Acute Vascular Thrombosis Research Articles

Endogenous Protein C Activation with AB002 Improves Outcomes in a Rat Model of Acute Ischemic Stroke

Background: The hemorrhagic side-effects of current thrombolytic agents limit their usefulness to a small subset of acute ischemic stroke patients. An early, effective, and hemostatically safe antithrombotic/neuroprotectant in addition to standard of care could improve outcomes. AB002 (E-WE thrombin) is an engineered recombinant thrombin analog (W215A/E217A) that activates cytoprotective and antithrombotic endogenous protein C on intravascular surfaces without any measurable procoagulant activity. In renal failure patients undergoing hemodialysis, AB002 treatment reduced dialyzer clotting without increasing markers of hemostasis impairment or coagulation (NCT03963895). Preclinical studies also showed that AB002 exhibits potent antithrombotic/thrombolytic effects in a non-human primate model of acute vascular graft thrombosis, as well as reduces infarct size and improves outcomes in an experimental acute myocardial ischemia-reperfusion model in mice. Aims: Here, we evaluated whether neuroprotective effects of AB002 can be observed following middle cerebral artery occlusion-recanalization (MCAO-R) in rats. Methods: The local animal care and use committee approved all studies. 8 to 9-week-old male rats (275-377 g) were anesthetized under isoflurane and a small laser-Doppler probe was affixed to the skull to monitor cortical perfusion and verify vascular occlusion and reperfusion. A silicone-coated 4-0 nylon monofilament was inserted into the right internal carotid artery (ICA) via the external carotid artery (ECA) until the laser-Doppler signal dropped to < 30 % of baseline. To evaluate the effect of AB002 on outcomes, rats (n = 4/ group) were treated with 25 µg/kg (0.25 mL/kg; i.v.) or saline placebo, administered 30 min after induction of ischemia. Since prolongation of the activated partial plasminogen time (aPTT) is a pharmacologic effect of high dose drug exposure, a 0.45 mL blood sample was collected at 20 min post treatment from the right jugular vein, processed to plasma and frozen for subsequent aPTT evaluation. At 90 min, the filament was removed, the surgical incisions were sutured closed and postoperative animals were monitored during recovery. Neurological performance scores and weight were assessed daily for 4 days. Rats were sacrificed on day 7 post-surgery and infarct size was measured using 2,3,5-triphenyltetrazolium chloride (TTC) staining. To account for the effect of edema, the infarcted area was estimated indirectly by subtracting the non-infarcted area in the ipsilateral hemisphere from the contralateral hemisphere and expressing infarct volume as a percentage of contralateral hemisphere. APTT was measured in duplicate using a KC-4 coagulometer. All analyses were performed by researchers blinded to treatment. Results: Compared to placebo, rats that received AB002 exhibited less ischemic damage, evidenced by a statistically significant reduction in infarct volume of the cortex (32.3% versus 8.9%, P < 0.05) and hemisphere (28.0% versus 9.8%, P < 0.01). In addition, rats had better neurological scores and greater weight gains during recovery following treatment with AB002, compared to placebo. Mean aPTT values were higher in AB002 treated rats compared to placebo (34 ± 2.2 s versus 21 ± 1.6 s), confirming drug exposure. Conclusions: Treatment with AB002 during ischemia reduced infarct volume and improved outcomes in the rat experimental stroke model. Considering its neuroprotective and antithrombotic properties, we propose that early treatment with AB002 may confer outcome benefit for patients experiencing acute thrombotic emergencies.

SARS-CoV-2 Positivity in Ambulatory Symptomatic Patients Is Not Associated With Increased Venous or Arterial Thrombotic Events in the Subsequent 30 Days

BackgroundCOVID-19 has been associated with increased risk of thromboembolism in critically ill patients. ObjectiveWe sought to examine the association of SARS-CoV-2 test positivity and subsequent acute vascular thrombosis, including venous thromboembolism (VTE) or arterial thrombosis (AT), in a large nationwide registry of emergency department (ED) patients tested with a nucleic acid test for suspected SARS-CoV-2. MethodsThe RECOVER (Registry of Potential COVID-19 in Emergency Care) registry includes 155 EDs across the United States. We performed a retrospective cohort study to produce odds ratios (ORs) for COVID-19–positive vs. COVID-19–negative status as a predictor of 30-day VTE or AT, adjusting for age, sex, active cancer, intubation, hospital length of stay, and intensive care unit (ICU) care. ResultsComparing 14,056 COVID-19–positive patients with 12,995 COVID-19–negative patients, the overall 30-day prevalence of VTE events was 1.4% vs. 1.3%, respectively (p = 0.44, χ2). Multivariable analysis identified that testing positive for SARS-CoV-2 status was negatively associated with both VTE (OR 0.76; 95% confidence interval [CI] 0.61–0.94) and AT (OR 0.51; 95% CI 0.32–0.80), whereas intubation, ICU care, and age 50 years or older were positively associated with both VTE and AT. ConclusionsIn contrast to other reports, results from this large, hetereogenous national sample of ED patients tested for SARS-CoV-2, showed no association between vascular thrombosis and COVID-19 test positivity.

Peripheral Non-cerebrovascular Arterial Stent Retriever Applications.

Several treatment options exist for acute intra-abdominal arterial thromboembolic events, including systemic thrombolytics, endovascular therapy, and less commonly surgery. A novel alternative treatment intervention for acute intra-abdominal arterial thrombus is the use of stent retriever (SR) devices, tools traditionally applied for treatment of acute vascular thrombosis in stroke patients. This brief report presents two cases of acute intra-abdominal arterial thrombosis successfully managed by deployment of SRs. Furthermore, it details the history, device mechanism, and design of SRs and describes cases in literature involving effective extracranial SR application.

Acute hepatitis post arteriovenous graft thrombectomy of hemodialysis vascular access.

The following paper reports the case of a woman on in-center hemodialysis through an arteriovenous graft, who attended with an acute vascular access thrombosis. Post percutaneous thrombectomy, the patient presented a rare case of self-limited acute hepatitis secondary to the revascularization procedure. We explain the probable trigger for this complication, its pathophysiology, management, and evolution.

A study of 25 patients on surgical management of acute mesenteric vascular thrombosis

Aim: To study outcome of surgical management of acute mesenteric vascular thrombosis likeExtent of diseaseExtent of resectionPost–operative survivalPatients and Methods: This study of 25 cases of diagnosed with acute mesenteric vascular thrombosis (MVT) from September 2016 to October 2018 in department of surgery, civil hospital Ahmadabad.Inclusion criteria: Patients with acute abdominal pain who is diagnosed as MVT in either on CT-scan or on exploration.Exclusion criteria: Patient with non-occlusive mesenteric ischemia that did not require laparotomy. Patient with only portal vein thrombosis.Results: Among 25 patients, 23 patients underwent exploratory laparotomy. Two patients were expired before surgery. In present study, maximum number of patients is in the age group 41-50 years. In 23 patients exploratory laparotomy was done based on their clinical feature with peritoneal signs with CECT-abdomen pelvis finding. Mortality rate was 64% in my study while 9 (36%) patients are in follow-up, so early diagnosis and decision of intervention has saved 36% of patients.Conclusion: Mesenteric vascular thrombosis is one of the most lethal vascular disorders. So, this type of moribund conditions require urgent use of abdominal CT-Scan and increasing use of anti-coagulative medication improved the outcome in patients. This disease entity is lethal prompt decisions should be taken for patients survival.

The treatment effect of rivaroxaban on clot characteristics in patients who present acutely with first time deep vein thrombosis.

The acute vascular disease deep vein thrombosis (DVT) requires oral anticoagulants to prevent progression. Monitoring therapeutic efficacy of direct oral anticoagulants (DOAC), including rivaroxaban, is problematic as no reliable test is available. Advances in rheometry have led to the development of a functional coagulation biomarker using Gel Point (GP) analysis which assesses clot structure formation. The biomarker measures incipient clot formation time (TGP) and quantifies fibrin clot structure in terms of fractal dimension (df). This study aimed to investigate clot structure formation in first time DVT and the effect of rivaroxaban treatment. This prospective observational cohort study measured the GP and standard laboratory markers at three sample points: pre-treatment and at 20 and 60 days following 15 mg BD and 20 mg OD rivaroxaban respectively. Forty DVT patients (mean age 64 years [SD±14.8]; 23 males, 17 female) were recruited. The results show that DVT vs non-DVT patients did not have a significantly different GP profile (df: 1.72±0.06 vs 1.70±0.06 and TGP: 267±68 sec vs 262±73 sec) with both within the defined healthy index. In addition, rivaroxaban therapy increased TGP to 392 s (±135 s) after 20 days, and subsequently increased to 395 s (±194 s) at 60 days but did not significantly increase df (from 1.69±0.05 to 1.71±0.06). The results indicate in this cohort of DVT patients there was no underlying hypercoagulable effect as determined by gel point analysis. Furthermore, the anticoagulant effect of rivaroxaban prolonged clotting, suggesting a protective effect against clot formation, without significantly reducing clot microstructural properties.

Cardiovascular Co-morbidity in COVID-19 Pandemic

At present, we are in the middle of a global pandemic due to COVID 19 disease caused by SARS-CoV-2 viral infection. It has now spread virtually to every corner of the globe. Medical professionals are faced with the challenge of managing diverse clinical manifestations and multisystem involvement of this infection. Although respiratory system is mainly involved COVID-19 disease, there have been diverse manifestations within the cardiovascular (CV) system that posing unique therapeutic challenges. Clinically, a patient may have features of myocarditis, heart failure, acute myocardial infarction, arrhythmia, and vascular thrombosis. Of these manifestations, the most common mechanism implicated is direct myocardial injury, whereas systemic inflammation, oxygen supply-demand mismatch, plaque rupture have also been suggested. Furthermore, current available data suggest cardiovascular related manifestations lead to increased morbidity and mortality. Also, patients with underlying cardiac conditions are more prone for severe disease and death. Although there are limited treatment options available for COVID-19 currently, it is imperative that the potential cardiovascular implications of these therapies are to be considered in these patients. There is need to review current available information regarding the implication of cardiovascular co-morbidity in COVID-19 disease so that we have uptodate and better understanding in this global problem. This review highlights the manifestations, pathophysiological mechanisms for cardiovascular manifestations of COVID-19 and address specific concerns of cardiac patients regarding medications and further management.

S1671 Ischemic Colitis Secondary to Cryoglobulinemic Vasculitis: A Rare Entity

INTRODUCTION: Cryoglobulinemic vasculitis is a small-to-medium vessel vasculitis caused by cryoglobulin-containing immune complexes mainly involving the skin, the joints, the peripheral nerve system, and the kidneys. Gastrointestinal involvement can be seen in approximately 5% of the cases, manifested as ischemic bowel disease, gastrointestinal hemorrhage, peritonitis, and acute lesions of the pancreas and gallbladder. We present the case of a 66-year-old female patient who developed ischemic colitis as a consequence of cryoglobulinemic vasculitis. CASE DESCRIPTION/METHODS: The patient is a 66-year-old female with a medical history of hypertension, cerebrovascular accident, congestive heart failure, mitral valve regurgitation, and cryoglobulinemic vasculitis who was taken to the emergency department for confusion. She was initially admitted to the intensive care unit under the impression of acute encephalopathy secondary to hypoglycemia, and heart failure exacerbation. Her course was complicated with hematochezia and hematemesis, for which the gastroenterology team was consulted. On physical exam the patient was afebrile, hemodynamically stable, the abdomen was soft and diffusely tender. She also had ischemia of her digits (Figure 1). The rectal exam revealed blood in stools. Computed tomography angiography (CTA) of the abdomen revealed moderate to high-grade stenosis of the proximal celiac axis with post stenotic dilation. She then underwent a colonoscopy that revealed patchy erythematous mucosa with ulcerations/denudation and pseudomembrane formation in the examined portion of the colon (Figure 2). The endoscopic picture was consistent with underlying ischemic pathology. Biopsies were taken and pathology showed surface epithelial necrosis in the background of acute inflammation and vascular thrombosis, consistent with ischemic colitis (Figure 3). The clinical course was posteriorly complicated with acute respiratory failure secondary to severe mitral regurgitation for which was transferred to another facility for mitral valve repair and was lost to follow up. DISCUSSION: Cryoglobulinemic vasculitis usually runs a slow course, but flares can present with life-threatening manifestations, of which gastrointestinal involvement is one of the most severe. Prompt diagnosis and adequate immunosuppressive therapy, revascularization, or surgical treatment in the appropriate settings are crucial for a successful recovery and prevention of irreversible damage or death.Figure 1.: Physical exam showing ischemic changes of the patients digits.Figure 2.: Colonoscopy revealing patchy erythematous mucosa with ulcerations and pseudomembrane formation.Figure 3.: Surface epithelial necrosis in the background of acute inflammation and vascular thrombosis, consistent with ischemic colitis.

Regulation of von-Willebrand Factor Secretion from Endothelial Cells by the Annexin A2-S100A10 Complex.

Endothelial cells serve as gatekeepers of vascular hemostasis and local inflammatory reactions. They can rapidly respond to changes in the environment, caused, for example, by blood vessel injury, tissue damage or infection, by secreting in a strictly regulated manner factors regulating these processes. These factors include adhesion receptors for circulating leukocytes and platelets, P-selectin and von-Willebrand factor (VWF) that are stored in specialized secretory granules of endothelial cells, the Weibel-Palade bodies (WPB). Acute exposure of these adhesion molecules converts the endothelial cell surface from an anti-adhesive state enabling unrestricted flow of circulating blood cells to an adhesive one capable of capturing leukocytes (through P-selectin) and platelets (through VWF). While these are important (patho)physiological responses, compromised or dysregulated WPB secretion can cause pathologies such as excessive bleeding or vascular occlusion. Several factors are involved in regulating the exocytosis of WPB and thus represent potential targets for therapeutic interventions in these pathologies. Among them, the annexin A2 (AnxA2)-S100A10 complex has been shown to participate in the tethering/docking of secretion-competent WPB at the plasma membrane, and interference with AnxA2/S100A10 expression or complex formation significantly reduces acute WPB exocytosis and VWF release. Thus, developing specific means to efficiently block AnxA2-S100A10 complex formation in endothelial cells could lead to novel avenues towards interfering with acute vascular thrombosis.

Chylothorax as a Risk Factor for Thrombosis in Adults: A Proof-of-Concept Study

Postoperative chylothorax in children is associated with an increased risk of vascular thrombosis, hypothesized to be from loss of antithrombin into chylous fluid resulting in a hypercoagulable state. In adults, an increased thrombotic risk with chylothorax has not been described. Adults undergoing Ivor-Lewis esophagogastrectomy have two strong thrombotic risk factors-active malignancy and postoperative state-allowing for relative homogeneity in baseline thrombotic risk; therefore, we studied the association of chylothorax with thrombosis in this population. We performed a single-center retrospective cohort study at a tertiary care academic center. Patients included adults undergoing Ivor-Lewis esophagogastrectomy between January 1, 2006, and December 31, 2012. We collected demographics, pleural fluid characteristics, and relevant imaging within 30 days after the operation. Using nominal logistic regression, we studied the effects of chylothorax, age, sex, body mass index, American Society of Anesthesiologists Physical Status Classification, operative duration, and hospital length of stay on the incidence of postoperative thrombosis. We identified 608 patients who underwent Ivor-Lewis esophagogastrectomy. Of these, 524 (86.2%) had no pleural fluid analysis, 48 (7.9%) had nonchylous effusions, and 36 (5.9%) had chylothoraces, with incident acute vascular thrombosis within 30 days postoperatively occurring in 22 of 524 (4.2%), 2 of 48 (4.2%), and 8 of 36 (22.2%), respectively (p= 0.001). In multivariate analyses, after adjusting for the above factors, chylothorax was associated with significantly higher odds of any vascular thrombosis (odds ratio, 5.46; p= 0.0013) and deep venous thrombosis/pulmonary embolism (odds ratio, 6.76; p=0.0016). Chylothorax is associated with a significantly higher incidence of vascular thrombosis in adults undergoing Ivor-Lewis esophagogastrectomy. Vascular thrombosis was associated with a significantly higher 90-day mortality rate.

Utilization of diagnostic ultrasound and intravenous lipid-encapsulated perfluorocarbons in non-invasive targeted cardiovascular therapeutics.

Diagnostic ultrasound (DUS) pressures have the ability to induce inertial cavitation (IC) of systemically administered microbubbles; this bioeffect has many diagnostic and therapeutic implications in cardiovascular care. Diagnostically, commercially available lipid-encapsulated perfluorocarbons (LEP) can be utilized to improve endocardial and vascular border delineation as well as assess myocardial perfusion. Therapeutically, the liquid jets induced by IC can alter endothelial function and dissolve thrombi within the immediate vicinity of the cavitating microbubbles. The cavitating LEP can also result in the localized release of any bound therapeutic substance at the site of insonation. DUS-induced IC has been tested in pre-clinical studies to determine what effect it has on acute vascular and microvascular thrombosis as well as nitric oxide (NO) release. These pre-clinical studies have consistently shown that DUS-induced IC of LEP is effective in restoring coronary vascular and microvascular flow in acute ST segment elevation myocardial infarction (STEMI), with microvascular flow improving even if upstream large vessel flow has not been achieved. The initial clinical trials examining the efficacy of short pulse duration DUS high mechanical index impulses in patients with STEMI are underway, and preliminary studies have suggested that earlier epicardial vessel recanalization can be achieved prior to arriving in the cardiac catheterization laboratory. DUS high mechanical index impulses have also been effective in pre-clinical studies for targeting DNA delivery that has restored islet cell function in type I diabetes and restored vascular flow in the extremities downstream from a peripheral vascular occlusion. Improvements in this technique will come from three dimensional arrays for therapeutic applications, more automated delivery techniques that can be applied in the field, and use of submicron-sized acoustically activated LEP droplets that may better permeate the clot prior to DUS activation and cavitation. This article will focus on these newer developments for DUS therapeutic applications.Electronic supplementary materialThe online version of this article (doi:10.1186/s40349-016-0062-y) contains supplementary material, which is available to authorized users.

Abstract P5-05-03: Targeting hypoxia-induced cancer cell metabolism in breast cancer

Abstract Rational: Hypoxia contributes to high tumor grade in human breast cancer and is associated with resistance to radiation and chemotherapy. Hypoxia is generally encountered in perinecrotic regions throughout the heterogeneous tumor microenvironment and may be due to rapid tumor grow, insufficient neovascularization or as a result of antiangiogenic and chemoradiation therapies which cause acute vascular thrombosis. Cancer stem-like cells residing within these hypoxic zones compensate for the low concentration of oxygen through alterations in metabolism that favor aerobic glycolysis and de novo fatty acid synthesis. These metabolic derangements are known to enhance proliferation and survival, although the contributing molecular mechanisms are not fully understood. Here we evaluate a panel of FDA approved azole drugs for alternative use as glycolytic inhibitors with and without the fatty acid synthase (FASN) inhibitor, TBV-3166. TVB-3166 is currently in phase II clinical trials and is the first FASNi approved for human testing. METHODS: IC50 values of single or combined agents were determined by MTT under conditions of normoxia and hypoxia using sister plates of estrogen receptor positive or triple negative breast cancer cells, MCF-7, SKBR3 and MDA-MB-231. RESULTS: Because the combination of Itraconazole and TVB-3166 displayed a synergistic enhancement in cell death at a low nanomolar concentrations in MCF-7 cells, we next assessed the efficacy of these drugs in an in vivo xenograft model of breast cancer. Here, 3.6 million MCF-7 cells were implanted into the right flanks of (n=16) athymic nude mice, which were then randomized by tumor volume into 4 groups. Itraconazole and TVB-3166 were administered at 60 mg/kg daily by oral gavage as single agents or combined throughout the duration of the study. After three weeks, mice treated with combined inhibitors exhibited best response with a statistically significant decrease in tumor volume compared to the vehicle control group. CONCLUSION: Given the significant tumor response to the combination of metabolic inhibitors, further studies that evaluate the radiosensitizing effects under conditions of hypoxia are warranted. By targeting hypoxia-induced metabolic pathways during radiotherapy, we may enhance cancer stem-like cell death to dramatically improve patient outcome. Citation Format: Cavazos DA, Gruslova A, Garcia M, Brenner AJ. Targeting hypoxia-induced cancer cell metabolism in breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-05-03.

METB-03TARGETING CANCER CELL METABOLISM IN GLIOBLASTOMA

RATIONALE: Hypoxia contributes to high tumor grade in human glioblastoma and is associated with resistance to radiation and chemotherapy. Hypoxia is generally encountered in perinecrotic regions throughout the heterogeneous tumor microenvironment and may be due to rapid tumor grow, insufficient neovascularization or as a result of antiangiogenic and chemoradiation therapies which cause acute vascular thrombosis. Cancer stem-like cells residing within these hypoxic zones compensate for the low concentration of oxygen through alterations in metabolism that favor aerobic glycolysis and de novo fatty acid synthesis. These metabolic derangements are known to enhance proliferation and survival, although the contributing molecular mechanisms are not fully understood. Here we evaluate a panel of FDA approved azole drugs for alternative use as glycolytic hexoinase 2 inhibitors with and without the fatty acid synthase (FASN) inhibitor, TBV-3166. TVB-3166 is currently in phase II clinical trials and is the first FASNi approved for human testing. METHODS: IC50 values of single or combined agents were determined by MTT under conditions of normoxia and hypoxia using sister plates of the commercial GBM cell lines, U87 and T98. Because the combination of Itraconazole and TVB-3166 displayed a synergistic enhancement in cell death at low nanomolar concentrations in GBM cells, we next assessed the efficacy of these drugs on clonogenic potential. Here, 100 cells were seeded onto 10 cm2 plates and grown under normoxic or hypoxic conditions for 10 days after exposure to single or combined agents. After 10 days post-treatment the plates treated with the combination of metabolic inhibitors exhibited best response. CONCLUSION: Given the significant clonogenic response to the combination of metabolic inhibitors, additional studies that further evaluate the chemotherapeutic effects of these metabolic inhibitors are warranted. By targeting hypoxia-induced metabolic pathways, we may enhance cancer stem-like cell death and eventually improve patient outcome.

Lack of Substantial Antithrombotic Effect of Low Circulating Coagulation Factor VII Levels in a Baboon Model of Acute Vascular Graft Thrombosis

Localized pathologic thrombin generation by the tissue factor/factor VII (TF/FVII)-dependent extrinsic pathway of blood coagulation has been suggested to be the key initiator of thrombosis following blood vessel injury and exposure of blood to the subendothelial matrix that contains coagulation/platelet activator matrix proteins, such as collagen and TF. Inherited FVII deficiency (<1% FVII activity) causes severe symptomatic coagulopathy. Yet, there are no data to suggest that it also protects against thrombosis; in fact, the contrary may be true (Giansily-Blaziot et al, Thromb Res. 2012;130:S47). It has been reported that active site-blocked FVIIa (FVIIai) at doses that do not affect the prothrombin time (PT) help restore cyclic flow variations in stenotic carotids of rabbits without affecting clotting times (Cirillo et al., J Thromb Haemost. 2003;1:992). However, in a previous primate study, we could not demonstrate the antithrombotic effect of FVIIai at a dose that caused significant prolongation of the bleeding time in our established baboon model of acute vascular graft thrombosis (Gruber et al., Thromb Res. 2007;119:121-7). The present study was designed to determine the effect of severe yet incomplete experimental FVII deficiency in the same standardized primate model of thrombosis that we used for evaluating the effect of FVIIai. First, baseline (negative control) graft thrombosis was evaluated in baboon studies (N=6), followed by establishing the efficacy of the low molecular weight heparin (LMWH), enoxaparin, at a single 1 mg/kg dose, as positive control. LMWH at this dose was moderately but demonstrably antithrombotic, as assessed by measuring the inhibition of fibrin and platelet deposition in TF- or collagen-coated vascular grafts. Reducing circulating FVII activity levels by 95% to 99% after a 2 week long pre-treatment with a FVII antisense oligonucleotide (FVII ASO) caused significant and sustained (>30 days) systemic anticoagulation, as evidenced by PT increase that reached 2.0-2.6 fold baseline. Surprisingly, fibrin deposition was not affected, and platelet deposition in the thrombogenic devices (N=8) was also not inhibited on collagen-coated grafts, and only marginally inhibited on TF. Treatment with vitamin K antagonists that reduces the level of vitamin K-dependent coagulation enzymes, including FVII, also prolong the PT. Warfarin-induced doubling of the PT is antithrombotic and moderately safe. Yet, in this study where FVII ASO selectively reduced FVII levels, the observed and significant PT prolongation was not associated with anti-fibrin or anti-platelet effects on collagen, and showed an unremarkable anti-platelet effect on TF. We conclude that if the TF/FVII pathway drives the propagation of large vessel thrombi under flow in primates indeed, very low FVII activity (≈1%) must be sufficient to sustain thrombogenesis, supporting the clinical data on deep vein thrombosis, routinely observed in FVII deficiency. Since FVII activity cannot be entirely eliminated without bleeding risks, these data suggest that targeting the TF/FVII pathway with FVII ASO or inhibitors may not be an entirely sound antithrombotic treatment approach. DisclosuresWallisch:Aronora, Inc: Employment. Tucker:Aronora, Inc: Employment, Equity Ownership. Murray:Isis Pharmaceuticals, Inc.: Employment. Crosby:Isis Pharmaceuticals, Inc.: Employment. Monia:Isis Pharmaceuticals, Inc.: Employment. Gruber:Aronora, Inc: Employment, Equity Ownership.

Acute Absorb bioresorbable vascular scaffold thrombosis in ST-segment elevation myocardial infarction: to stent or not to stent?

Acute Absorb bioresorbable vascular scaffold thrombosis in ST-segment elevation myocardial infarction: to stent or not to stent?

Hemolysis and free hemoglobin revisited: exploring hemoglobin and hemin scavengers as a novel class of therapeutic proteins

AbstractHemolysis occurs in many hematologic and nonhematologic diseases. Extracellular hemoglobin (Hb) has been found to trigger specific pathophysiologies that are associated with adverse clinical outcomes in patients with hemolysis, such as acute and chronic vascular disease, inflammation, thrombosis, and renal impairment. Among the molecular characteristics of extracellular Hb, translocation of the molecule into the extravascular space, oxidative and nitric oxide reactions, hemin release, and molecular signaling effects of hemin appear to be the most critical. Limited clinical experience with a plasma-derived haptoglobin (Hp) product in Japan and more recent preclinical animal studies suggest that the natural Hb and the hemin-scavenger proteins Hp and hemopexin have a strong potential to neutralize the adverse physiologic effects of Hb and hemin. This includes conditions that are as diverse as RBC transfusion, sickle cell disease, sepsis, and extracorporeal circulation. This perspective reviews the principal mechanisms of Hb and hemin toxicity in different disease states, updates how the natural scavengers efficiently control these toxic moieties, and explores critical issues in the development of human plasma–derived Hp and hemopexin as therapeutics for patients with excessive intravascular hemolysis.

Histopathological changes induced by extracts from the tissue covering the stingers of Potamotrygon falkneri freshwater stingrays

Pain is the most conspicuous symptom observed in patients wounded by stingrays, and skin necrosis is common in accidents by freshwater stingrays. The extract from the stinger integumentary tissue of Potamotrygon falkneri containing toxic components (venom) was tested for its ability to induce histopathological changes in the dorsal skin of mice at different times. 3–6 h after injection, foci of necrosis in isolated basal epidermal cells were observed. Full coagulative necrosis of the skin, subcutaneous tissue and skeletal muscle was evident as soon as 24 h after venom exposure, with a clear demarcation from the normal skin. After 48 h, round collections of necrotic cells start to coalesce originating extensive skin necrotic plaques that detach from viable tissue after 72–96 h. Inflammatory infiltrate was observed after 6 h, but was always mild. Acute vascular thrombosis was rare, and hemorrhage was not present at any time. Superficial bacterial infection was present in two of the examined cases. In conclusion, the venom of P. falkneri is responsible for the development of an early necrosis with mild inflammatory reaction, probably due to direct action of the venom. The severe local damage is probably worsened by the mechanical trauma caused by the stinger.

Acute hyperparathyroidism and vascular thrombosis; An unrecognized association

Acute hyperparathyroidism and vascular thrombosis; An unrecognized association

Shortened activated partial thromboplastin time, a hemostatic marker for hypercoagulable state during acute coronary event

Various factors may contribute to a hypercoagulable state and acute vascular thrombosis. A prospective study was conducted involving 165 coronary heart disease (CHD) patients from the Cardiology Unit, Hospital Universiti Sains Malaysia. The purpose of this study was to investigate the relationship among factor VIII (FVIII), prothrombin time (PT), activated partial thromboplastin time (APTT), and activated protein C resistance (APC-R) state among CHD patients and to look for potential clinical applications from these laboratory findings. There were 110 cases diagnosed as acute coronary syndrome (ACS), whereas another 55 were stable coronary artery disease (SCAD) patients. PT, APTT, FVIII, and APC-R assays were performed on all subjects. There was a significant difference between the FVIII level and the APTT results (P value < 0.0001). A negative relationship was found between the FVIII level and the APTT from linear regression analysis (R(2) = 10%, P value < 0.0001). For each 1% increase in the FVIII level, the APTT was reduced by 0.013 s (95% confidence interval (CI) between -0.019 and -0.007). Interestingly, none of the SCAD patients had abnormally short APTT. Approximately 68.4% of cases with a positive APC-R assay were found to have a high FVIII level. In conclusion, the APTT test is a potential hemostatic marker for hypercoagulable state including in arterial thrombosis.

Inhibition of acute vascular thrombosis in chimpanzees by an anti-human tissue factor antibody targeting the factor X binding site

Tissue factor (TF) antagonists targeting the factor VII (FVII) binding domain have been shown to interrupt acute vascular thrombus formation without impairing haemostasis in non-human primates. In this study, we evaluate whether a human/mouse chimeric monoclonal antibody (ALT-836, formerly known as Sunol-cH36) blocking the factor X/factor IX (FX/FIX) binding site of tissue factor could achieve similar clinical benefits in an arterial thrombosis model induced by surgical endarterectomy in chimpanzees. In this model, sequential surgical endarterectomies on right and left superficial femoral arteries were performed 30 days apart in five chimpanzees. A bolus (1 mg/kg) of ALT-836 was injected intravenously immediately preceding the restoration of flow in the endarterectomised femoral artery. Pre-surgical labelling of autologous platelets using (111)In-Oxine and post-surgical gamma camera imaging of (111)In-platelet deposition at endarterectomy sites was performed. The manipulated arterial segments were harvested for patency analysis 30 days following surgery. The results indicate that ALT-836 was highly effective at reducing acute vascular thrombosis, with no significant variations in surgical blood loss and template-bleeding time in the treated group compared to the control animals. These data suggest that ALT-836 is an effective and safe antithrombotic agent in preventing TF-initiated vascular thrombogenesis without compromising haemostasis.