ABO and Rhesus Blood Groups in Acute Puumala Hantavirus Infection.

Puumala hantavirus (PUUV) causes hemorrhagic fever with renal syndrome. We aimed to evaluate whether ABO and rhesus blood groups associate with the susceptibility or the severity of PUUV infection. We analyzed blood groups in 289 adult patients treated in Tampere University hospital due to PUUV infection during the years 1982-2017. Patients' blood group distribution was compared to that of healthy, voluntary blood donors living in the Tampere University Hospital responsibility area (n = 21,833). The severity of PUUV infection, as judged by the severity of acute kidney injury (AKI), thrombocytopenia, inflammation, capillary leakage, and the length of hospital care, was analyzed across the groups. The ABO and rhesus blood group distributions did not differ between the patients and blood donors. Patients with non-O blood groups had lower systolic blood pressure compared to patients with blood group O, but there was no difference in other markers of capillary leakage or in the severity of AKI. Minor deviations in the number of platelets and leukocytes were detected between the O and non-O blood groups. To conclude, patients with blood group O may be less susceptible to hypotension, but otherwise blood groups have no major influences on disease susceptibility or severity during acute PUUV infection.

Systemic capillary leak syndrome: a rare but potentially life-threatening cause of protein loss and oedema in B cell prolymphocytic leukaemia.

A 64-year-old man had a several year history of B prolymphocytic leukaemia (PLL) which behaved indolently and had not required any treatment. Five years after diagnosis, he developed hypoalbuminaemia associated with severe lower-limb oedema, consistent with systemic capillary leak syndrome (SCLS). He recovered spontaneously but went on to have three further increasingly severe and protracted episodes over the subsequent 18 months. There was no identifiable precipitating factor for these episodes, but his peripheral lymphocyte count continued to increase slowly. The start of treatment for his PLL with chemoimmunotherapy was followed by a rapid resolution of residual oedema and normalisation of serum albumin. He has had no further attacks of SCLS in the 14 months since he started therapy for PLL. SCLS is a rare consequence of haematological malignancy which may show an excellent response to treatment of the haematological disease.

Low hormone levels during an attack of systemic capillary leak syndrome normalizing after treatment.

We report herein the case of a patient with low blood levels of different hormones during a systemic capillary leak syndrome (Clarkson's disease) attack.

The effects of severe hemoconcentration on acid-base equilibrium in critically ill patients: the forgotten role of buffers in whole blood.

PURPOSE: Idiopathic Systemic Capillary Leak Syndrome (ISCLS) is a paroxysmal permeability disorder characterized by abrupt onset of shock and hemoconcentration due to massive shift of fluids and proteins from the intravascular to the interstitial compartment. We hypothesize that increased hemoglobin concentration has a pivotal role in the acid-base imbalance during life-threatening crises. MATERIALS AND METHODS: Analysis of the acid-base balance fluctuations during six severe ISCLS flares admitted to ICU of a referral center for ISCLS. RESULTS: Acid-base equilibrium was assessed for plasma and the whole blood by single and multicompartmental models. The acute phase of ISCLS was characterized by shock, hypoalbuminemia, severe hemoconcentration, and acidosis. The physical-chemical approach for plasma found a remarkable component of unmeasured anions (SIG) during the acute phase. After correction of the physical-chemical model for the whole blood, the SIG variations disappeared because the buffer role of hemoglobin was relevant. CONCLUSION: Hemoglobin has a remarkable role in buffering metabolic acidosis during the shock phase of ISCLS. In these circumstances, the assessment of acid-base equilibrium in plasma alone may overestimate unmeasured anions. On the contrary, the physical-chemical model corrected for whole blood better explains the metabolic component of acid-base imbalance when marked shift of hemoglobin concentration occurs.

Coupled Plasma Filtration Adsorption for Treatment of Capillary Leak Syndrome Superimposed to Acute Generalized Exanthematous Pustolosis: A Case Report.

Coupled plasma filtration adsorption (CPFA) is an extracorporeal supportive therapy based on nonspecific adsorption of pro- and anti-inflammatory mediators combined with continuous renal replacement therapy. The main field of CPFA application is septic shock, and there are limited data about its efficacy in the treatment of other acute conditions characterized by a dysregulation in immune homeostasis. Capillary leak syndrome (CLS) defines a life-threatening condition sustained by hypercytokinemia and characterized by abrupt onset of increased capillary permeability leading to severe generalized edema and hypovolemic shock refractory to fluid administration. Therapy for CLS is not specific and, at present time, it consists in the use of steroids or intravenous immunoglobulins. We present the case of a 34-year-old woman who developed CLS superimposed to acute generalized exanthematous pustulosis after initiating therapy with hydroxychloroquine for undifferentiated connective tissue disease. CLS did not respond to steroids and intravenous immunoglobulins, while it was successfully treated with CPFA. This observation supports the possible role of CPFA in restoring a proper immunologic homeostasis not only in sepsis but also in other devastating conditions sustained by hypercytokinemia.

C1 esterase inhibitor in pediatric cardiac surgery with cardiopulmonary bypass plays a vital role in activation of the complement system.

Our prospective study was therefore designed to determine which part of the systemic inflammatory response after cardiac operations resulted from Cardiopulmonary bypass (CPB) in neonates and infants. After approval by the human ethical committee of the Gunma Children's Medical Center (GCMC) and informed consent of the parents, 40 consecutive term congenital heart disease patients aged until 1 year who underwent long CPB time (> 3 h) at surgery were included in the prospective study between January 2012 and December 2014. C1 esterase inhibitor (C1-inh) drug (@Berinert) was generously provided by CSL Behring (King of Prussia, PA). The C1-inh (20 IU/kg) was given intravenously 60 min after CPB. Blood samples for complement factors were obtained before and 48 h after administration of C1-inh. Six patients did not survive and their data were not included. Of 34 patients included, median age was 6.5 months, median body weight was 6050 g, and 16 (47%) were female. According to the Mann-Whitney U test, there were no differences between the two groups concerning demographic and intraoperative data, postoperative chemical data. C1q concentration was only significant lower in patients with C1-inh non-treated group than in patients with C1-inh treated group. But, the consumption of C1q, C3, C4, CH50, and C1-inh in patients with C1-inhibitor non-treated group was observed early postoperatively. There is a significant difference in the values before and after C1-inh treatment between the two groups. The lower value in the C1-inh-treated group is explained by the activation of the classical pathway through the replenishment of complements by C1-inh treatment. This study proposes the administration of C1-inh is an effective therapy to reduce the activation and improve the clinical capillary leak syndrome.

Neutrophil activation in systemic capillary leak syndrome (Clarkson disease).

Systemic capillary leak syndrome (SCLS; Clarkson disease) is a rare orphan disorder characterized by transient yet recurrent episodes of hypotension and peripheral oedema due to diffuse vascular leakage of fluids and proteins into soft tissues. Humoral mediators, cellular responses and genetic features accounting for the clinical phenotype of SCLS are virtually unknown. Here, we searched for factors altered in acute SCLS plasma relative to matched convalescent samples using multiplexed aptamer-based proteomic screening. Relative amounts of 612 proteins were changed greater than twofold and 81 proteins were changed at least threefold. Among the most enriched proteins in acute SCLS plasma were neutrophil granule components including bactericidal permeability inducing protein, myeloperoxidase and matrix metalloproteinase 8. Neutrophils isolated from blood of subjects with SCLS or healthy controls responded similarly to routine pro-inflammatory mediators. However, acute SCLS sera activated neutrophils relative to remission sera. Activated neutrophil supernatants increased permeability of endothelial cells from both controls and SCLS subjects equivalently. Our results suggest systemic neutrophil degranulation during SCLS acute flares, which may contribute to the clinical manifestations of acute vascular leak.

[The difference between hematocrit and plasma albumin in the course of systemic capillary leak syndrome: a systematic review].

OBJECTIVE: To investigate the changes of the difference between hematocrit (Hct) and plasma albumin (Alb) in the course of patients with systemic capillary leak syndrome (SCLS). METHODS: 281 case reports on human vascular leaking from the PubMed database from January 1st, 1996 to September 30th, 2015 were screened by systematic review method. Studies related to intracranial vascular leakage or intraocular vascular leakage were excluded. 213 articles related to SCLS were identified (164 in English, 16 in French, 8 in Japanese, 7 in German, 7 in Spanish, 4 in Italian, 2 in Chinese, 2 in Danish, 2 in Dutch, and 1 in Swedish). Due to the unavailable full text, 40 articles were excluded. A total of 173 articles related to SCLS were screened, of which 84 patients were enrolled. The data of Alb, Hct, age, gender, weight change, the length of hospital stay and 24-hour fluid infusion volume in SCLS patients were recorded, and the difference between Hct and plasma Alb (Hct-Alb) was calculated. According to the time when accurate Hct and Alb data were collected, they were divided into three groups: basic value group before onset, value group at onset and value group at recovery/discharge after onset. The levels of Hct and Alb and Hct-Alb at different time points in the course of the disease were compared. Pearson test was used to analyze the correlation between Hct-Alb and 24-hour fluid infusion volume. RESULTS: (1) A total of 12 cases with both exact values of Alb and Hct [or hemoglobin (Hb)] at the time of onset and recovery after treatment were selected from 84 cases of SCLS. It was shown that the Hct-Alb at the time of onset was significantly higher than that after treatment (26.33±16.36 vs. 0.55±8.81, P < 0.001). (2) A total of 17 cases with both the pre-onset baseline value and the exact values of Alb and Hct (or Hb) at the time of onset were selected from 84 cases of SCLS. It was shown that the Hct-Alb at the time of onset was significantly higher than that of the pre-onset basic value (15.83±11.37 vs. 1.82±7.97, P < 0.001). (3) A total of 14 cases with both exact values of Alb, Hct and 24-hour fluid infusion volume at the time of onset were selected from 84 cases of SCLS. It was shown that the Hct-Alb was 35.45±19.58 at the time of onset. The average 24-hour fluid infusion volume was (9.82±4.95) L, and the maximum volume of fluid infusion was 20 L. Pearson correlation analysis showed that the Hct-Alb at the time of onset was significantly positively correlated with 24-hour fluid infusion volume (r = 0.578, P < 0.05). CONCLUSIONS: In the analysis of SCLS cases published with adequate data available from 1996 to 2015, it was revealed that: (1) the difference in Hct-Alb levels at the onset of SCLS was 32.06±17.41. (2) The greater the difference between Hct and plasma Alb, the more amount of fluid required to maintain normal blood pressure.

Raised Serum Levels of Syndecan-1 (CD138), in a Case of Acute Idiopathic Systemic Capillary Leak Syndrome (SCLS) (Clarkson's Disease).

BACKGROUND Systemic capillary leak syndrome (SCLS) (Clarkson's disease) is a rare disorder of unknown etiology, characterized by transient episodes of hypotension, and the microvascular leak of fluids into the peripheral tissues, resulting in edema. Between 80-90% of patients with SCLS have a concomitant monoclonal gammopathy. Although translational in vitro studies have implicated vascular endothelial barrier dysfunction in the etiology of SCLS, the etiology and disease associations in clinical cases remain unknown. CASE REPORT We report a case of SCLS in a 49-year-old woman who initially presented with an upper respiratory tract infection, which was complicated by edema and compartment syndromes in the extremities that required fasciotomies. Serum levels of the cell surface heparan sulfate proteoglycan, syndecan-1 (CD138), a measure of endothelial surface glycocalyx (ESG) damage, were measured by enzyme-linked immunoassay (ELISA), peaked at up to 500 ng/mL (reference range, 50-100 ng/mL) and normalized on disease remission. CONCLUSIONS This case report supports the view that damage to the microvascular endothelium, has a role in the pathogenesis of acute SCLS. This case also indicated that monitoring serum levels of syndecan-1 (CD138) might be used to monitor the progression and resolution of episodes of SCLS.

Microangiopathic hemolytic anemia due to ADAMTS-13 loss in idiopathic systemic capillary leak syndrome.

Essentials Idiopathic systemic capillary leak syndrome (SCLS) is characterized by episodes of vascular leakage. We present the case of a patient with SCLS who developed microangiopathic hemolytic anemia (MAHA). We propose that this anemia is the result of ADAMTS-13 loss in the third-space fluid. This suggests that MAHA can occur in patients with significant extravasation of proteins. SUMMARY: Idiopathic systemic capillary leak syndrome (SCLS) is a rare process characterized by acute and recurrent episodes of vascular leakage with severe hypotension, hypoalbuminemia, hemoconcentration and edema. Anemia and thrombocytopenia are not part of this syndrome, but here we present the case of a pediatric patient with a clinical presentation consistent with SCLS who subsequently developed microangiopathic hemolytic anemia at a time when she had significant fluid loss and anasarca. Based on serial ADAMTS-13 levels, we propose that the anemia in this patient developed as a result of ADAMTS-13 loss in the third-space fluid, a novel mechanism for acquired microangiopathic hemolytic anemia.

Isoform D of vascular endothelial growth factor in systemic capillary leak syndrome: a case report.

BACKGROUND: Systemic capillary leak syndrome is a rare condition characterized by episodic attacks of hypovolemia due to systemic capillary hyperpermeability, which results in profound hypotension and edema. Although the implication of vascular endothelial growth factor, angiopoietin-2, and C-X-C motif chemokine 10 has been suggested, the pathogenesis of systemic capillary leak syndrome remains unclear. In this report, we describe a case of systemic capillary leak syndrome in which serum isoform D of vascular endothelial growth factor was elevated. To the best of our knowledge, this is the first reported case of systemic capillary leak syndrome in which isoform D of vascular endothelial growth factor is suggested as the plausible biomarker. CASE PRESENTATION: A 41-year-old Japanese man was transferred to our emergency department. He was hypotensive, tachycardic, and edematous over the trunk and all four limbs. He received aggressive intravenous fluid therapy and underwent fasciotomy of the right forearm to prevent muscle necrosis. A diagnosis of systemic capillary leak syndrome was suspected. The presence of serum monoclonal immunoglobulin G and κ light chain supported this diagnosis. Prevention of hypotensive crises was unsuccessfully attempted with theophylline, intravenous immunoglobulin, high-dose dexamethasone, bortezomib, melphalan, and prednisolone; however, the patient's attacks dramatically disappeared after the introduction of thalidomide. The serum of the patient was stored soon after the onset of hypotensive crisis and analyzed to profile possible mediators responsible for the capillary leak. The concentration of vascular endothelial growth factor, angiopoietin-2, and C-X-C motif chemokine 10 were all within normal ranges. Meanwhile, we found that isoform D of vascular endothelial growth factor was elevated, which was normalized after the introduction of thalidomide. CONCLUSIONS: In our patient, isoform D of vascular endothelial growth factor (instead of vascular endothelial growth factor) may have been a causative factor of hypotensive crises, since isoform D contributes to vascular endothelial growth factor receptor-2 signaling, which is the major mediator of the permeability-enhancing effects of vascular endothelial growth factor. We suggest the measurement of isoform D of vascular endothelial growth factor in patients with systemic capillary leak syndrome in whose serum vascular endothelial growth factor is not elevated.

Metabolic Serum Profiles for Patients Receiving Allogeneic Stem Cell Transplantation: The Pretransplant Profile Differs for Patients with and without Posttransplant Capillary Leak Syndrome.

Allogeneic stem cell transplantation is commonly used in the treatment of younger patients with severe hematological diseases, and endothelial cells seem to be important for the development of several posttransplant complications. Capillary leak syndrome is a common early posttransplant complication where endothelial cell dysfunction probably contributes to the pathogenesis. In the present study we investigated whether the pretreatment serum metabolic profile reflects a risk of posttransplant capillary leak syndrome. We investigated the pretransplant serum levels of 766 metabolites for 80 consecutive allotransplant recipients. Patients with later capillary leak syndrome showed increased pretherapy levels of metabolites associated with endothelial dysfunction (homocitrulline, adenosine) altered renal regulation of fluid and/or electrolyte balance (betaine, methoxytyramine, and taurine) and altered vascular function (cytidine, adenosine, and methoxytyramine). Additional bioinformatical analyses showed that capillary leak syndrome was also associated with altered purine/pyrimidine metabolism (i.e., metabolites involved in vascular regulation and endothelial functions), aminoglycosylation (possibly important for endothelial cell functions), and eicosanoid metabolism (also involved in vascular regulation). Our observations are consistent with the hypothesis that the pretransplant metabolic status can be a marker for posttransplant abnormal fluid and/or electrolyte balance.

Idiopathic systemic capillary leak syndrome in children.

Adult subjects with systemic capillary leak syndrome (SCLS) present with acute and recurrent episodes of vascular leak manifesting as severe hypotension, hypoalbuminemia, hemoconcentration, and generalized edema. We studied clinical disease characteristics, serum cytokine profiles, and treatment modalities in a cohort of children with documented SCLS. Six children with SCLS were recruited from the United States, Australia, Canada, and Italy. Serum cytokines from SCLS subjects and a group of 10 healthy children were analyzed. Children with SCLS (aged 5-11 years old) presented with at least 1 acute, severe episode of hypotension, hypoalbuminemia, and hemoconcentration in the absence of underlying causes for these abnormalities. In contrast to what is observed in adult SCLS, identifiable infectious triggers precipitated most episodes in these children, and none of them had a monoclonal gammopathy. We found elevated levels of chemokine (C-C motif) ligand 2 (CCL2), interleukin-8, and tumor necrosis factor α in baseline SCLS sera compared with the control group. All patients are alive and well on prophylactic therapy, with 4 patients receiving intravenous or subcutaneous immunoglobulins at regular intervals. The clinical manifestations of pediatric and adult SCLS are similar, with the notable exceptions of frequent association with infections and the lack of monoclonal gammopathy. Prophylactic medication, including high dose immunoglobulins or theophylline plus verapamil, appears to be safe and efficacious therapy for SCLS in children.

Heparin-binding protein (HBP/CAP37) - a link to endothelin-1 in endotoxemia-induced pulmonary oedema?

BACKGROUND: Vascular leakage and oedema formation are key components in sepsis. In septic patients, plasma levels of the vasoconstrictive and pro-inflammatory peptide endothelin-1 (ET-1) correlate with mortality. During sepsis, neutrophils release heparin-binding protein (HBP) known to increase vascular permeability and to be a promising biomarker of human sepsis. As disruption of ET-signalling in endotoxemia attenuates formation of oedema, we hypothesized that this effect could be related to decreased levels of HBP. To investigate this, we studied the effects of ET-receptor antagonism on plasma HBP and oedema formation in a porcine model of sepsis. In addition, to further characterize a potential endothelin/HBP interaction, we investigated the effects of graded ET-receptor agonist infusions. METHODS: Sixteen anesthetized pigs were subjected to 5 h of endotoxemia and were randomized to receive either the ET-receptor antagonist tezosentan or vehicle after 2 h. Haemodynamics, gas-exchange and lung water were monitored. In separate experiments, plasma HBP was measured in eight non-endotoxemic animals exposed to graded infusion of ET-1 or sarafotoxin 6c. RESULTS: Endotoxemia increased plasma ET-1, plasma HBP, and extravascular lung water. Tezosentan-treatment markedly attenuated plasma HBP and extravascular lung water, and these parameters correlated significantly. Tezosentan decreased pulmonary vascular resistance and increased respiratory compliance. In non-endotoxemic pigs graded ET-1 and sarafotoxin 6c infusions caused a dose-dependent increase in plasma HBP. CONCLUSIONS: ET-receptor antagonism reduces porcine endotoxin-induced pulmonary oedema and plasma levels of the oedema-promoting protein HBP. Moreover, direct ET-receptor stimulation distinctively increases plasma HBP. Together, these results suggest a novel mechanism by which ET-1 contributes to formation of oedema during experimental sepsis.

Systemic capillary leak syndrome: recognition prevents morbidity and mortality.

Idiopathic systemic capillary leak syndrome (SCLS) is extremely rare but carries a high morbidity and mortality. The diagnosis is made clinically by a classic triad of hypotension, hypoalbuminaemia and haemoconcentration. There have been recent advances in understanding the pathophysiological basis for SCLS and in effective prophylaxis. We report a case of SCLS to increase awareness of the condition and to highlight the benefits of prophylactic intravenous immunoglobulin in this condition.

Manifestaciones sistémicas del dengue / Systemic manifestations of dengue

Introducción: el dengue es una infección que puede afectar múltiples órganos.Objetivo: determinar la afectación multisistémica por dengue. Metodología: estudio observacional, descriptivo, prospectivo realizado en sujetos adultos con dengue grave con signos de alarma internados en el Hospital Nacional entre diciembre 2012 y mayo 2013. La infección debía estar confirmada con antígeno NS1 y/o serología IgM (+). Resultados: se encontró 10,1% de hepatitis, 85,6% de transaminitis, 48% con relación CPKmb/CPK total >5%, 22,5% de alteraciones electrocardiográficas, 70,4% con proteinuria de 24 hs elevada y 9,3% con proteinuria en rango nefrótico. Conclusiones: la afectación multisistémica es frecuente, generalmente pasa desapercibida y en general es autolimitada aunque se requieren más estudios para evaluar la evolución a largo plazo en estos casos.

Introduction: dengue is an infection that could affect multiple organs. Objective: to determine the multisystem involvement of dengue. Methodology: observational, descriptive, prospective study conducted in adult subjects with severe and warning signs of dengue admitted to the National Hospital between December 2012 and May 2013. Infection should be confirmed with NS1 antigen and / or IgM serology (+). Results: we found 10.1% of hepatitis, 85.6% of transaminitis the relation CPKmb / total CPK > 5% in 48%, electrocardiographic alterations in 22.5%, elevated proteinuria in 70.4% and nephrotic proteinuria in 9.3%. Conclusions: multisystemic involvement is frecuent, usually asymptomatic and generally self-limited although more studies are needed to evaluate the long-term outcome in these cases.

Circulating IL-6 mediates lung injury via CXCL1 production after acute kidney injury in mice.

Serum IL-6 is increased in patients with acute kidney injury (AKI) and is associated with prolonged mechanical ventilation and increased mortality. Inhibition of IL-6 in mice with AKI reduces lung injury associated with a reduction in the chemokine CXCL1 and lung neutrophils. Whether circulating IL-6 or locally produced lung IL-6 mediates lung injury after AKI is unknown. We hypothesized that circulating IL-6 mediates lung injury after AKI by increasing lung endothelial CXCL1 production and subsequent neutrophil infiltration. To test the role of circulating IL-6 in AKI-mediated lung injury, recombinant murine IL-6 was administered to IL-6-deficient mice. To test the role of CXCL1 in AKI-mediated lung injury, CXCL1 was inhibited by use of CXCR2-deficient mice and anti-CXCL1 antibodies in mice with ischemic AKI or bilateral nephrectomy. Injection of recombinant IL-6 to IL-6-deficient mice with AKI increased lung CXCL1 and lung neutrophils. Lung endothelial CXCL1 was increased after AKI. CXCR2-deficient and CXCL1 antibody-treated mice with ischemic AKI or bilateral nephrectomy had reduced lung neutrophil content. In summary, we demonstrate for the first time that circulating IL-6 is a mediator of lung inflammation and injury after AKI. Since serum IL-6 is increased in patients with either AKI or acute lung injury and predicts prolonged mechanical ventilation and increased mortality in both conditions, our data suggest that serum IL-6 is not simply a biomarker of poor outcomes but a pathogenic mediator of lung injury.

Vascular endothelial hyperpermeability induces the clinical symptoms of Clarkson disease (the systemic capillary leak syndrome).

The systemic capillary leak syndrome (SCLS) is a rare disorder characterized by transient episodes of hypotensive shock and anasarca thought to arise from reversible microvascular barrier dysfunction. Although the high prevalence of a monoclonal gammopathy of unknown significance in SCLS suggests a pathogenic contribution of endogenous immunoglobulins, the mechanisms of vascular hyperpermeability remain obscure. Herein, we report clinical and molecular findings on 23 patients, the largest SCLS case series to date. Application of episodic SCLS sera, but neither the purified immunoglobulin fraction nor sera obtained from patients during remission, to human microvascular endothelial cells caused vascular endothelial cadherin internalization, disruption of interendothelial junctions, actin stress fiber formation, and increased permeability in complementary functional assays without inducing endothelial apoptosis. Intravenous immunoglobulin, one promising therapy for SCLS, mitigated the permeability effects of episodic sera. Consistent with the presence of endogenous, nonimmunoglobulin, circulating permeability factor(s) constrained to SCLS episodes, we found that vascular endothelial growth factor (VEGF) and angiopoietin 2 (Ang2), were elevated in episodic SCLS sera but not in remission sera. Ab-based inhibition of Ang2 counteracted permeability induced by episodic SCLS sera. Comparable experiments with anti-VEGF Ab (bevacizumab) yielded less interpretable results, probably because of endothelial toxicity of VEGF withdrawal. Our results support a model of SCLS pathogenesis in which nonimmunoglobulin humoral factors such as VEGF and Ang2 contribute to transient endothelial contraction, suggesting a molecular mechanism for this highly lethal disorder.