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Background: The disease-causative variant remains unidentified in approximately 0.5% to 2% of hemophilia B patients using conventional genetic investigations, and F9 deep intronic variations could be responsible for these phenotypes., Objectives: This study aimed to characterize deep intronic variants in hemophilia B patients for whom genetic investigations failed., Methods: We performed whole F9 sequencing in 17 genetically unsolved hemophilia B patients. The pathogenic impact of the candidate variants identified was studied using both in silico analysis (MaxEntScan and spliceAI) and minigene assay., Results: In total, 9 candidate variants were identified in 15 patients; 7 were deep intronic substitutions and 2 corresponded to insertions of mobile elements. The most frequent variants found were c.278-1806A>C and the association of c.278-1244A>G and c.392-864T>G, identified in 4 and 6 unrelated individuals, respectively. In silico analysis predicted splicing impact for 4 substitutions (c.278-1806A>C, c.392-864T>G, c.724-2385G>T, c.723+4297T>A). Minigene assay showed a deleterious splicing impact for these 4 substitutions and also for the c.278-1786_278-1785insLINE. In the end, 5 variants were classified as likely pathogenic using the American College of Medical Genetics and Genomics guidelines, and 4 as of unknown significance. Thus, the hemophilia B-causing variant was identified in 13/17 (76%) families., Conclusion: We elucidated the causing defect in three-quarters of the families included in this study, and we reported new F9 deep intronic variants that can cause hemophilia B., (Copyright © 2022 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Background: Pregnancy-related venous thromboembolism is a leading cause of maternal morbidity and mortality, and thromboprophylaxis is indicated in pregnant and post-partum women with a history of venous thromboembolism. The optimal dose of low-molecular-weight heparin to prevent recurrent venous thromboembolism in pregnancy and the post-partum period is uncertain., Methods: In this open-label, randomised, controlled trial (Highlow), pregnant women with a history of venous thromboembolism were recruited from 70 hospitals in nine countries (the Netherlands, France, Ireland, Belgium, Norway, Denmark, Canada, the USA, and Russia). Women were eligible if they were aged 18 years or older with a history of objectively confirmed venous thromboembolism, and with a gestational age of 14 weeks or less. Eligible women were randomly assigned (1:1), before 14 weeks of gestational age, using a web-based system and permuted block randomisation (block size of six), stratified by centre, to either weight-adjusted intermediate-dose or fixed low-dose low-molecular-weight heparin subcutaneously once daily until 6 weeks post partum. The primary efficacy outcome was objectively confirmed venous thromboembolism (ie, deep-vein thrombosis, pulmonary embolism, or unusual site venous thrombosis), as determined by an independent central adjudication committee, in the intention-to-treat (ITT) population (ie, all women randomly assigned to treatment). The primary safety outcome was major bleeding which included antepartum, early post-partum (within 24 h after delivery), and late post-partum major bleeding (24 h or longer after delivery until 6 weeks post partum), assessed in all women who received at least one dose of assigned treatment and had a known end of treatment date. This study is registered with ClinicalTrials.gov, NCT01828697, and is now complete., Findings: Between April 24, 2013, and Oct 31, 2020, 1339 pregnant women were screened for eligibility, of whom 1110 were randomly assigned to weight-adjusted intermediate-dose (n=555) or fixed low-dose (n=555) low-molecular-weight heparin (ITT population). Venous thromboembolism occurred in 11 (2%) of 555 women in the weight-adjusted intermediate-dose group and in 16 (3%) of 555 in the fixed low-dose group (relative risk [RR] 0·69 [95% CI 0·32-1·47]; p=0·33). Venous thromboembolism occurred antepartum in five (1%) women in the intermediate-dose group and in five (1%) women in the low-dose group, and post partum in six (1%) women and 11 (2%) women. On-treatment major bleeding in the safety population (N=1045) occurred in 23 (4%) of 520 women in the intermediate-dose group and in 20 (4%) of 525 in the low-dose group (RR 1·16 [95% CI 0·65-2·09])., Interpretation: In women with a history of venous thromboembolism, weight-adjusted intermediate-dose low-molecular-weight heparin during the combined antepartum and post-partum periods was not associated with a lower risk of recurrence than fixed low-dose low-molecular-weight heparin. These results indicate that low-dose low-molecular-weight heparin for thromboprophylaxis during pregnancy is the appropriate dose for the prevention of pregnancy-related recurrent venous thromboembolism., Funding: French Ministry of Health, Health Research Board Ireland, GSK/Aspen, and Pfizer., Competing Interests: Declaration of interests FNÁ reports grants as principal investigator from the Irish Health Research Board during the conduct of the study, and grants as principal investigator from Daiichi-Sankyo, Bayer, and Sanofi (investigator-initiated studies, fees paid to university) outside of the submitted work. AB reports grants from the French Ministry of Health, during the conduct of the study. JD reports grants as principal investigator from the Irish Health Research Board during the conduct of the study. NvE reports fees for scientific presentation from Bristol-Meyers Squibb (fee transferred to institution) and advisory board fees from LEO Pharma and Bayer (fees transferred to institution), outside of the submitted work. AFJ reports personal fees from Sanofi-Aventis outside of the submitted work. SM reports grants from GSK, Aspen, and Pfizer during the conduct of the study; grants and personal fees from Daiichi-Sankyo, Bayer, Pfizer, and Boehringer Ingelheim; and personal fees from Portola/Alexion, AbbVie, Pfizer/Bristol-Meyers Squibb, Norgine, Viatris, and Sanofi, outside of the submitted work. MTD reports personal fees from Sanofi Genzyme and Bioproducts Laboratory outside of the submitted work. PV reports grants and personal fees from LEO Pharma, Boehringer Ingelheim, Daiichi-Sankyo, Bayer, and Pfizer/Bristol-Meyers Squibb and personal fees from Anthos and Portola/Alexion, outside of the submitted work. All other authors declare no competing interests, (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Venous thromboembolism (VTE) is a concern for patients with newly diagnosed multiple myeloma., Objectives: We aimed to evaluate VTE incidence, risk factors, and risk score., Patients/methods: We performed a substudy of the "Intergroupe Francophone du Myelome 2009" randomized controlled trial., Results: We assessed 700 patients receiving lenalidomide/bortezomib/dexamethasone, followed or not by autologous hematopoietic stem cell transplantation. VTE incidence at 6 months was 4.8% (95% confidence interval [CI]: 3.3-6.9%) and 1.5% (95% CI: 0.8-2.9%) from 6 to 12 months. Using multivariate analysis we confirmed history of VTE (odds ratio 5.1 [1.6-16.7], P = .007) as a strong VTE-related risk factor, invalidated erythropoietin exposure (0.6 [0.2-1.7], P = .3) as risk factor, and added two new risk factors: fracture at diagnosis (2.6 [1.3-5.5], P = .01), and serum gamma globulin level > 27 g/L (2.8 [1.2-6.8,] P = .02). Moreover, we noticed that VTE occurred earlier in patients with gamma globulin levels >27 g/L, suggesting a need to revisit the thromboprophylaxis timeframe. Heparin administration was associated with a decreased risk (0.3 [0.1-0.7], P = .005) but failed to erase the risk regardless of dose. The area under the receiver operating characteristic curve of the IMPEDE VTE score was 0.67, as previously reported, confirming our cohort was well representative., Conclusions: Prospective studies are warranted in light of these results to improve VTE risk stratification and to design adapted thromboprophylaxis in terms of timing and dose., (© 2022 International Society on Thrombosis and Haemostasis.)

Background: Diagnosis of heparin-induced thrombocytopenia (HIT) requires pretest probability assessment and dedicated laboratory assays., Objective: To develop a pretest score for HIT., Design: Observational; analysis of prospectively collected data of hospitalized patients suspected with HIT (ClinicalTrials.gov NCT00748839)., Setting: Thirty-one tertiary hospitals in France, Switzerland, and Belgium., Patients: Patients tested for HIT antibodies (2280 evaluable), randomly allocated to derivation and validation cohorts., Measurements: Independent adjudicators diagnosed HIT based on the prospectively collected data and serotonin release assay results., Results: Heparin-induced thrombocytopenia was diagnosed in 234 (14.7%) and 99 (14.5%) patients in the two cohorts. Eight features were associated with HIT (in brackets, points assigned for score calculation of the score): unfractionated heparin (1); therapeutic-dose heparin (1); cardiopulmonary bypass (cardiac surgery) (2); major trauma (3); 5- to 21-day interval from anticoagulation initiation to suspicion of HIT (4); ≥40% decrease in platelet count over ≤6 days (3); thrombotic event, arterial (3) or venous (3). The C-statistic was 0.79 (95% CI, 0.76-0.82). In the validation cohort, the area under the receiver operating characteristic curve was 0.77 (95% CI, 0.74-0.80). Three groups of scores were defined; HIT prevalence reached almost 30% in the high-probability group., Limitation: The performance of the score may depend on settings and practices., Conclusion: The objective, easy-to-collect, clinical features of HIT we evidenced were incorporated into a pretest score, which may guide clinical decisions regarding diagnostic testing and anticoagulation., (© 2021 International Society on Thrombosis and Haemostasis.)

Background: Multiple myeloma (MM) is associated with a high risk of thrombosis, particularly during the first months of treatment including immunomodulatory drugs (IMiDs). There is no consensus on prevention of thromboembolic risk in patients with de novo MM, and identification of patients requiring anticoagulant thromboprophylaxis remains challenging. Evaluating coagulability by an in vitro thrombin generation (TG) test might be a way of identifying such patients., Objective: To determine whether TG assessment could reveal an increase in coagulability during the first three chemotherapy cycles., Methods: This prospective and longitudinal observational study included patients newly diagnosed with MM. TG was determined in platelet-rich and platelet-poor plasma using calibrated automated thrombography with a low tissue factor (TF) concentration., Results: Seventy-one patients were enrolled, allowing TG analysis during 213 chemotherapy cycles. TG remained unchanged throughout follow-up irrespective of treatment regimen, but values determined before cycles 2 and 3 were significantly higher in patients receiving iMiDs-containing regimens. No association was found between TG and its changes and thrombosis occurrence during follow-up: venous thrombosis in eight patients; no cardiovascular event. A significantly (87%) lower risk of venous thrombosis was observed in patients receiving prophylaxis with a low-molecular-weight heparin (LMWH; OR: 0.13 (95% CI: 0.02-0.76). Neither bortezomib- nor dexamethasone-containing regimens were associated with thrombotic risk. Changes in TG, as studied, were not associated with thrombotic events., Conclusions: The only factor associated with a reduction in early thrombotic risk was prophylaxis with LMWH. The issue of how to identify patients requiring prophylactic anticoagulation remains unresolved.

Essentials Bleeding incidence as hemorrhagic risk factors are unknown in palliative care inpatients. We conducted a multicenter observational study (22 Palliative Care Units, 1199 patients). At three months, the cumulative incidence of clinically relevant bleeding was 9.8%. Cancer, recent bleeding, thromboprophylaxis and antiplatelet therapy were independent risk factors., Summary: Background The value of primary thromboprophylaxis in patients admitted to palliative care units is debatable. Moreover, the risk of bleeding in these patients is unknown. Objectives Our primary aim was to assess the bleeding risk of patients in a real-world practice setting of hospital palliative care. Our secondary aim was to determine the incidence of symptomatic deep vein thrombosis and to identify risk factors for bleeding. Patients/Methods In this prospective, observational study in 22 French palliative care units, 1199 patients (median age, 71 years; male, 45.5%), admitted for the first time to a palliative care unit for advanced cancer or pulmonary, cardiac or neurologic disease were included. The primary outcome was adjudicated clinically relevant bleeding (i.e. a composite of major and clinically relevant non-major bleeding) at 3 months. The secondary outcome was symptomatic deep vein thrombosis. Results The most common reason for palliative care was cancer (90.7%). By 3 months, 1087 patients (91.3%) had died and 116 patients had presented at least one episode of clinically relevant bleeding (fatal in 23 patients). Taking into account the competing risk of death, the cumulative incidence of clinically relevant bleeding was 9.8% (95% confidence interval [CI], 8.3-11.6). Deep vein thrombosis occurred in six patients (cumulative incidence, 0.5%; 95% CI, 0.2-1.1). Cancer, recent bleeding, antithrombotic prophylaxis and antiplatelet therapy were independently associated with clinically relevant bleeding at 3 months. Conclusions Decisions regarding the use of thromboprophylaxis in palliative care patients should take into account the high risk of bleeding in these patients., (© 2016 International Society on Thrombosis and Haemostasis.)

Background: The incidence of superficial vein thrombosis (SVT) in the general adult population remains unknown., Objectives: To assess the annual diagnosis rate of symptomatic, objectively confirmed lower limb SVT, associated or not with concomitant deep vein thrombosis and/or symptomatic pulmonary embolism., Methods/patients: We conducted, from November 14, 2011, to November 13, 2012, a multicenter, community-based study in the Saint-Etienne urban area, France, representing a population of 265 687 adult residents (according to the 2009 census). All 248 general practitioners located within the area were asked to refer any patient with clinically suspected lower limb acute SVT to a vascular physician for systematic compression ultrasonography. All 28 vascular physicians located within the area participated in the study. The annual diagnosis rate, with the corresponding 95% confidence interval (CI), was calculated as the number of patients with symptomatic, objectively confirmed SVT divided by the number of person-years at risk defined by population data of the area. All venous thromboembolic events were validated by an independent central adjudication committee., Results: Overall, 171 patients with symptomatic, confirmed SVT were reported. The annual diagnosis rate was 0.64& (95% CI, 0.55%-0.74&), was higher in women, and increased with advancing age regardless of gender [corrected]. Concomitant deep vein thrombosis (20 proximal) was observed in 42 patients (24.6% [95% CI, 18.3%-31.7%]), and concomitant symptomatic pulmonary embolism was observed in eight patients (4.7% [95% CI, 2.0%-9.0%])., Conclusions: This first community-based study showed that symptomatic SVT with confirmed diagnosis is a relatively common disease frequently associated with thromboembolic events in the deep venous system., (© 2014 International Society on Thrombosis and Haemostasis.)

Lower limbs superficial venous thrombosis (LLSVT) is usually considered as common and of a benign prognosis. LLSVT can, however, be responsible for major thromboembolic complications: lower limbs deep vein thrombosis (LLDVT) and pulmonary embolism (PE). We report a case of a LLSVT complicated with a massive bilateral PE and an ischemic cerebral stroke, occurring immediately after a varicose vein surgery. Venous ultrasonography of the lower limbs must be systematically performed in case of LLSVT, in order to evaluate the presence of an associated LLDVT. A rigorous diagnostic and therapeutic approach is the only way to optimize the treatment of this disorder, and to avoid the occurrence of dramatic venous thromboembolic complications., (Copyright © 2013. Published by Elsevier SAS.)

The incidence of venous thromboembolism in multiple myeloma depends on the disease characteristics that include recent diagnosis, persistent or recurrent multiple myeloma, patient characteristics, and the type of treatment received such as thalidomide or lenalidomide especially in combination with high-dose dexamethasone, or combined chemotherapy. Currently, recommendations could be challenged by the results of the first randomized study evaluating aspirin, low molecular weight heparins and vitamin K antagonists in the antithrombotic prophylaxis. The recent data from the literature show that it is not possible to propose a therapeutic management for venous thromboembolism prophylaxis in multiple myeloma and that the use of antithrombotic prophylaxis may not be mandatory., (Copyright © 2012 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.)

We present the case of a 34-year-old woman who developed, in postpartum period of an uncomplicated pregnancy, a thunderclap headache with visual disturbance associated with a severe arterial hypertension. Both clinical evolution and cerebral imaging including angio-MR confirmed the diagnosis of postpartum reversible vasoconstriction syndrome. One of the leading causes of this syndrome is the use of vasoactive drugs as it was observed in the case of this patient. It is important to consider this syndrome in the differential diagnosis in patients presenting with headache in the postpartum period., (Copyright © 2010 Elsevier Masson SAS. All rights reserved.)

Background: Heparin-induced thrombocytopenia (HIT) is a severe complication of heparin therapy. IgG antibodies targeting the platelet factor 4-heparin complex activate platelets and generate microparticles with procoagulant activity., Objectives: To determine whether the thrombin generation assay is capable of detecting procoagulant activity induced by patient platelet-poor plasma (PPP) in donor platelet-rich plasma (PRP)., Patients and Methods: We explored two groups of patients; group 1 (n = 23): patients with a positive clinical and biological diagnosis of HIT; group 2 (n = 25): patients with a negative clinical and biological diagnosis of HIT. Mixtures of donor PRP and patient PPP (1:1) were incubated either with unfractionated heparin 0.2 U mL(-1) or with physiological saline. Thrombin generation was assessed by calibrated thrombinography. The effect of heparin on the mixtures was evaluated according to the ratio of the values with and without heparin (wH/woH) of the five thrombogram parameters., Results: With low heparin concentrations, plasma of group 1 activates donor platelets and generates procoagulant activity. A set of three ratios outside the cut-off values corresponds to the 'HIT thrombogram profile', characterized by a highly specific aspect of the thrombogram wH in relation to the thrombogram woH. None of the group 2 patients presented a HIT thrombogram profile. The results of thrombinography correlate well with the results of the platelet aggregation test., Conclusion: Our studies illustrate the central paradox of HIT, namely enhancement of thrombin generation in the presence of heparin. The HIT thrombogram profile as it is defined in this study can detect the procoagulant activity of HIT IgG antibodies.

The antithrombotic efficacy of lepirudin in patients with heparin-induced thrombocytopenia (HIT) is compromised by an increased risk for bleeding. A retrospective observational analysis in 181 patients (median age, 67 years) with confirmed HIT treated in routine practice with lepirudin was performed to identify predictive factors for thrombotic and bleeding complications. Lepirudin was administered at a mean (+/- SD) dose of 0.06 +/- 0.04 mg/kg/h (compared with a recommended initial dose of 0.15 mg/kg/h). Mean activated partial thromboplastin time was greater than 1.5 times baseline value in 99.4% of patients. Median treatment duration was 7.7 days. Until discharge from the hospital, 13.8% and 20.4% of patients experienced a thrombotic or a major bleeding event, respectively. On multivariate analysis, mean lepirudin dose was not a significant predictive factor for thrombosis. In contrast, mean lepirudin dose greater than 0.07 mg/kg/h, long duration of lepirudin treatment, and moderate to severe renal impairment were significant positive factors for major bleeding. Overall, these results suggest that the recommended dose of lepirudin in patients with HIT is too high; the use of reduced doses may be safer with regard to bleeding risk and does not compromise antithrombotic efficacy.

Tissue factor pathway inhibitor (TFPI) is of major importance in regulating the coagulation triggering effects of tissue factor. An association between TFPI deficiency and thrombosis has still not been clearly demonstrated. We evaluated the anticoagulant activity of exogenous TFPI added either to the plasma of patients with venous thrombosis (n = 118) or to the plasma of healthy controls similar in terms of mean age and sex ratio (n = 107). A poor anticoagulant response to TFPI, defined as TFPI resistance, was observed in 4.7% of controls and in 11.0% of patients. TFPI resistance was associated with an almost threefold increase in the risk of thrombosis and could therefore represent a novel hemostatic risk factor for venous thrombosis.

Some cases of heparin-induced thrombocytopenia (HIT) have been reported to be associated with antibodies against interleukin-8 (IL-8), a chemokine related to platelet factor 4. We found that sera from 5 HIT patients containing immunoglobulin G (IgG) or IgM antibodies to IL-8, as evidenced using surface plasmon resonance spectroscopy, were able to trigger IL-8-dependent activation of washed platelets, leading to procoagulant activity. This activation occurred at IL-8 concentrations achievable in vivo and was facilitated by heparin (0.1 U/mL). Activation was also induced by affinity-purified anti-IL-8 IgG and involved FcgammaRIIa. In the 2 patients who could be followed up, antibodies were no longer detectable 4 months after heparin withdrawal. One additional patient with paraneoplastic recurrent thrombosis without thrombocytopenia was found to have platelet-activating anti-IL-8 IgM, but in this case heparin was inhibitory. This is another example of potentially pathogenic platelet activation by antibodies.

The presence of contaminated sediment poses a barrier to essential waterway maintenance and construction in many ports and harbors, which support 95% of US foreign trade. Cost effective solutions to remediate contaminated sediments in waterways need to be applied. Capping is the least expensive remediation alternative available for marine sediments that is unsuitable for open water disposal. Dredged material capping and in situ capping alternatives, however, are not widely used because regulatory agencies are concerned about the potential for contaminant migration through the caps. Numerous studies have been conducted on the effects of diffusion through caps, however, there is a lack of experimental data documenting the effects of consolidation induced transport of contaminants through caps. This study examines consolidation induced convective contaminant transport in capped sediment utilizing a research centrifuge. In this study, consolidation induced convective transport was modeled for 7h at 100 x g, which modeled a contaminant migration time of 8 years for a prototype that was 100 times larger than the centrifuge model. In this study, hydrodynamic dispersion was a function of the seepage velocity. And, advection and dispersion dominated the migration of contaminants. Centrifuge model results were compared to an analytical solution for advection and dispersion. The advection-dispersion equation demonstrated that the centrifuge test is a conservative estimate for predicting contaminant transport. In conducting sensitivity analysis of the advection-dispersion equation to the centrifuge modeling, as hydrodynamic dispersion decreased, the time for contaminant breakthrough increased. Moreover, as the sediment to water distribution coefficient increased, the contaminant concentration into the overlying water decreased.

Unlabelled: Thrombotic accidents in the newborn, particularly cerebrovascular accidents, are reported in case of abnormalities in the coagulation system and rarely in heterozygous protein C deficiency; a low protein C level could be either physiological or acquired., Case Report: Two cases of heterozygous protein C deficiency are reported in neonates. Severe neurologic distress was associated with bloody cerebrospinal fluid, and hemorrhagic lesions due to cerebral sinovenous occlusion were visualised by cerebral imaging. The course was severe. One case was associated with renal thrombosis. Mutation in the 168 proline/leucine was detected by molecular biology in the neonates and their mothers. In one case a treatment with protein C had no beneficial effect., Conclusion: Cerebral sinus venous thrombosis has to be sought by magnetic resonance imaging in the case of neurologic distress with profound cerebral hemorrhage in the newborn. A low level of protein C has to be interpreted with caution. The diagnosis of a heterozygous deficiency status can only be made through molecular biology. The effect of treatment with protein C concentrate is questionable.

Objective: To evaluate the effectiveness and the safety of danaparoid sodium in the treatment of critically ill patients with standard unfractionated heparin-induced thrombocytopenia (HIT) or low-molecular-weight HIT., Setting: University hospital., Patients and Methods: Retrospective analysis of 42 consecutive critically ill patients who were admitted for HIT between October 1992 and February 1997 and were treated either with therapeutic or prophylactic doses of danaparoid sodium., Results: Among the 26 patients treated with therapeutic doses, neither new thrombotic complications nor thrombosis extension was clinically suspected. Two deaths were directly related to lower limb acute arterial thrombosis associated with HIT. Two major hemorrhagic complications were observed when aspirin in addition to danaparoid sodium was administered. When danaparoid sodium was used in prophylactic doses (20 courses of treatment) to prevent either postsurgical or medical thrombotic complications, no thrombotic event was observed. No death related to HIT or danaparoid sodium treatment was observed. One aggravation of a postsurgical cerebral lesion was observed. During danaparoid sodium treatment, a persistence or a recurrence of thrombocytopenia was observed in 6.5% of patients without thrombotic complications., Conclusion: Danaparoid sodium appears to be an efficient and safe treatment in critically ill patients with HIT. The concomitant use of aspirin in addition to danaparoid sodium seems to represent an important additional hemorrhagic risk that should be avoided in patient management.

Eighty-seven patients with heparin-associated thrombocytopenia (HAT) showed either a positive heparin platelet aggregometry test result and/or the presence of antibodies to heparin-platelet factor 4 (H-PF4) complexes by enzyme-linked immunosorbent assay (ELISA). Fifteen of these patients lacked antibodies to H-PF4, and plasma from these patients was analyzed for the presence of antibodies to PF4-related chemokines, Neutrophil-activating peptide-2 (NAP-2) and interleukin-8 (IL-8). Of these 15 patients, 6 showed antibodies to IL-8 and 3 to the platelet basic protein (PBP)-derived protein, NAP-2. Antibodies to IL-8 and NAP-2 were not observed in control patients (n = 38), patients with HAT and H-PF4 autoantibodies (n = 72), patients with autoimmune diseases (n = 21), or patients with non-HAT thrombocytopenia (n = 30). Five of these nine patients with anti-IL-8 or anti-NAP-2 developed thrombosis during heparin treatment, which is not statistically different from the patients with H-PF4 antibodies. The existence of autoantibodies to IL-8 and NAP-2 in HAT patients highlights the significance of chemokines in the pathogenesis of HAT. The contribution of heparin in vitro was minimal in patients with anti-IL-8 and anti-NAP-2 antibodies, suggesting a biologic difference from the majority of patients with HAT and anti-PF4 antibodies. It may be that antibodies to IL-8 and NAP-2 have weaker affinity for heparin and that the ELISA system may not reflect in vivo heparin-chemokine complex formation. Alternatively, antichemokine autoantibodies may predate heparin exposure, and the role of heparin in initiating HAT may be to mobilize the chemokines and to target them to platelets, neutrophils, or endothelial cells. Subsequent chemokine-binding autoantibodies then lead to cell activation resulting in thrombocytopenia and thrombosis.

Inferior vena cava thrombosis is a major complication after filter placement. The thrombus can propagate through the filter leading to a high risk of pulmonary embolism. We report such a case in a patient with a Günther filter, successfully treated with urokinase, and we discuss the efficacy and the safety of thrombolytic therapy in such situations.

Close cooperation is necessary between the cardiologist and anesthesiologist preoperatively in order to identify the risks associated with a surgical procedure. This article reviews the various types of anesthesia and their effects on the cardiovascular system, in particular in relation to the category of cardiovascular disease. Accurate definition of the operative risk involves thorough evaluation of three essential parameters: cardiovascular status, the type of surgery and the type of anesthesia. These high-risk patients require management not only pre- and peroperatively, but also postoperatively, which is the period when the majority of complications occur. Mention is also made of drug interactions between anesthetic and cardiovascular agents.

The authors report a case of type 2 dissection, strictly confined to the terminal portion of the ascending aorta, not seen by transesophageal echocardiography because of the existence of a blind spot and responsible for a false negative. The role of TEE in the diagnostic approach to dissections is reviewed, as are its limitations, of which it is important to be aware because of the poor prognosis of pathology of this type.

Tissue factor (TF) which initiates clotting process can be expressed by stimulated endothelial cells (EC). TF is an apolipoprotein requiring an association with phospholipids (PL) in order to become active. Also PL constitute an important storage pool of polyunsaturated fatty acids (PUFAs) in EC which can be modulated by diet or cell medium supplementation. In order to test the effect of such manipulation upon TF activity, we have pre-enriched human EC cultures with different fatty acids of nutritional interest. TF was evaluated after 4 h of thrombin stimulation by using a chromogenic method. Without additional stimulating agents, these acids have no effect on the basal level of TF. Eicosapentaenoic and docosapentaenoic acids appeared to be ineffective at the stimulated TF level. Only adrenic acid (22:4(n-6)) has been found to significantly enhance TF activity of thrombin-stimulated endothelial cells. Other TF inducers were also tested after 22:4(n-6) enrichment. An increase tendency of TF expression was found only with tumor necrosis factor, whereas interleukin-1 beta, lipopolysaccharide and especially phorbol myristate acetate stimulations were not significantly modified. The priming effect of adrenic acid on thrombin stimulated TF expression might involve alterations of signal transduction pathways rather than modifications of apolipoprotein III environment. Adrenic acid, which is a prostacyclin inhibitor, appears to be potential prothrombotic agent.

4 patients had typical features of thrombotic thrombocytopenic purpura (TTP) after 3 to 8 weeks of ticlopidine therapy. In 2 ticlopidine was the only medication taken before TTP; in another, rechallenge with drugs other than ticlopidine that the patient had been taking did not produce relapse. In all patients the delay between start of ticlopidine and TTP was in the same range as the latent period before ticlopidine-induced neutropenia. No relapse occurred in the 4 to 43 months of follow-up in the 3 surviving patients.

Persistent left superior vena cava is encountered in about 0.3 to 0.4% of human beings. It derives from remnants of the left cardinal vein system. This results in either a duplication of the superior vena cava or in a single left vena cava. The diagnosis is easy in case of associated cardiovascular anomalies. Two cases of single left vena cava and one case of duplication of the superior vena cava are described. All were identified owing to repeatedly aberrant courses of central venous catheters. Diagnosis was easily provided by angiography. Clinical course was uneventful. Despite its usual good tolerance, the persistence of a left vena cava, as an isolated anomaly, must not be neglected as it carries many practical implications which are reviewed.