPVO is associated with a reduction in liver-dependent coagulation factor transcription and an increase in hepatocyte proliferation. Portal blood flow deprivation alters hepatic homeostasis and initiates mechanisms that attempt to restore liver-dependent coagulation factors.

Intestinal lymphangiectasia with protein-losing enteropathy in Waldenstrom macroglobulinemia.

Gastrointestinal complications of Waldenstrom macroglobulinemia (WM) are unusual but often treatable. We report a case of WM associated with significant gastrointestinal involvement manifest as chronic diarrhea with protein-losing enteropathy and recurrent venous thromboses. Small bowel biopsy was negative for amyloidosis but revealed intestinal lymphangiectasia with deposition of monoclonal IgM. The patient was treated with cyclophosphamide, vincristine, and prednisone with rapid and complete resolution of the peripheral edema and diarrhea. We follow the case report with a retrospective analysis of patients with WM and gastrointestinal symptoms seen at our institution, and review the available literature on this unusual association. An increased awareness of the gastrointestinal manifestations of WM may help to explain and to treat the chronic, debilitating, and potentially life-threatening symptoms in patients with this lymphoproliferative disorder.

Mesenteric vein thrombosis associated with primary cytomegalovirus infection: a case report.

In the past few years several studies have supported an interplay between cytomegalovirus infections and a prothrombotic state. We describe a case of primary cytomegalovirus infection in an immunocompetent adult that was complicated with mesenteric vein thrombosis. Transient protein C deficiency, lupus anticoagulant and activated protein C resistance were found, in combination with a heterozygous prothrombin G20210A mutation. We discuss the possible mechanisms of cytomegalovirus-related venous thrombosis.

[Mesenteric vein thrombosis and protein C and S deficiency in a patient with chronic hepatitis C on treatment with interferon and ribavirin]. / Trombosis mesentérica y déficit de proteínas C y S en un paciente con hepatitis C crónica en tratamiento con interferón y ribavirina.

We describe the case of a 67 year old male with chronic hepatitis C on treatment with pegylated interferon and ribavirin who, after two and a half months of combined treatment, presented with a picture of acute mesenteric vein thrombosis that required urgent surgery. It re-occurred several days later and was his cause of death. In the thrombophilia study carried out immediately after surgery a decrease in protein C and S was considered as a cause of hypercoagulability. Protein C and S deficiency, natural anticoagulants synthesised in the liver, in patients without hepatic disease is a known cause of mesenteric thrombosis. Its decrease has also been described in the context of chronic hepatic diseases, including C virus chronic hepatitis, although it is not known for sure if this hypercoagulability state is a primary or secondary manifestation. Chronic hepatitis C and treatment with interferon has often been associated with a procoagulant state, and on many occasions due to different factors and mechanisms.

Catastrophic antiphospholipid syndrome associated with malignancies (case report and review of the literature).

We describe a 58-year old female patient with rapid development of arterial and venous thromboembolisms, including deep vein thrombosis (DVT) in the lower limbs, recurrent cerebral infarctions and bilateral pulmonary emboli. Her laboratory data on admission showed positive anticardiolipin antibody of IgG isotype (IgG aCL) and positive anti-beta2 glycoprotein-I antibody of IgG isotype (IgG abeta2-GPI), and decreased protein C activity and protein S antigen. Systemic examinations revealed the presence of an ovarian cancer. Surgical resection was attempted, but her cancer infiltrated the pelvic wall and could not be resected. Despite treatment with unfractionated heparin followed by warfarin, she died due to recurrent episodes of cerebral infarction. This case was considered as probable catastrophic antiphospholipid syndrome (CAPS), which might be associated with ovarian cancer. Known as Trousseau's syndrome, arterial and, more commonly, venous thrombosis is a frequent complication of cancer and sometimes a harbinger of occult cancer. Our case indicates that there is an overlap between antiphospholipid syndrome (APS) and Trousseau's syndrome. It is important to bear in mind that a thrombotic event associated with cancer can be the first manifestation of CAPS.

Utilising cardiopulmonary bypass for cancer surgery. Malignancy-induced protein C deficiency and thrombophilia.

Cardiopulmonary bypass has evolved over the last 30 years. It is an important tool for the cardiac surgeon today and also has applications in non-cardiac operations such as surgery to extract tumours. Such patients undergoing surgery for cancer may be at an increased risk of a thromboembolic event post surgery, due to disturbances in the normal clotting pathway leading to hypercoagulability. One such disturbance is malignancy-induced Protein C deficiency. A deficiency of Protein C can cause hypercoagulabitity. Recent studies have examined cardiopulmonary bypass and inherited Protein C deficiency. However, surgery for cancer patients with a malignancy-induced Protein C deficiency involving cardiopulmonary bypass has not been reported. Surgery using CPB in these patients may result in increased morbidity and mortality. The objective of this article is to review the literature in order to discuss the occurrence, the aetiology and possible management of cancer patients with malignancy-induced Protein C deficiencies that require cardiopulmonary bypass for their surgery.

Infarto isquémico cerebral provocado por factor V de Leiden, esferocitosis hereditaria y tabaquismo / Ischemic cerebral infarction due to factor V Leiden, hereditary spherocytosis and smoking

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