scholarly journals Heparin and Arginine Based Plasmin Nanoformulation for Ischemic Stroke Therapy

2021 ◽  
Vol 22 (21) ◽  
pp. 11477
Author(s):  
Ramsha Aamir ◽  
Cameron Fyffe ◽  
Netanel Korin ◽  
Daniel A. Lawrence ◽  
Enming J. Su ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Thrombolytic Therapy ◽  
Drug Stability ◽  
Stroke Therapy ◽  
Stress Effects ◽  
Significant Toxicity ◽  
Increased Risk ◽  
Significant Efficacy ◽  
Risk Of Hemorrhage

Ischemic stroke is the most common type of stroke and thrombolytic therapy is the only approved treatment. However, current thrombolytic therapy with tissue plasminogen activator (tPA) is often hampered by the increased risk of hemorrhage. Plasmin, a direct fibrinolytic, has a significantly superior hemostatic safety profile; however, if injected intravenously it becomes rapidly inactivated by anti-plasmin. Nanoformulations have been shown to increase drug stability and half-life and hence could be applied to increase the plasmin therapeutic efficacy. Here in this paper, we report a novel heparin and arginine-based plasmin nanoformulation that exhibits increased plasmin stability and efficacy. In vitro studies revealed significant plasmin stability in the presence of anti-plasmin and efficient fibrinolytic activity. In addition, these particles showed no significant toxicity or oxidative stress effects in human brain microvascular endothelial cells, and no significant blood brain barrier permeability. Further, in a mouse photothrombotic stroke model, plasmin nanoparticles exhibited significant efficacy in reducing stroke volume without overt intracerebral hemorrhage (ICH) compared to free plasmin treatment. The study shows the potential of a plasmin nanoformulation in ischemic stroke therapy.

scholarly journals Neutrophil extracellular traps promote tPA-induced brain hemorrhage via cGAS in mice with stroke

Blood ◽  
2021 ◽  
Author(s):  
Ranran Wang ◽  
Yuanbo Zhu ◽  
Zhongwang Liu ◽  
Luping Chang ◽  
Xiaofei Bai ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Thrombolytic Therapy ◽  
Clinical Problem ◽  
Neutrophil Extracellular Traps ◽  
Artery Occlusion ◽  
Type I ◽  
Brain Hemorrhage ◽  
Extracellular Traps ◽  
Dnase 1

Intracerebral hemorrhage associated with thrombolytic therapy with tissue plasminogen activator (tPA) in acute ischemic stroke continues to present a major clinical problem. Here, we report that infusion of tPA resulted in a significant increase in markers of neutrophil extracellular traps (NETs) in the ischemic cortex and plasma of mice subjected to photothrombotic middle cerebral artery occlusion. Peptidylarginine deiminase 4 (PAD4), a critical enzyme for NET formation, is also significantly upregulated in the ischemic brains in tPA-treated mice. Blood-brain barrier (BBB) disruption following ischemic challenge in an in vitro model of BBB was exacerbated after exposure to NETs. Importantly, disruption of NETs by DNase 1 or inhibition of NET production by PAD4 deficiency restored tPA-induced loss of BBB integrity and consequently decreased tPA-associated brain hemorrhage after ischemic stroke. Furthermore, either DNase 1 or PAD4 deficiency reversed tPA-mediated upregulation of the DNA sensor cyclic GMP-AMP (cGAMP) synthase (cGAS). Administration of cGAMP after stroke abolished DNase 1-mediated downregulation of the STING pathway and type I interferon (IFN) production, and blocked the antihemorrhagic effect of DNase 1 in tPA-treated mice. We also show that tPA-associated brain hemorrhage after ischemic stroke was significantly reduced in cGas-/- mice. Collectively, these findings demonstrate that NETs significantly contribute to tPA-induced BBB breakdown in ischemic brain, and suggest that targeting NETs or cGAS may ameliorate thrombolytic therapy for ischemic stroke by reducing tPA-associated hemorrhage.

scholarly journals Aspirin for primary prevention of stroke in traumatic cerebrovascular injury: association with increased risk of transfusion

2019 ◽  
Vol 130 (5) ◽  
pp. 1520-1527 ◽  
Author(s):  
Russell L. Griffin ◽  
Stephanie R. Falatko ◽  
Stella Aslibekyan ◽  
Virginia Strickland ◽  
Mark R. Harrigan
Keyword(s):  
Ischemic Stroke ◽  
Blunt Trauma ◽  
Age Groups ◽  
Significant Risk ◽  
Antiplatelet Agents ◽  
Packed Red Blood Cells ◽  
Cerebrovascular Injury ◽  
Increased Risk ◽  
Negative Findings ◽  
Risk Of Hemorrhage

OBJECTIVEBlunt traumatic extracranial carotid or vertebral artery injury (i.e., traumatic cerebrovascular injury [TCVI]) occurs in 1%–2% of all blunt trauma admissions, carries a 10% risk of thromboembolic ischemic stroke, and accounts for up to 9600 strokes annually in the US. Screening CT angiograms (CTAs) of patients with trauma has become ubiquitous in recent years, and patients with initially asymptomatic TCVI are commonly treated with antiplatelet agents to prevent stroke. Prophylaxis with antiplatelets is thought to be safer than anticoagulation, which carries a significant risk of hemorrhage in patients with trauma. However, the risk of hemorrhagic complications due to antiplatelets has not been assessed in this population.METHODSThis is a retrospective cohort study of patients in whom a screening CTA was obtained after admission for blunt trauma at a Level 1 trauma center. Patients with CTAs indicating TCVI were treated routinely with 325 mg aspirin daily. The risk of transfusion > 24 hours after admission was compared according to CTA findings (CTA+ or CTA− for positive or negative findings, respectively) and aspirin treatment (ASA+ or ASA− for treatment or no treatment, respectively).RESULTSThe mean overall transfusion amount (number of units of packed red blood cells [PRBCs]) was 0.9 ± 2.1 for CTA+/ASA+ patients (n = 196) and 0.3 ± 1.60 for CTA−/ASA− patients (n = 2290) (p < 0.0001). In adjusted models, the overall relative risk (RR) of PRBC transfusion was 1.70 (1.32–2.20) for CTA+/ASA+ patients compared with CTA−/ASA− patients. Among age groups, participants whose ages were 50–69 years had the greatest significantly elevated RR (1.71, 95% CI 1.08–2.72) for CTA+/ASA+ patients compared with CTA−/ASA− patients.CONCLUSIONSTreatment with aspirin for the prevention of stroke in patients with initially asymptomatic TCVI carries a significantly increased risk of PRBC transfusion. Future studies are needed to determine if this risk is offset by a reduced risk of ischemic stroke.

scholarly journals Drug-associated thrombocytopenia

Hematology ◽  
2018 ◽  
Vol 2018 (1) ◽  
pp. 576-583 ◽  
Author(s):  
Tamam Bakchoul ◽  
Irene Marini
Keyword(s):  
Platelet Count ◽  
Clinical Symptoms ◽  
Scoring Systems ◽  
Severe Thrombocytopenia ◽  
Thromboembolic Complications ◽  
Drug Induced ◽  
Increased Risk ◽  
High Doses ◽  
Risk Of Hemorrhage

Abstract Many drugs have been implicated in drug-induced immune thrombocytopenia (DITP). Patients with DITP develop a drop in platelet count 5 to 10 days after drug administration with an increased risk of hemorrhage. The diagnosis of DITP is often challenging, because most hospitalized patients are taking multiple medications and have comorbidities that can also cause thrombocytopenia. Specialized laboratory diagnostic tests have been developed and are helpful to confirm the diagnosis. Treatment of DITP involves discontinuation of the offending drug. The platelet count usually starts to recover after 4 or 5 half-lives of the responsible drug or drug metabolite. High doses of intravenous immunoglobulin can be given to patients with severe thrombocytopenia and bleeding. Although in most cases, DITP is associated with bleeding, life-threatening thromboembolic complications are common in patients with heparin-induced thrombocytopenia (HIT). Binding of antiplatelet factor 4/heparin antibodies to Fc receptors on platelets and monocytes causes intravascular cellular activation, leading to an intensely prothrombotic state in HIT. The clinical symptoms include a decrease in platelet counts by >50% and/or new thromboembolic complications. Two approaches can help to confirm or rule out HIT: assessment of the clinical presentation using scoring systems and in vitro demonstration of antiplatelet factor 4/heparin antibodies. The cornerstone of HIT management is immediate discontinuation of heparin when the disease is suspected and anticoagulation using nonheparin anticoagulant. In this review, we will provide an update on the pathophysiology, diagnosis, and management of both DITP and HIT.

scholarly journals Factor VII activating protease (FSAP) inhibits the outcome of ischemic stroke in mouse models.

2022 ◽  
Author(s):  
Jeong-Yeon Kim ◽  
Dipankar Manna ◽  
Trygve B Leergaard ◽  
Sandip M Kanse
Keyword(s):  
Ischemic Stroke ◽  
Serine Protease ◽  
Artery Occlusion ◽  
Factor Vii ◽  
Clot Lysis ◽  
Negative Effects ◽  
Stroke Treatment ◽  
Serine Protease Domain ◽  
Increased Risk

Factor VII activating protease (FSAP) is a circulating serine protease, and individuals with the Marburg I (MI) single nucleotide polymorphism (SNP), which results in an inactive enzyme, have an increased risk of stroke. The outcome of ischemic stroke is more marked in FSAP-deficient mice compared to their wild-type (WT) counterparts. Plasma FSAP levels are raised in patients as well as mice after stroke. In vitro, FSAP promotes fibrinolysis by cleavage of fibrinogen, activates protease-activated receptors and decreases the cellular cytotoxicity of histones. Since these are desirable properties in stroke treatment, we tested the effect of recombinant serine protease domain of FSAP (FSAP-SPD) on ischemic stroke in mice. A combination of tissue plasminogen activator (tPA) and FSAP-SPD enhanced clot lysis, improved microvascular perfusion and neurological outcome and reduced infarct volumes in a mouse model of thromboembolic stroke. In the tail bleeding model FSAP-SPD treatment provoked a faster clotting time indicating that it has a pro-coagulant effect that is described before. FSAP-SPD improved stroke outcome and diminished the negative effects of co-treatment with tPA in the transient middle cerebral artery occlusion model. The inactive MI-isoform of FSAP did not have any effects in either model. In mice with FSAP deficiency there were minor differences in the outcomes of stroke but the treatment with FSAP-SPD was equally effective. Thus, FSAP represents a promising novel therapeutic strategy in the treatment of ischemic stroke that requires further evaluation.

Abstract 64: Perlecan LG3 is Neuroprotective When Administered Intra-arterially After Experimental Ischemic Stroke

Stroke ◽  
2016 ◽  
Vol 47 (suppl_1) ◽  
Author(s):  
Kathleen Salmeron ◽  
Michael Maniskas ◽  
Justin Fraser ◽  
Gregory Bix
Keyword(s):  
Ischemic Stroke ◽  
Therapeutic Potential ◽  
Vital Signs ◽  
Artery Occlusion ◽  
Experimental Stroke ◽  
Stroke Therapy ◽  
Treatment Conditions ◽  
Endogenous Protection

Despite recent advances in stroke therapy, stroke remains a leading cause of morbidity and mortality. We have previously demonstrated the therapeutic potential of exploiting the brain’s endogenous protection and repair processes following stroke. Specifically, we reported that the LG3 protein fragment of the heparan sulfate proteoglycan perlecan is neuroprotective and proangiogenic in vitro. We now hypothesize that LG3 could be therapeutic in experimental stroke. However, as previous in vivo LG3 studies suggest that it may not readily target stroke-affected brain upon systemic administration, we administered LG3 in a super selective intra-arterial (IA) model (into the ipsilateral common carotid artery) following transient (1 hour) middle cerebral artery occlusion in 3 month old male mice. Upon reperfusion the mice received LG3 or vehicle controls via IP (5 mg/kg) or IA (0.15 mg/kg) administration. No differences in vital signs were noted between the treatment groups. We observed that all LG3 treated mice, regardless of route of administration, had a smaller infarct compared to controls on post-stroke day 3. Importantly, those mice that received IA LG3 had much smaller strokes and performed significantly better in forced movement and in free movement settings than all other treatment conditions. Our results demonstrate that acute LG3 administration is beneficial after experimental ischemic stroke, IA LG3 is safe and much more effective than IP, and support further investigation of LG3 as a novel acute stroke therapy.

Fibrin-specificity of a Plasminogen Activator Affects the Efficiency of Fibrinolysis and Responsiveness to Ultrasound: Comparison of Nine Plasminogen Activators In Vitro

1999 ◽  
Vol 81 (04) ◽  
pp. 605-612 ◽  
Author(s):  
Dmitry V. Sakharov ◽  
Marrie Barrett-Bergshoeff ◽  
Rob T. Hekkenberg ◽  
Dingeman C. Rijken
Keyword(s):  
Thrombolytic Therapy ◽  
Plasminogen Activator ◽  
Tissue Type ◽  
Bolus Administration ◽  
High Frequency Ultrasound ◽  
Single Chain ◽  
Response Curves ◽  
Maximal Speed ◽  
Frequency Ultrasound

SummaryIn a number of cases, thrombolytic therapy fails to re-open occluded blood vessels, possibly due to the occurrence of thrombi resistant to lysis. We investigated in vitro how the lysis of hardly lysable model thrombi depends on the choice of the plasminogen activator (PA) and is accelerated by ultrasonic irradiation. Lysis of compacted crosslinked human plasma clots was measured after addition of nine different PAs to the surrounding plasma and the effect of 3 MHz ultrasound on the speed of lysis was assessed.Fibrin-specific PAs showed bell-shaped dose-response curves of varying width and height. PAs with improved fibrin-specificity (staphylokinase, the TNK variant of tissue-type PA [tPA], and the PA from the saliva of the Desmodus rotundus bat) induced rapid lysis in concentration ranges (80-, 260-, and 3,500-fold ranges, respectively) much wider than that for tPA (a 35-fold range). However, in terms of speed of lysis, these three PAs exceeded tPA only slightly. Reteplase and single-chain urokinase were comparable to tPA, whereas two-chain urokinase, anistreplase, and streptokinase were inferior to tPA. In the case of fibrin-specific PAs, ultrasonic treatment accelerated lysis about 1.5-fold. For streptokinase no acceleration was observed. The effect of ultrasound correlated with the presence of plasminogen in the outer plasma, suggesting that it was mediated by facilitating the transport of plasminogen to the surface of the clot.In conclusion, PAs with improved fibrin-specificity induce rapid lysis of plasminogen-poor compacted plasma clots in much wider concentration ranges than tPA. This offers a possibility of using single-or double-bolus administration regimens for such PAs. However, it is not likely that administration of these PAs will directly cause a dramatic increase in the rate of re-opening of the occluded arteries since they are only moderately superior to tPA in terms of maximal speed of lysis. Application of high-frequency ultrasound as an adjunct to thrombolytic therapy may increase the treatment efficiency, particularly in conjunction with fibrin-specific PAs.

Assays for Phospholipid-Dependent Formation of Thrombin and Xa: A Potential Method for Quantifying Lupus Anticoagulant Activity

1991 ◽  
Vol 66 (04) ◽  
pp. 453-458 ◽  
Author(s):  
John T Brandt
Keyword(s):  
Specific Activity ◽  
Anticoagulant Activity ◽  
Factor Xa ◽  
Clinical Importance ◽  
Potential Method ◽  
Quantitative Expression ◽  
Increased Risk ◽  
Apparent Association

SummaryLupus anticoagulants (LAs) are antibodies which interfere with phospholipid-dependent procoagulant reactions. Their clinical importance is due to their apparent association with an increased risk of thrombo-embolic disease. To date there have been few assays for quantifying the specific activity of these antibodies in vitro and this has hampered attempts to purify and characterize these antibodies. Methods for determining phospholipid-dependent generation of thrombin and factor Xa are described. Isolated IgG fractions from 7 of 9 patients with LAs were found to reproducibly inhibit enzyme generation in these assay systems, permitting quantitative expression of inhibitor activity. Different patterns of inhibitory activity, based on the relative inhibition of thrombin and factor Xa generation, were found, further substantiating the known heterogeneity of these antibodies. These systems may prove helpful in further purification and characterization of LAs.

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