Platelet Shp2 negatively regulates thrombus stability under high shear stress.

Essentials Shp2 negatively regulates thrombus stability under pathological shear rate. Shp2 suppresses TXA2 receptor-mediated platelet dense granule secretion. Through αIIbß3 outside-in signaling, Shp2 targets calmodulin-dependent activation of Akt. Shp2 may serve to prevent the formation of unwanted occlusive thrombi. SUMMARY: Background Perpetuation is the final phase of thrombus formation; however, its mechanisms and regulation are poorly understood. Objective To investigate the mechanism of Shp2 in platelet function and thrombosis. Methods and results We demonstrate that the platelet-expressed Src homology region 2 domain-containing protein tyrosine phosphatase Shp2 is a negative regulator of thrombus stability under high shear stress. In a ferric chloride-induced mesenteric arteriole thrombosis model, megakaryocyte/platelet-specific Shp2-deficient mice showed less thrombi shedding than wild-type mice, although their occlusion times were comparable. In accordance with this in vivo phenotype, a microfluidic whole-blood perfusion assay revealed that the thrombi formed on collagen surfaces by Shp2-deficient platelets were more stable under high shear rates than those produced by wild-type platelets. Whereas Shp2 deficiency did not alter platelet responsiveness towards thrombin, ADP and collagen stimulation, Shp2-deficient platelets showed increased dense granule secretion when stimulated by the thromboxane A2 analog U46619. Shp2 appears to act downstream of integrin αIIb ß3 outside-in signaling, inhibiting the phosphorylation of Akt (Ser473 and Thr308) and dense granule secretion. Calmodulin was also shown to bind both Shp2 and Akt, linking Shp2 to Akt activation. Conclusions Platelet Shp2 negatively regulates thrombus perpetuation under high shear stress. This signaling pathway may constitute an important mechanism for the prevention of unwanted occlusive thrombus formation, without dramatically interfering with hemostasis.

Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio Are Effective Predictors of Prognosis in Patients with Acute Mesenteric Arterial Embolism and Thrombosis.

BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been shown to be valuable prognostic markers for a variety of pathological conditions including solid tumors, sepsis, and others. However, the prognostic values of the NLR and PLR in patients with acute mesenteric arterial embolism (AMAE) and acute mesenteric arterial thrombosis (AMAT) have not been elucidated. The aim of this study was to determine the predictive value of the NLR and PLR for poor prognosis in patients with AMAE and AMAT. METHODS: A total of 137 patients with AMAE (n = 77) or AMAT (n = 60) were divided into a poor outcome group (cases of intestinal necrosis or death) and a better outcome group (cases without intestinal necrosis who survived successfully), according to prognosis. Neutrophil, platelet, and lymphocyte counts were recorded before pharmacotherapy or surgery. The NLR and PLR were calculated, and logistic regression analysis was performed to test their prognostic values. RESULTS: The cutoff values for NLR and PLR were 11.05 and 156.26, respectively. The PLR was linearly associated with the NLR (R = 0.769, P < 0.001). NLR (odds ratio [OR] = 6.835, 95% confidence interval [CI] = 2.282-20.469, P = 0.001), PLR (OR = 4.871, 95% CI = 1.627-14.587, P = 0.005), and coronary heart disease (OR = 3.388, 95% CI = 1.156-9.929, P = 0.026) were found to be independent prognostic factors for the patients. CONCLUSIONS: NLR ≥ 11.05, PLR ≥ 156.26, and coronary heart disease were shown to be risk factors for poor prognosis in patients with AMAE and AMAT. According to these factors, patients can be divided into 3 prognostic groups: good, NLR < 11.05 with PLR < 156.26; moderate, NLR < 11.05 with PLR ≥ 156.26 or NLR ≥ 11.05 with PLR < 156.26; and poor, NLR ≥ 11.05 with PLR ≥ 156.26.

Predictive Factors of Intestinal Necrosis in Acute Mesenteric Ischemia: Prospective Study from an Intestinal Stroke Center.

OBJECTIVES: To identify predictive factors for irreversible transmural intestinal necrosis (ITIN) in acute mesenteric ischemia (AMI) and establish a risk score for ITIN. METHODS: This single-center prospective cohort study was performed between 2009 and 2015 in patients with AMI. The primary outcome was the occurrence of ITIN, confirmed by specimen analysis in patients who underwent surgery. Patients who recovered from AMI with no need for intestinal resection were considered not to have ITIN. Clinical, biological and radiological data were compared in a Cox regression model. RESULTS: A total of 67 patients were included. The origin of AMI was arterial, venous, or non-occlusive in 61%, 37%, 2% of cases, respectively. Intestinal resection and ITIN concerned 42% and 34% of patients, respectively. Factors associated with ITIN in multivariate analysis were: organ failure (hazard ratio (HR): 3.1 (95% confidence interval (CI): 1.1-8.5); P=0.03), serum lactate levels >2 mmol/l (HR: 4.1 (95% CI: 1.4-11.5); P=0.01), and bowel loop dilation on computerized tomography scan (HR: 2.6 (95% CI: 1.2-5.7); P=0.02). ITIN rate increased from 3% to 38%, 89%, and 100% in patients with 0, 1, 2, and 3 factors, respectively. Area under the receiver operating characteristics curve for the diagnosis of ITIN was 0.936 (95% CI: 0.866-0.997) depending on the number of predictive factors. CONCLUSIONS: We identified three predictive factors for irreversible intestinal ischemic injury requiring resection in the setting of AMI. Close monitoring of these factors could help avoid unnecessary laparotomy, prevent resection, as well as complications due to unresected necrosis, and possibly lower the overall mortality.

Protective role of adiponectin in a rat model of intestinal ischemia reperfusion injury.

AIM: To determine the potential protective role of adiponectin in intestinal ischemia reperfusion (I/R) injury. METHODS: A rat model of intestinal I/R injury was established. The serum level of adiponectin in rats with intestinal I/R injury was determined by enzyme-linked immunosorbent assay (ELISA). The serum levels of interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α were also measured by ELISA. Apoptosis of intestinal cells was detected using the terminal deoxynucleotidyl transferase dUTP nick end labeling assay. The production of malondialdehyde (MDA) and superoxide dismutase (SOD) and villous injury scores were also measured. RESULTS: Adiponectin was downregulated in the serum of rats with intestinal I/R injury compared with sham rats. No significant changes in the expression of adiponectin receptor 1 and adiponectin receptor 2 were found between sham and I/R rats. Pre-treatment with recombinant adiponectin attenuated intestinal I/R injury. The production of pro-inflammatory cytokines, including IL-6, IL-1ß, and TNF-α, in rats with intestinal I/R injury was reduced by adiponectin pre-treatment. The production of MDA was inhibited, and the release of SOD was restored by adiponectin pre-treatment in rats with intestinal I/R injury. Adiponectin pre-treatment also inhibited cell apoptosis in these rats. Treatment with the AMP-activated protein kinase (AMPK) signaling pathway inhibitor, compound C, or the heme oxygenase 1 (HO-1) inhibitor, Snpp, attenuated the protective effects of adiponectin against intestinal I/R injury. CONCLUSION: Adiponectin exhibits protective effects against intestinal I/R injury, which may involve the AMPK/HO-1 pathway.

Protective effects of osthole on intestinal ischemia-reperfusion injury in mice.

OBJECTIVES: The purpose of this study was to evaluate the effect of intravenous injection of osthole on intestinal ischemia-reperfusion injury and parameters of oxidative stress. MATERIALS AND METHODS: In 45 Kunming male mice, treatment included sham surgery (15 mice); intestinal ischemia-reperfusion injury (clamping of the superior mesenteric artery, 2 h; clamp release, 1 h; 15 mice); or osthole treatment before and after ischemia-reperfusion injury (15 mice). Evaluation included histopathology, determination of intestinal wet/dry weight ratio, and measurement of levels of diamine oxidase, superoxide dismutase, malondialdehyde, interleukin 1ß, tumor necrosis factor α, and interleukin 2. Intestinal barrier permeability was evaluated with Evans blue test. RESULTS: The mean wet-to-dry weight ratio, Evans blue content, and Chiu score were significantly greater in the ischemia-reperfusion than in the sham group and lower in the osthole-treated than the ischemia-reperfusion group. The mean serum diamine oxidase, malondialdehyde, interleukin 1ß, and tumor necrosis factor α levels were significantly greater in the ischemia-reperfusion than in the sham group and lower in the osthole-treated than in the ischemia-reperfusion group. The mean superoxide dismutase activity and interleukin 2 levels were lower in the ischemia-reperfusion than in the sham group and greater in the osthole-treated than in the ischemia-reperfusion group. CONCLUSIONS: Treatment with osthole may protect against oxidative stress and tissue damage from intestinal ischemia-reperfusion injury.

Bone-marrow mesenchymal stem cells reduce rat intestinal ischemia-reperfusion injury, ZO-1 downregulation and tight junction disruption via a TNF-α-regulated mechanism.

AIM: To investigate the effect of bone-marrow mesenchymal stem cells (BM MSCs) on the intestinal mucosa barrier in ischemia/reperfusion (I/R) injury. METHODS: BM MSCs were isolated from male Sprague-Dawley rats by density gradient centrifugation, cultured, and analyzed by flow cytometry. I/R injury was induced by occlusion of the superior mesenteric artery for 30 min. Rats were treated with saline, BM MSCs (via intramucosal injection) or tumor necrosis factor (TNF)-α blocking antibodies (via the tail vein). I/R injury was assessed using transmission electron microscopy, hematoxylin and eosin (HE) staining, immunohistochemistry, western blotting and enzyme linked immunosorbent assay. RESULTS: Intestinal permeability increased, tight junctions (TJs) were disrupted, and zona occludens 1 (ZO-1) was downregulated after I/R injury. BM MSCs reduced intestinal mucosal barrier destruction, ZO-1 downregulation, and TJ disruption. The morphological abnormalities after intestinal I/R injury positively correlated with serum TNF-α levels. Administration of anti-TNF-α IgG or anti-TNF-α receptor 1 antibodies attenuated the intestinal ultrastructural changes, ZO-1 downregulation, and TJ disruption. CONCLUSION: Altered serum TNF-α levels play an important role in the ability of BM MSCs to protect against intestinal I/R injury.

Postconditioning attenuates acute intestinal ischemia-reperfusion injury.

The aim of this study was to test the hypothesis that postconditioning (POC) would reduce the detrimental effects of the acute intestinal ischemia-reperfusion (I/R) compared to those of the abrupt onset of reperfusion. POC has a protective effect on intestinal I/R injury by inhibiting events in the early minutes of reperfusion in rats. Twenty-four Wistar-Albino rats were subjected to the occlusion of superior mesenteric artery for 30 minutes, then reperfused for 120 minutes, and randomized to the four different modalities of POC: (1) control (no intervention); (2) POC-3 (three cycles of 10 seconds of reperfusion-reocclusion, 1 minute total intervention); (3) POC-6 (six cycles of 10 seconds of reperfusion-reocclusion, 2 minutes total intervention); and (4) sham operation (laparotomy only). The arterial blood samples [0.3 mL total creatine kinase (CK) and 0.6 mL malondialdehyde (MDA)] and the intestinal mucosal MDA were collected from each after reperfusion. POC, especially POC-6, was effective in attenuating postischemic pathology by decreasing the intestinal tissue MDA levels, serum total CK activity, inflammation, and total histopathological injury scores. POC exerted a protective effect on the intestinal mucosa by reducing the mesenteric oxidant generation, lipid peroxidation, and neutrophil accumulation. The six-cycle algorithm demonstrated the best protection.

Diagnostic and prognostic value of procalcitonin and phosphorus in acute mesenteric ischemia.

BACKGROUND: In this study, using an animal model of acute mesenteric ischemia (AMI), we investigated the possible use of procalcitonin and phosphorus in the early diagnosis of AMI. METHODS: In this study, 21 New Zealand rabbits were used. Subjects were allocated into three groups as Control, Sham and Ischemia. No intervention was performed in the subjects in the Control group. In the subjects in the Sham and Ischemia groups, laparotomy was performed with midline incision. In the Ischemia group, the superior mesenteric artery was found and tied after laparotomy. Blood was drawn from the animals in all groups at 0, 1, 3 and 6 hours, and procalcitonin and phosphorus levels were studied in these samples. RESULTS: In the Ischemia group, the increase in the levels of serum phosphorus and procalcitonin was found to be statistically significant compared to the Control and Sham groups (p<0.05). The levels of phosphorus and procalcitonin were detected to increase from the 1st hour after ischemia onset, and the increase continued for the following 6 hours (p<0.05). CONCLUSION: Phosphorus and procalcitonin may be important parameters for use in the early diagnosis and prognosis of AMI.

Mesenteric vascular thromboembolism in inflammatory bowel disease: a single center experience.

BACKGROUND: Vascular thrombotic complications in inflammatory bowel disease (IBD) are well recognized, although mesenteric vascular thrombotic disease is rare. METHODS: We describe nine patients in a tertiary care center with IBD that developed thrombosis of the mesenteric arterial or venous vasculature (e.g., mesenteric thrombosis, MT). RESULTS: Eight subjects developed mesenteric venous thrombosis (five located in the superior mesenteric vein and three located in a branch of the portal vein) and one had a mesenteric arterial embolus, located in the splenic artery. Five subjects had Crohn's disease (CD), and four had ulcerative colitis. The one subject diagnosed with an arterial thrombosis had CD. Mean time from diagnosis of IBD to diagnosis of thrombosis was 24.6 ± 13.5 years. Five of the nine subjects developed mesenteric venous thrombosis while their IBD was clinically in remission. Seven of nine subjects were symptomatic from the development of MT, including bowel infarction that led to development of short bowel syndrome. CONCLUSION: Mesenteric thrombosis is a rare complication of IBD and may develop during clinical remission, suggesting a potential role for factors other than clinically significant inflammation in its pathogenesis.

JAK2 V617F mutation, mesenteric vein thrombosis, and myeloproliferative disorders.

Mesenteric vein thrombosis is a rare disorder that is often the first manifestation of a systemic condition such as a hypercoagulable state or cancer. In particular, myeloproliferative disorders can present as mesenteric vein thrombosis even in the setting of relatively normal peripheral blood counts. A recent novel mutation in the Janus activated kinase 2 gene involving a gain-of-function substitute of valine to phenylalanine at position 617 (JAK2 V617F) has been discovered to be prevalent in patients with mesenteric vein thrombosis and myeloproliferative disorders. This article reports a patient who presented with mesenteric vein thrombosis and relatively normal peripheral blood counts. He was diagnosed with essential thrombocythemia after he tested positive for the JAK2 V617F mutation.

Intraoperative endotoxin adsorption for visceral malperfusion complicating acute type A aortic dissection.

A 65-year-old man presenting with visceral malperfusion complicating acute type A aortic dissection underwent emergent surgery. Bypass grafting from the right common iliac artery to the superior mesenteric artery was performed prior to central aortic repair because intestinal ischemia caused hemodynamic instability. Subsequently, the ascending aorta was replaced with a Dacron graft under a condition of circulatory arrest with selective cerebral perfusion. Endotoxin adsorption was carried out intraoperatively in parallel with cardiopulmonary bypass to prevent postoperative end-organ failure. The patient recovered uneventfully and was discharged from our hospital 31 days after surgery.

Hyperhomocysteinaemia, low folate concentrations and methylene tetrahydrofolate reductase C677T mutation in acute mesenteric venous thrombosis.

OBJECTIVES: Acute mesenteric venous thrombosis (AMVT) was first reported by Fagge and was recognised as a distinct clinical entity by Warreen in 1935. However, its pathogenesis is still unclear. Elevated plasma levels of homocysteine (Hcy) are associated with an increased risk of deep vein thrombosis. This case-control study examines the potential association among hyperhomocysteinaemia (hyper-Hcy), low serum folate and vitamin B(12) levels and the common C677T mutation of the MTHFR gene in patients with AMVT. MATERIALS AND METHODS: Sixty-three patients with AMVT and 75 sex- and age-matched healthy controls were recruited, and their plasma Hcy, folate and vitamin B(12) levels were measured by high performance liquid chromatography (HPLC) and immunological assays. The polymorphism of MTHFR C677T was detected by PCR-RFLP. RESULTS: The mean plasma Hcy levels were significantly higher in patients with AVMT compared with controls (23.5 standard deviation (S.D.) 8.8 vs. 12.6+/-6.6micromoll(-1), P<0.01). The fasting Hcy correlated negatively with folate (AMVT: r=-0.42, P<0.01; CONTROL: r=-0.40, P<0.01). The frequency of homozygous (TT) genotype in MTHFR C677T mutation was significantly higher in patients with AMVT than that in control subjects (33% vs. 17%; chi square (chi(2))=6.31, P<0.05; odds ratio (OR)=2.80; 95% confidence interval (CI): 1.25-6.25). Compared with the control subjects, the mean serum vitamin B(12) levels were lower in patients, but it was not statistically significant (365+/-88pmoll(-1) vs. 408+/-108pmoll(-1), P>0.05). CONCLUSIONS: Hyper-Hcy and low serum folate levels were associated with an increased risk of AMVT. The homozygous (TT) genotype of MTHFR gene mutation may be a crucial hereditary risk factor in the development of AMVT for a Chinese population.

Acute mesenteric and aortic thrombosis associated with antithrombin deficiency: a rare occurrence.

Antithrombin is a potent inhibitor of the coagulation cascade exerting its primary effects on activated factors X, IX and II. It is the mechanism by which heparin and low-molecular weight heparin cause anti-coagulation. Deficiency of antithrombin presents as a hypercoagulable state, and may result in unexplained deep venous thrombosis, arterial thrombosis and systemic embolization.

[Portal vein thrombosis after splenectomy in childhood: report of 4 cases]. / Thrombose portale après splénectomie chez l'enfant: à propos de 4 observations.

Portal vein thrombosis is a major complication of splenectomy. Its frequency is underestimated because of asymptomatic cases. Mesenteric occlusion with intestinal infarcts is the first cause of mortality. Secondarily, in the absence of repermeabilisation, a portal hypertension can occur. We present in this study 4 cases of portal vein thrombosis in childhood. Portal vein thrombosis is frequent (8% of splenectomies) and may be asymptomatic. Doppler postoperative surveillance is justified. Thrombocytosis seems to be a determinant factor. Early diagnosis and treatment may reduce lethal outcome.

Aortic, celiac axis, and superior mesenteric artery thrombosis associated with sigmoid colon adenocarcinoma and hypercoagulable state.

A patient with sigmoid colon adenocarcinoma and hypercoagulable state developed acute visceral ischemia secondary to thrombus involving the suprarenal aorta, celiac axis and superior mesenteric artery. A large, laminated fibrin thrombus was removed via supraceliac aortotomy. Attempts to clear thrombus from branches of the celiac axis and superior mesenteric artery by open and catheter-based techniques were of limited success. Extensive visceral infarction ensued and the patient died.

An experimental evaluation of the lactate concentration following mesenteric ischemia.

PURPOSE: Although a diagnosis of mesenteric necrosis can easily be made, mesenteric ischemia is sometimes overlooked, especially in the acute phase. We experimentally evaluated the time course of the lactate concentration, which may be a possibly useful variable in making a diagnosis of mesenteric ischemia, and determined how an early diagnosis can be made. METHODS: The superior mesenteric artery (SMA) was surgically ligated in an anesthetized pig. Blood tests, including a blood gas analysis, were done using samples from the superior mesenteric vein (SMV), hepatic vein, femoral vein, and artery until 6 h after SMA ligation. RESULTS: There were no variables in any samples that showed a significant change within 4 h after SMA ligation except for samples taken from the SMV. All acidosis-related variables had changed significantly within 6 h after ischemia. Among them, the lactate concentration only in the SMV was observed to have increased significantly within one hour after SMA ligation. CONCLUSIONS: Currently available peripheral blood tests, including tests using blood obtained from the hepatic vein, do not enable the detection of mesenteric ischemia within 4 h after onset. In a case in which an exploratory laparotomy is performed, the measurement of the lactate concentration in SMV is thus considered to be a useful supplementary test for making a prompt diagnosis of mesenteric ischemia in an early phase.

[pH value and potassium level of diagnostic peritoneal lavage fluid in the early diagnosis of acute mesenteric ischemia secondary to arterial occlusion in rats]. / Siçanlarda arteriyel oklüzyona bagli akut mezenterik iskeminin erken tanisinda diyagnostik peritoneal lavaj sivisinda pH ve potasyum.

BACKGROUND: In this experimental study we evaluated the pH and potassium changes of the peritoneal irrigation fluid in the early phase of mesenteric ischemia. METHODS: The Wistar albino rats were assigned randomly to 5 equal groups of 10 rats: sham operation, 30, 60, 120 and 180 minutes ischemia by arterial occlusion. We enregistred the ranges of pH and potassium in peritoneal irrigation fluid and serum pH. RESULTS: Lower pH and increased potassium levels in peritoneal irrigation fluid were observed in 30 and 60 min ischemia groups. In 120 and 180 ischemia groups the level of pH continued to be lower and potassium level increased gradually, the serum pH were markedly lower in these groups. Histological analysis showed a positive correlation between the intestinal injury and ischemia time. CONCLUSION: In contrast to sham group, increase in potassium and decrease in in pH levels in peritoneal irrigation fluid were seen in 30 and 60 min ischemia groups. The decrease of serum pH was enregistred after 120 min of ischemia. In early phase the measurement of potassium and pH in peritoneal irrigation fluid may be an early diagnostic tool for mesenteric ischemia.

Hypothalamic digoxin, hemispheric chemical dominance, and mesenteric artery occlusion.

The role of the isoprenoid pathway in vascular thrombosis, especially mesenteric artery occlusion and its relation to hemispheric dominance, was assessed in this study. The following parameters were measured in patients with mesenteric artery occlusion and individuals with right hemispheric, left hemispheric, and bihemispheric dominance: (1) plasma HMG CoA reductase, digoxin, dolichol, ubiquinone, and magnesium levels; (2) tryptophan/tyrosine catabolic patterns; (3) free radical metabolism; (4) glycoconjugate metabolism; and (5) membrane composition. In patients with mesenteric artery occlusion there was elevated digoxin synthesis, increased dolichol and glycoconjugate levels, low ubiquinone, and elevated free radical levels. The RBC membrane Na(+)-K+ ATPase activity and serum magnesium were decreased. There was also an increase in tryptophan catabolites and reduction in tyrosine catabolites in the serum. There was an increase in cholesterol:phospholipid ratio and a reduction in glycoconjugate level of RBC membrane in these patients. The biochemical patterns obtained in mesenteric artery occlusion is similar to those obtained in left-handed/right hemispheric dominant individuals by the dichotic listening test. But all the patients with mesenteric artery occlusion were right-handed/left hemispheric dominant by the dichotic listening test. Hemispheric chemical dominance has no correlation with handedness or the dichotic listening test. Mesenteric artery occlusion occurs in right hemispheric chemically dominant individuals and is a reflection of altered brain function. Hemispheric chemical dominance may thus control the risk for developing vascular thrombosis in individuals.

Behavior of plasma hemoglobin in an experimental model of occlusive mesenteric ischemia.

The difficulties in establishing the diagnosis of mesenteric ischemia are responsible for the high mortality rate that is associated with this clinical condition. We studied the behavior of plasma hemoglobin in an experimental model of occlusive mesenteric ischemia in mice. Our results showed a clear relationship between the duration of ischemia and plasma hemoglobin levels. With regard to the time frames studied (3 hours, 6 hours, 12 hours, and 24 hours), comparison with control groups produced calculated P values of less than 0.01 for all time frames with the exception of the 3-hour group. This test may have the potential to aid in the diagnosis of mesenteric ischemia as well as the follow-up of its course after various therapeutic approaches.

[High plasma levels of factor VIII and von Willebrand factor in a patient with portal vein thrombosis]. / Pfortaderthrombose bei einem Patienten mit erhöhtem Faktor-VIII-Spiegel und von-Willebrand-Faktor.

In portal vein thrombosis, various hypercoagulable conditions and inherited or acquired thrombophilias have already been described as predisposing factors. In a 33-year-old man admitted to a hospital with upper abdominal pain, a partial portal vein and upper mesenteric vein thrombosis, respectively, and a complete splenic vein thrombosis were diagnosed. Further diagnostic procedures showed no evidence for local precipitating factors or any underlying infectious, paraneoplastic or inflammatory disease. Thrombophilia screening demonstrated elevated factor VIII levels (206 %) and von Willebrand factor levels (> 440 %). An acute-phase reaction was excluded. Oral anticoagulant therapy with phenprocoumon was started. Factor VIII and von Willebrand factor were reproducibly elevated to high activity levels over a period of 12 months in absence of acute or chronic inflammatory reaction. Increased levels of factor VIII and von Willebrand factor may play a pathogenetic role in the development of portal, splenic, and mesenteric thrombosis.