scholarly journals The Evolution of Safe and Effective Coaguligands for Vascular Targeting and Precision Thrombosis of Solid Tumors and Vascular Malformations

Biomedicines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 776
Author(s):  
Fahimeh Faqihi ◽  
Marcus A. Stoodley ◽  
Lucinda S. McRobb

In cardiovascular and cerebrovascular biology, control of thrombosis and the coagulation cascade in ischemic stroke, myocardial infarction, and other coagulopathies is the focus of significant research around the world. Ischemic stroke remains one of the largest causes of death and disability in developed countries. Preventing thrombosis and protecting vessel patency is the primary goal. However, utilization of the body’s natural coagulation cascades as an approach for targeted destruction of abnormal, disease-associated vessels and tissues has been increasing over the last 30 years. This vascular targeting approach, often termed “vascular infarction”, describes the deliberate, targeted delivery of a thrombogenic effector to diseased blood vessels with the aim to induce localized activation of the coagulation cascade and stable thrombus formation, leading to vessel occlusion and ablation. As systemic delivery of pro-thrombotic agents may cause consternation amongst traditional stroke researchers, proponents of the approach must suitably establish both efficacy and safety to take this field forward. In this review, we describe the evolution of this field and, with a focus on thrombogenic effectors, summarize the current literature with respect to emerging trends in “coaguligand” development, in targeted tumor vessel destruction, and in expansion of the approach to the treatment of brain vascular malformations.

2012 ◽  
Vol 32 (10) ◽  
pp. 1831-1840 ◽  
Author(s):  
Peter Kraft ◽  
Simon F De Meyer ◽  
Christoph Kleinschnitz

The present antithrombotic drugs used to treat or prevent ischemic stroke have significant limitations: either they show only moderate efficacy (platelet inhibitors), or they significantly increase the risk for hemorrhages (thrombolytics, anticoagulants). Although most strokes are caused by thrombotic or embolic vessel occlusions, the pathophysiological role of platelets and coagulation is largely unclear. The introduction of novel transgenic mouse models and specific coagulation inhibitors facilitated a detailed analysis of molecular pathways mediating thrombus formation in models of acute ischemic stroke. Prevention of early platelet adhesion to the damaged vessel wall by blocking platelet surface receptors glycoprotein Ib alpha (GPIb α) or glycoprotein VI (GPVI) protects from stroke without provoking bleeding complications. In addition, downstream signaling of GPIb α and GPVI has a key role in platelet calcium homeostasis and activation. Finally, the intrinsic coagulation cascade, activated by coagulation factor XII (FXII), has only recently been identified as another important mediator of thrombosis in cerebrovascular disease, thereby disproving established concepts. This review summarizes the latest insights into the pathophysiology of thrombus formation in the ischemic brain. Potential clinical merits of novel platelet inhibitors and anticoagulants as powerful and safe tools to combat ischemic stroke are discussed.


2021 ◽  
pp. 1-8
Author(s):  
Hazem Kamal ◽  
Mohamed Khodery ◽  
Hassan Elnady ◽  
Ahmed Borai ◽  
Jan Hendrik Schaefer ◽  
...  

<b><i>Background:</i></b> The burden of stroke weighs heavily in developing countries where recurrence rates clearly exceed that of developed countries. The impact of nonadherence to antithrombotic treatment within this context has been poorly investigated. <b><i>Objective:</i></b> The objective of this study was to evaluate patients with recurrent ischemic stroke in Egypt and Germany with focus on stroke subtype distribution and adherence to antithrombotic therapy. <b><i>Methods:</i></b> We conducted a comparative cross-sectional retrospective cohort study enrolling consecutive patients hospitalized for recurrent ischemic stroke in 2017 in 2 academic centers. Data were collected on demographics, risk factors, stroke subtypes, and medication adherence. Nonadherence to antithrombotic agents was analyzed at the time point of index stroke (recurrent stroke). Predictors of nonadherence were analyzed using logistic regression. <b><i>Results:</i></b> A total of 373 Egyptian and 468 German patients with ischemic stroke were included. The proportion of recurrent ischemic stroke among all patients was higher in the Egyptian cohort compared to the German cohort (33 vs. 10%, <i>p</i> &#x3c; 0.05). Small-vessel occlusion stroke was the most frequent subtype in Egyptians, with a significantly greater proportion than in Germans (45 vs. 26%, <i>p</i> &#x3c; 0.05). Nonadherence to antiplatelets at the time point of the recurrent stroke was higher in Egyptians than in Germans (82 vs. 19%, <i>p</i> &#x3c; 0.001). Low educational attainment among Egyptians (OR 0.14, 95% CI [0.00–0.19], <i>p</i> &#x3c; 0.01) and high comorbidity scores among Germans (OR 2.45, 95% CI [1.06–5.66], <i>p</i> &#x3c; 0.05) were found to be predictors of nonadherence to antithrombotic treatment. <b><i>Conclusions:</i></b> The large stroke recurrence burden in Egypt may be partly explained by differing adherence to secondary preventative antithrombotic pharmacotherapy. Predictors of medication nonadherence have to be addressed to reduce stroke recurrence disparities.


1978 ◽  
Vol 48 (2) ◽  
pp. 201-219 ◽  
Author(s):  
Richard A. Dirrenberger ◽  
Thoralf M. Sundt

✓ The healing of the canine carotid endarterectomy was defined at intervals from 30 minutes to 3 months after surgery by means of angiography, light microscopy, and scanning electron microscopy. Immediately after flow was established, a fibrin-platelet carpet formed on the endarterectomized surface. A typical thrombus formed on this initial layer resulting in vessel occlusion in 52% of non-heparinized animals. By 48 hours after surgery, there was little evidence of active thrombus formation, and reendothelialization from existing endothelial cells was noted. One week later, most of the mural thrombus had disappeared and re-endothelialization was well underway; by 3 months after surgery, re-endothelialization was complete. Intraoperative heparinization resulted in a striking reduction in mural thrombus formation and 100% patency rate. Vessel closure with vein-patch grafts resulted in no improvement of vessel patency. However, the results of this aspect of the study cannot be totally extrapolated to human carotid endarterectomy for the reasons discussed. The survival of the vein-patch grafts was investigated.


2020 ◽  
Vol 10 (9) ◽  
pp. 590
Author(s):  
Kurt Cicilioni ◽  
Brian Cristiano ◽  
J. Paul Jacobson ◽  
Daniel Hoss ◽  
Matthew Lund ◽  
...  

Background and Importance: Since Trousseau’s initial publication, the development of thromboembolic events related to malignancy has been well established. The pathophysiology of this is understood to be through activation of the coagulation cascade through neoplastic cells themselves or the therapy initiated (chemotherapy or surgery). To date, there have been a variety of studies, such as the OASIS-CANCER trial, which highlight the relationship of hypercoagulability to ischemic stroke. Despite these efforts, clear evidence is lacking for the utilization of antiplatelet or anticoagulation therapy in the secondary prevention of stroke following mechanical thrombectomy in patients with suspected or confirmed malignancy. Clinical Presentation: A 71-year-old female with a history of immune thrombocytopenia, diabetes mellitus, and hypertension who was undergoing an evaluation for a lung nodule, later determined to be adenocarcinoma of the lung, underwent three successful mechanical thrombectomies for acute ischemic stroke with large vessel occlusion over a one month period. This patient had improved National Institutes of Health Stroke Scale (NIHSS) scores following each of her thrombectomies. However, her history of immune thrombocytopenia and underlying malignancy complicated her discharge medication regimen following each of her thrombectomies and may have contributed to her repeat strokes. Conclusion: Clear guidance is lacking regarding the utilization of antiplatelet and anticoagulation therapy in patients with suspected or confirmed malignancy following mechanical thrombectomy. Review of the literature suggests that controlling a patient’s hypercoagulability may lead to improved clinical outcomes, but further clinical trials are warranted.


2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Wing Tak Wong ◽  
Shuangtao Ma ◽  
Yu Huang ◽  
Xiaoyu Tian

Objective: Atherosclerosis, which underlies most cardiovascular diseases (CVD), is a leading cause of mortality and disability in developed countries. The endothelium is an important site of vascular regulation, and its dysfunction initiates atherosclerosis and supports its progression. Current drug therapies, percutaneous angioplasty, and stenting alleviate symptoms but do not reverse atherosclerosis. Thus, more effective strategies that prevent or reverse atherosclerosis via improved endothelial function are needed. Approach: E-selectin serves as a surface marker of inflamed endothelial cells (ECs). We attempted to deliver microRNA (miR)-146a and miR-181b to inflamed endothelium covering atherosclerotic plaques with an E-selectin-targeting multistage vector (ESTA-MSV to inhibit atherosclerosis. Cy5-conjugated miR-146a and miR-181b were packaged in polyethylene glycol-polyethyleneimine (PEG/PEI) nanoparticles and then loaded into ESTA-MSV microparticles. Male apolipoprotein E-deficient mice were fed with Western diet and injected intravenously with the particles prepared as above biweekly for 12 weeks. Results: Atherosclerotic plaque size decreased with treatment of miRs packaged in ESTA-MSV but not in PEG/PEI. Moreover, vascular inflammation markers such as macrophages in aortic root lesion and expression of chemokines in aortic tissues were decreased while the vascular smooth muscle cells and collagen were increased in plaques from ESTA-MSV/miRs-treated mice compared with vehicle-treated group. Systemic delivery of miR-146a/-181b significantly improved the ACh-induced relaxation of aortas and carotid arteries and inhibited ACh-induced endothelium-dependent contraction of carotid arteries of ApoE-/- mice fed with Western diet for 12 weeks Conclusions: Our data demonstrate that the ESTA-MSV microparticle-mediated delivery of miR-146a/-181b ameliorates the endothelial dysfunction and prevents atherosclerosis.


1997 ◽  
Vol 78 (05) ◽  
pp. 1408-1414 ◽  
Author(s):  
Frank Roesken ◽  
Martin Ruecker ◽  
Brigitte Vollmar ◽  
Nicole Boeckel ◽  
Eberhard Morgenstern ◽  
...  

SummaryThe alteration of rheological blood properties as well as deterioration of vascular perfusion conditions and cell-cell interactions are major determinants of thrombus formation. Herein, we present an experimental model which allows for quantitative in vivo microscopic analysis of these determinants during both thrombus formation and vascular recanalisation. The model does not require surgical preparation procedures, and enables for repeated analysis of identical microvessels over time periods of days or months, respectively. After i.v. administration of FITC-dextran thrombus formation was induced photochemically by light exposure to individual arterioles and venules of the ear of ten anaesthetised hairless mice. In venules, epiillumination induced rapid thrombus formation with first platelet deposition after 0.59 ± 0.04 min and complete vessel occlusion within 7.48 ±1.31 min. After a 24-h time period, 75% of the thrombosed venules were found recanalised. Marked leukocyte-endothelial cell interaction in those venules indicated persistent endothelial cell activation and/or injury, even after an observation period of 7 days. In arterioles, epi-illumination provoked vasomotion, while thrombus formation was significantly (p <0.05) delayed with first platelet deposition after 2.32 ± 0.22 min and complete vessel occlusion within 20.07 ±3.84 min. Strikingly, only one of the investigated arterioles was found recanalised after 24 h, which, however, did not show leukocyte-endothelial cell interaction. Heparin (300 U/kg, i.v.) effectively counteracted the process of thrombus formation in this model, including both first platelet deposition and vessel occlusion. We conclude that the model of the ear of the hairless mouse allows for distinct in vivo analysis of arteriolar and venular thrombus formation/ recanalisation, and, thus, represents an interesting tool for the study of novel antithrombotic and thrombolytic strategies, respectively.


2020 ◽  
Vol 132 (4) ◽  
pp. 1182-1187 ◽  
Author(s):  
Carrie E. Andrews ◽  
Nikolaos Mouchtouris ◽  
Evan M. Fitchett ◽  
Fadi Al Saiegh ◽  
Michael J. Lang ◽  
...  

OBJECTIVEMechanical thrombectomy (MT) is now the standard of care for acute ischemic stroke (AIS) secondary to large-vessel occlusion, but there remains a question of whether elderly patients benefit from this procedure to the same degree as the younger populations enrolled in the seminal trials on MT. The authors compared outcomes after MT of patients 80–89 and ≥ 90 years old with AIS to those of younger patients.METHODSThe authors retrospectively analyzed records of patients undergoing MT at their institution to examine stroke severity, comorbid conditions, medical management, recanalization results, and clinical outcomes. Univariate and multivariate logistic regression analysis were used to compare patients < 80 years, 80–89 years, and ≥ 90 years old.RESULTSAll groups had similar rates of comorbid disease and tissue plasminogen activator (tPA) administration, and stroke severity did not differ significantly between groups. Elderly patients had equivalent recanalization outcomes, with similar rates of readmission, 30-day mortality, and hospital-associated complications. These patients were more likely to have poor clinical outcome on discharge, as defined by a modified Rankin Scale (mRS) score of 3–6, but this difference was not significant when controlled for stroke severity, tPA administration, and recanalization results.CONCLUSIONSOctogenarians, nonagenarians, and centenarians with AIS have similar rates of mortality, hospital readmission, and hospital-associated complications as younger patients after MT. Elderly patients also have the capacity to achieve good functional outcome after MT, but this potential is moderated by stroke severity and success of treatment.


2020 ◽  
Vol 17 (4) ◽  
pp. 361-375
Author(s):  
Victor C. Schulz ◽  
Pedro S.C. de Magalhaes ◽  
Camila C. Carneiro ◽  
Julia I.T. da Silva ◽  
Vivian N. Silva ◽  
...  

Background: It is unknown if improvements in ischemic stroke (IS) outcomes reported after cerebral reperfusion therapies (CRT) in developed countries are also applicable to the “real world” scenario of low and middle-income countries. We aimed to measure the long-term outcomes of severe IS treated or not with CRT in Brazil. Methods: Patients from a stroke center of a state-run hospital were included. We compared the survival probability and functional status at 3 and 12 months in patients with severe IS treated or not with CRT. From 2010 to 2011, we performed intravenous reperfusion when patients arrived within 4.5 h time-window (IVT group) and after 2011, mechanical thrombectomy (MT) combined or not with intravenous alteplase (IAT group). Those who arrived >4.5 h in 2010-2011 and >6 h in 2012-2017 did not undergo CRT (NCRT group). Results: From 2010 to 2017, we registered 917 patients: 74% (677/917) in the NCRT group, 19% (178/917) in the IVT group and 7% (62/917) in the IAT group. Compared to the NCRT group, IVT patients had a 28% higher (HR: 0.72; 95% CI 0.53-0.96) 3-month adjusted probability of survival and risk of functional dependence was 19% lower (adjusted RR: 0.81; 95% CI 0.73-0.91). For those who underwent MT, the adjusted probability of survival was 59 % higher (HR: 0.41; 95% CI 0.21-0.77) and the risk of functional dependence was 21% lower (adjusted RR: 0.79; 95% CI 0.66-094). These outcomes remained significantly better throughout the first year. Conclusion: CRT led to better outcomes in patients with severe IS in Brazil.


2020 ◽  
Vol 17 ◽  
Author(s):  
Shiling Chen ◽  
Chao Pan ◽  
Ping Zhang ◽  
Yingxin Tang ◽  
Zhouping Tang

Abstract:: Acute Ischemic Stroke (AIS) is currently the most frequently reported neurological complication of Coronavirus disease 2019 (COVID-19). This article will elaborate on the clinical features of inpatients with COVID-19 and AIS and the pathophysiological mechanism of AIS under the background of COVID-19. Through a detailed search of relevant studies, we found that the incidence of AIS among COVID-19 patients varied from 0.9% to 4.6%, and AIS has been observed in many people without underlying diseases and cardiovascular risk factors as well as young people. The National Institute of Health Stroke Scale (NIHSS) score of COVID-19 patients with AIS was higher than historical AIS patients, and the proportion of large vessel occlusion (LVO) was about 64.2%. COVID-19 patients with AIS have commonly high levels of D-D dimer, fibrinogen, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR), suggesting systemic hyperinflammatory and hypercoagulable state. The pooled mortality of COVID-19 patients with AIS was 38% and the mortality of LVO patients is higher (45.9%). Compared with COVID-19-negative AIS patients in the same period in 2020 and 2019, COVID- 19 patients with AIS had a worse prognosis.


2015 ◽  
Vol 35 (04) ◽  
pp. 338-350 ◽  
Author(s):  
L. Labberton ◽  
E. Kenne ◽  
T. Renné

SummaryBlood coagulation is essential for hemostasis, however excessive coagulation can lead to thrombosis. Factor XII starts the intrinsic coagulation pathway and contact-induced factor XII activation provides the mechanistic basis for the diagnostic aPTT clotting assay. Despite its function for fibrin formation in test tubes, patients and animals lacking factor XII have a completely normal hemostasis. The lack of a bleeding tendency observed in factor XII deficiency states is in sharp contrast to deficiencies of other components of the coagulation cascade and factor XII has been considered to have no function for coagulation in vivo. Recently, experimental animal models showed that factor XII is activated by an inorganic polymer, polyphosphate, which is released from procoagulant platelets and that polyphosphate-driven factor XII activation has an essential role in pathologic thrombus formation. Cumulatively, the data suggest to target polyphosphate, factor XII, or its activated form factor XIIa for anticoagulation. As the factor XII pathway specifically contributes to thrombosis but not to hemostasis, interference with this pathway provides a unique opportunity for safe anticoagulation that is not associated with excess bleeding.The review summarizes current knowledge on factor XII functions, activators and inhibitors.


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