Hermitian splines for modeling biological soft tissue systems that exhibit nonlinear force-elongation curves.

Numerical simulation of soft tissue mechanical properties is a critical step in developing valuable biomechanical models of live organisms. A cubic Hermitian spline optimization routine is proposed in this paper to model nonlinear experimental force-elongation curves of soft tissues, in particular when modeled as lumped elements. Boundary conditions are introduced to account for the positive definiteness and the particular curvature of the experimental curve to be fitted. The constrained least-square routine minimizes user intervention and optimizes fitting of the experimental data across the whole fitting range. The routine provides coefficients of a Hermitian spline or corresponding knots that are compatible with a number of constraints that are suitable for modeling soft tissue tensile curves. These coefficients or knots may become inputs to user-defined component properties of various modeling software. Splines are particularly advantageous over the well-known exponential model to account for the traction curve flatness at low elongations and to allow for more flexibility in the fitting process. This is desirable as soft tissue models begin to include more complex physical phenomena.

Hepatocellular carcinoma in Budd-Chiari syndrome: characteristics and risk factors.

BACKGROUND AND AIMS: To analyse the characteristics of and the factors associated with the development of hepatocellular carcinoma (HCC) in patients with Budd-Chiari syndrome (BCS). PATIENTS AND METHODS: 97 consecutive patients with BCS and a follow-up > or = 1 year were evaluated retrospectively. Liver nodules were evaluated using serum alpha-fetoprotein (AFP) level and imaging features (CT/MRI). Biopsy of nodules was obtained when one of the following criteria was met: number < or = 3, diameter > or = 3 cm, heterogeneity, washout on portal venous phase, increase in size on surveillance, or increase in AFP level. RESULTS: Patients were mainly Caucasian (69%) and female (66%). Mean age at the diagnosis of BCS was 35.8 (SE 1.2 years), and median follow-up 5 years (1-20 years). The inferior vena cava (IVC) was obstructed in 13 patients. Liver nodules were found in 43 patients, 11 of whom had HCC. Cumulative incidence of HCC during follow-up was 4%. Liver parenchyma adjacent to HCC showed cirrhosis in nine patients. HCC was associated with male sex (72.7% v 29.0%, p = 0.007); factor V Leiden (54.5% v 17.5%, p = 0.01); and IVC obstruction (81.8% v 4.6%, p < 0.001). Increased levels of serum AFP were highly accurate in distinguishing HCC from benign nodules: PPV = 100% and NPV = 91% for a cut-off level of 15 ng/ml. CONCLUSION: The incidence of HCC in this large cohort of BCS patients was similar to that reported for other chronic liver diseases. IVC obstruction was a major predictor for HCC development. Serum AFP appears to have a higher utility for HCC screening in patients with BCS than with other liver diseases.

[Nadroparin-induced skin necrosis then thrombocytosis in intensive care unit: difficulty in diagnosis]. / Nécrose cutanée et thrombocytose induites par la nadroparine en réanimation: un diagnostic inhabituel.

Skin necrosis is a rare complication in intensive care unit. A case-report of nadroparine-induced skin necrosis and thrombocytosis in a patient with traumatic paraplegia is reported. This case emphasised the difficulty in diagnosis despite absence of thrombopenia. A skin necrosis could suggest the diagnosis and a substitutive therapy must be administrated after heparin therapy withdrawal. A thrombocytosis is a little reported complication of low-molecular-weight heparins without complication.

The decrease of fibrinogen is an early predictor of the severity of postpartum hemorrhage.

BACKGROUND: Postpartum hemorrhage (PPH) is a major source of maternal morbidity. OBJECTIVES: This study's objective was to determine whether changes in hemostasis markers during the course of PPH are predictive of its severity. PATIENTS AND METHODS: We enrolled 128 women with PPH requiring uterotonic prostaglandin E2 (sulprostone) infusion. Two groups were defined (severe and non-severe PPH) according to the outcome during the first 24 hours. According to our criteria, 50 of the 128 women had severe PPH. Serial coagulation tests were performed at enrollment (H0), and 1, 2, 4 and 24 hours thereafter. RESULTS: At H0, and through H4, women with severe PPH had significantly lower fibrinogen, factor V, antithrombin activity, protein C antigen, prolonged prothrombin time, and higher D-dimer and TAT complexes than women with non-severe PPH. In multivariate analysis, from H0 to H4, fibrinogen was the only marker associated with the occurrence of severe PPH. At H0, the risk for severe PPH was 2.63-fold higher for each 1 gL(-1) decrease of fibrinogen. The negative predictive value of a fibrinogen concentration >4 gL(-1) was 79% and the positive predictive value of a concentration

Splanchnic vein thrombosis in candidates for liver transplantation: usefulness of screening and anticoagulation.

BACKGROUND AND AIMS: Splanchnic vein thrombosis is a significant source of complications in candidates for liver transplantation. The aims of this study were: (a) to determine the prevalence of and risk factors for splanchnic vein thrombosis in cirrhotic patients awaiting transplantation and (b) to assess the usefulness of anticoagulation. METHODS: A total of 251 cirrhotic patients listed for transplantation were analysed. All underwent systematic screening for thrombosis with Doppler ultrasonography. During the second period of the study, all patients with thrombosis received anticoagulation up to transplantation while during the first period none had received anticoagulation. RESULTS: The incidence of splanchnic vein thrombosis at evaluation was 8.4%. Seventeen additional patients (7.4%) developed de novo thrombosis after evaluation. Independent risk factors for thrombosis were low platelet count (77.4 (36.3) v 111.6 (69.2) 10(9)/l; p = 0.001), a past history of variceal bleeding (47.4% v 29.1%; p = 0.003), and a prolonged interval from listing to transplantation (8.5 (6.8) v 4.8 (4.4) months; p = 0.002). The proportion of partial or complete recanalisation was significantly higher in those who received (8/19) than in those who did not receive (0/10, p = 0.002) anticoagulation. Survival was significantly lower in those who had complete portal vein thrombosis at the time of surgery (p = 0.04). CONCLUSION: These results support a systematic screening for splanchnic vein thrombosis in patients awaiting transplantation. They suggest that in these patients, anticoagulation is safe and has a significant impact on recanalisation as well as prevention of extension of thrombosis.

Association of idiopathic hepatic sinusoidal dilatation with the immunological features of the antiphospholipid syndrome.

BACKGROUND: Isolated sinusoidal dilatation is an uncommon hepatic lesion and the cause is largely unknown. OBJECTIVE: To investigate whether prothrombotic disorders or perisinusoidal cell changes could be involved in pure idiopathic hepatic sinusoidal dilatation (HSD). METHODS: Evaluation for associated conditions, prothrombotic disorders, and studies of hepatic perisinusoidal cell activation in consecutive patients, seen between 1993 and 2002, with isolated sinusoidal dilatation unrelated to outflow block, sinusoidal infiltration, or hepatic granulomas. RESULTS: Among 11 patients, associated conditions were prothrombotic disorders (n = 5) and oral contraceptive use (n = 3). Prothrombotic disorders were polycythemia vera (n = 1) and anticardiolipin antibodies combined with lupus anticoagulant (n = 4). No genetic thrombophilia factor was found. Of four patients with lupus anticoagulant, three had antinuclear factors and high serum levels of anticardiolipin antibodies at repeated testing. There was no evidence of intrahepatic or extrahepatic thrombosis in any of the patients. Sinusoidal dilatation was marked in six of 11 patients (54%), including two patients with antiphospholipid antibodies. Activated perisinusoidal cells were only found around markedly dilated sinusoids. CONCLUSION: Idiopathic pure HSD is frequently associated with the immunological features of the antiphospholipid syndrome. Therefore, finding pure HSD in a liver biopsy specimen should prompt the search for antiphospholipid antibodies.

Idiopathic non-cirrhotic intrahepatic portal hypertension in the West: a re-evaluation in 28 patients.

BACKGROUND: Non-cirrhotic portal hypertension of unknown cause is a poorly understood condition attributed to obstructive portal venopathy. AIM: To reassess the manifestations, course, and causes, with special attention to thrombosis. METHODS: Analysis of a cohort of 28 patients. RESULTS: Gastrointestinal bleeding occurred in 11 patients. Liver failure developed at the time of concurrent disease in eight patients, including all four patients who died. Portal vein thrombosis developed in 13 patients. A prothrombotic disorder was found in 12 of 23 fully investigated patients. Hepatoportal sclerosis was observed in 11 patients (with associated perisinusoidal fibrosis and/or nodular regenerative hyperplasia in six); periportal fibrosis, perisinusoidal fibrosis, nodular regenerative hyperplasia, or a combination thereof were observed in other patients. A morphometric evaluation showed an increased number of portal vessels in patients with hepatoportal sclerosis. There was no relation between pathological results and haemodynamic findings or prothrombotic disorders. CONCLUSIONS: Outcome was related to associated conditions. Overlap in pathological, haemodynamic, and causal features suggests a single entity, with prothrombotic disorders as major causal factors, and injury to sinusoids as well as to portal venules as the primary mechanism. Activated coagulation could mediate vascular injury in the absence of thrombosis. Anticoagulation should be considered.

Current outcome of portal vein thrombosis in adults: risk and benefit of anticoagulant therapy.

BACKGROUND & AIMS: The outcome of portal vein thrombosis in relation to associated prothrombotic states has not been evaluated. We assessed current outcome and predictors of bleeding and thrombotic events in a cohort of 136 adults with nonmalignant, noncirrhotic portal vein thrombosis, of whom 84 received anticoagulant therapy. METHODS: Multivariate Cox model analysis for event-free survival and analysis taking into account multiple events were used. RESULTS: Median follow-up was 46 months. The incidence rate of gastrointestinal bleeding was 12.5 (95% confidence interval [CI], 10-15) per 100 patient-years. Large varices were an independent predictor for bleeding. Anticoagulant therapy did not increase the risk or the severity of bleeding. The incidence rate of thrombotic events was 5.5 (95% CI, 3.8-7.2) per 100 patient-years. Underlying prothrombotic state and absence of anticoagulant therapy were independent predictors for thrombosis. In patients with underlying prothrombotic state, the incidence rates of splanchnic venous infarction were 0.82 and 5.2 per 100 patient-years in periods with and without anticoagulant therapy, respectively (P = 0.01). Two nonanticoagulated patients died of bleeding and thrombosis, respectively. CONCLUSIONS: In patients with portal vein thrombosis, the risk of thrombosis is currently as clinically significant as the risk of bleeding. The benefit-risk ratio favors anticoagulant therapy.

Factor V Leiden related Budd-Chiari syndrome.

BACKGROUND: The role of factor V Leiden as a cause of Budd-Chiari syndrome has only recently been described. AIMS: To assess the specific features of factor V Leiden related Budd-Chiari syndrome. PATIENTS: Sixty three consecutive patients with hepatic vein or terminal inferior vena cava thrombosis. METHODS: Standardised chart review. RESULTS: Factor V Leiden was found in 20 patients (31% (95% CI 20-43)). In the subgroup of patients with, compared with the subgroup without, factor V Leiden, a combination of prothrombotic states was more common (70% (95% CI 50-90) v 14% (95% CI 3-24)); inferior vena cava thrombosis was more frequent (40% (95% CI 19-61) v 7% (95% CI 0-14)); and distribution of initial alanine aminotransferase values was bimodal (almost normal or extremely increased) versus unimodal (p=0.003). Factor V Leiden accounted for four of five cases of massive ischaemic necrosis (transaminases >50-fold the upper limit of normal values) (p=0.014), and also for all three cases developing during pregnancy. Patients with and without factor V Leiden did not differ with regard to mortality, portosytemic shunting, or listing for liver transplantation. Hepatocellular carcinoma developed in two patients; both had factor V Leiden and indolent obstruction of the inferior vena cava. CONCLUSIONS: In patients with Budd-Chiari syndrome, factor V Leiden (a) is common; (b) precipitates thrombosis mostly when combined with another risk factor; (c) is associated with one of two contrasting clinical pictures: indolent thrombosis-particularly of the inferior vena cava-or massive ischaemic necrosis; and (d) is a major cofactor of Budd-Chiari syndrome developing during pregnancy.

Recent portal or mesenteric venous thrombosis: increased recognition and frequent recanalization on anticoagulant therapy.

Characteristics and outcomes of recent portal or mesenteric venous thrombosis are ill-known. We intended to compare these features with those of patients with portal cavernoma, and also to assess the incidence of recanalization of recent thrombosis on anticoagulation therapy. All patients seen between 1983 and 1999 were enrolled into this retrospective study if recent portal or mesenteric venous thrombosis or portal cavernoma had been documented, and if cancer of the liver, pancreas, or bile duct, intrahepatic block including cirrhosis, and obstruction of the hepatic veins had been ruled out. The proportion of recent thrombosis was 7% in patients seen before 1990 and 56% after 1994 (P <.05). Patients with recent thrombosis (n = 33) or cavernoma (n = 108) did not differ with regard to age, sex ratio, or prevalence of prothrombotic states and of previous thrombotic events. In patients with recent thrombosis, septic pylephlebitis was more common and the incidence of gastrointestinal bleeding was lower (2.4 vs. 12.7/100 patient-years). Recanalization occurred in 25 of 27 patients given anticoagulation and 0 of 2 patients not given anticoagulation. The probability of recanalization was related to the extent of thrombosis (P =.003). In conclusion, mesenteric or portal venous thrombosis is increasingly recognized at an early stage. The features differentiating recent thrombosis and cavernoma are related to silent onset precluding early recognition and therapy in the latter. Frequent association with prothrombotic states and frequent recanalization on anticoagulation support the recommendation of early anticoagulation therapy in all patients with recent portal vein thrombosis.

Cause of portal or hepatic venous thrombosis in adults: the role of multiple concurrent factors.

According to a recent hypothesis, venous thrombosis results from the concurrence of several factors. This hypothesis was assessed in patients with portal or hepatic venous thrombosis by simultaneously investigating most of the currently identified prothrombotic disorders, local precipitating factors, and other risk factors such as oral contraceptive use. Patients with a tumorous obstruction and patients with cirrhosis with portal vein thrombosis were excluded. The prothrombotic disorders that were investigated included classical and occult myeloproliferative disorders; antiphospholipid syndrome; protein C; protein S and antithrombin deficiency; factor V Leiden; factor II; and methylene-tetrahydrofolate-reductase gene mutations. We found 1 or several prothrombotic disorders and a local precipitating factor in 26 and 10 of the 36 patients with portal vein thrombosis, respectively; and in 28 and none of the 32 patients with hepatic vein thrombosis, respectively. We found a combination of prothrombotic disorders in 5 and 9 patients with portal and hepatic vein thrombosis, respectively, whereas such a combination is expected in less than 1% of asymptomatic subjects. Of the 10 patients with a local precipitating factor, 8 had a prothrombotic disorder. Of the 13 patients who use oral contraceptives, 10 had a prothrombotic disorder. We conclude that portal or hepatic venous thrombosis should be regarded as an index for 1 or several prothrombotic disorders, whether or not local precipitating factors or oral contraceptive use are found. Concurrence of prothrombotic disorders is more common than expected. Extensive investigation of prothrombotic disorders and anticoagulation should be considered in patients with portal or hepatic venous thrombosis.

[Biological examination in the diagnosis and monitoring of liver disease. Algorithms to aid the decision]. / Exploration biologique dans le diagnostic et la surveillance d'une maladie du foie. Schémas d'aide à la décision.

The goal of this article is to describe a rational step-wise strategy for using standard laboratory tests to obtain diagnostic orientation for a liver disorder; establish, support, or rule out a liver disorder; and monitor the course of treated and untreated patients with liver disorders.

[Liver diseases and hemostasis]. / Maladies du foie et hémostase.

The liver plays a key role in the regulation of hemostasis. By producing most clotting factors and inhibitors, as well as a number of the proteins involved in fibrinolysis, and by clearing from the bloodstream activated enzymes involved in clotting or fibrinolysis, the liver protects against both bleeding and undue activation of coagulation. It follows that liver diseases are commonly responsible for hemostasis abnormalities including decreased production of clotting factors, thrombocytopenia, platelet dysfunction, and increased circulating fibrinolytic activity. With the exception of cholestasis and in the absence of a specific setting such as pregnancy, the abnormalities are the same in all liver diseases, and their severity varies only with the degree of hepatocellular failure. Although liver diseases do not directly cause disseminated intravascular coagulation (DIC), they are a major risk factor for DIC in patients with infection or shock, as well as during pregnancy. In patients with liver diseases, hemostasis tests can be required to evaluate the degree of hepatocellular failure, the severity of hemostasis disorders manifesting as bleeding, or the bleeding risk before an invasive procedure. Prothrombin time determination is usually sufficient to evaluate the degree of hepatocellular failure, although in some cases assays of fibrinogen and factors II, VII, X, V are also useful. Evaluation of the bleeding risk prior to an invasive procedure requires a study of platelet function and measurement of circulating fibrinolytic activity, which is particularly likely to be abnormal in patients with severe hepatocellular failure and/or alcohol abuse. A less common reason for investigating hemostasis is a search for the cause of a thrombotic condition, such as portal vein thrombosis or Budd-Chiari syndrome.

Clopidogrel antiplatelet activity is independent of age and presence of atherosclerosis.

The pharmacodynamic and pharmacokinetic effects of clopidogrel 75 mg taken once daily in the morning before breakfast for 10 days were compared among three groups: 12 healthy young subjects, 10 healthy elderly subjects (>65 years) and 10 otherwise healthy elderly subjects with atherosclerosis, manifested by intermittent claudication. Platelet aggregation induced by 5 microM of ADP was measured in plasma samples taken at screening, 2 hours after dosing on day 1 to day 9; 2, 5, and 24 hours after dosing on day 10; and on alternate days until day 24. The inhibition of platelet aggregation was expressed as the percent reduction in maximum platelet aggregation with respect to baseline. The bleeding time was measured at screening, 5 hours after dosing on day 10, and on day 18. Plasma concentrations of SR26334, the main circulating metabolite of clopidogrel, were determined before dosing on day 1 to day 10 and at regular intervals over 72 hours after dosing on day 10. Inhibition of platelet aggregation appeared 2 hours after the first dose, became significant after the second dose, and progressed to a steady-state value of 55 to 57% by day 7 in the three groups, with no statistically significant difference between groups. A moderate, statistically significant prolongation of bleeding time of similar extent (prolongation factor of 1.5 to 1.6) was found on day 10 in the three groups. The pharmacodynamic parameters generally returned to baseline within 8 days after treatment. Based on AUC(0-24th) values, drug exposures were very similar for the two groups of elderly subjects but approximately twice that for the young group. The pharmacodynamic effects of clopidogrel were comparable in all three groups.

Auxiliary liver transplantation: how to improve regeneration of the native liver by surgery.

The technical factors which could influence regeneration of the native liver (NL) in auxiliary liver transplantation (ALT) for fulminant hepatic failure (FHF) are not well known. We studied NL regeneration according to the location of graft anastomosis in the recipient's portal system (superior mesenteric vein versus portal vein), and graft weight (50% reduced-size versus full-size graft) in a rat model of ALT with 80% reduction of the NL, and graft arterialization. NL regeneration was significantly more obvious when the graft was anastomosed on the recipient's superior mesenteric vein, thus establishing venous flow to the NL from the pancreas, the spleen, and the stomach, and when a full-size graft was used. The influence of portal venous flow on NL regeneration, assessed by 3H[-thymidine incorporation, was measurable as early as day 2. Both technical variables in combination resulted in significantly greater regeneration (ratio weight of NL/body weight at day 30: 2.32 +/- 0.68% versus 1.21 +/- 0.63% respectively, P = 0.02). Early preservation of portal flow to the NL is advisable to maximize NL regeneration in ALT. In any case, this regeneration is not impeded by the use of large auxiliary grafts.

Fibrinogen Poissy I: a new case of the A alpha Arg 16His fibrinogen variant.

A fibrinogen variant was identified in a patient with disseminated intravascular coagulation and in one member of her family. Coagulation studies showed marked prolongation of both the thrombin and reptilase times and discrepancy was noted between the levels of plasma fibrinogen, determined by a kinetic vs immunological determination or light scattering assay. Studies on purified fibrinogen revealed an impaired release of fibrinopeptides by thrombin. DNA sequencing revealed a heterozygous A to G point mutation in exon 2 of the A alpha chain, which substituted Arg for His at position 16. This mutation creates a Nla III cleavage site which was used to confirm the mutation.

Case report: cytomegalovirus infection as a cause of acute portal vein thrombosis.

We report on the case of a 31-year-old woman who developed acute portal vein thrombosis during the course of an acute cytomegalovirus (CMV) infection. We suggest a relationship between CMV infection, its endothelial cell-damaging effects and portal vein thrombosis.

Complementarity of lung scintigraphy and D-dimer test in pulmonary embolism.

D-dimer assay (DDA), measuring fibrin degradation products, was compared with lung scintigraphy (LS) in a prospective unselected series of 83 consecutive patients referred owing to suspicion of pulmonary embolism (PE). This patient series was also used to compare several methods of performing and interpreting LS images. The final diagnosis was established independently by a separate panel with all available information except for the result of DDA. D-dimer was determined by ELISA (threshold value 500 ng/ml). LS, including perfusion (.Q) and pseudo-ventilation (Technegas) (.V), was classified according to PIOPED, (1) immediately by the physician on duty, and (2) retrospectively by a blinded panel. A positive (19) or negative (61) diagnosis of PE was achieved in 80 patients, the prevalence of PE being 24%. Only one false-negative was noted on DDA (sensitivity=95%) but there were 42 false-positives (specificity=31%), resulting in a positive predictive value of 30% and a negative predictive value of 95%. Emergency and retrospective interpretations of LS were close (kappa=0.4). In a minority of patients, PE may be excluded with reasonable certainty if DDA is normal, resulting in a significant saving in terms of time and money.