scholarly journals Next-Generation Antithrombotics in Ischemic Stroke: Preclinical Perspective on ‘Bleeding-Free Antithrombosis’

2012 ◽  
Vol 32 (10) ◽  
pp. 1831-1840 ◽  
Author(s):  
Peter Kraft ◽  
Simon F De Meyer ◽  
Christoph Kleinschnitz
Keyword(s):  
Ischemic Stroke ◽  
Thrombus Formation ◽  
Coagulation Factor ◽  
Coagulation Cascade ◽  
Bleeding Complications ◽  
Factor Xii ◽  
Platelet Inhibitors ◽  
Platelet Surface ◽  
Surface Receptors ◽  
Glycoprotein Vi

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.

Molecular mechanisms of thrombus formation in ischemic stroke: novel insights and targets for treatment

Blood ◽  
2008 ◽  
Vol 112 (9) ◽  
pp. 3555-3562 ◽  
Author(s):  
Guido Stoll ◽  
Christoph Kleinschnitz ◽  
Bernhard Nieswandt
Keyword(s):  
Ischemic Stroke ◽  
Molecular Mechanisms ◽  
Thrombus Formation ◽  
Coagulation Factor ◽  
Experimental Stroke ◽  
Bleeding Complications ◽  
Severe Bleeding ◽  
Factor Xii ◽  
Stroke Treatment ◽  
Intracerebral Bleeding

In ischemic stroke, treatment options are limited. Therapeutic thrombolysis is restricted to the first few hours after stroke, and the utility of current platelet aggregation inhibitors, including GPIIb/IIIa receptor antagonists, and anticoagulants is counterbalanced by the risk of intracerebral bleeding complications. Numerous attempts to establish neuroprotection in ischemic stroke have been unfruitful. Thus, there is strong demand for novel treatment strategies. Major advances have been made in understanding the molecular functions of platelet receptors such as glycoprotein Ib (GPIb) and GPVI and their downstream signaling pathways that allow interference with their function. Inhibition of these receptors in the mouse stroke model of transient middle cerebral artery occlusion prevented infarctions without increasing the risk of intracerebral bleeding. Similarly, it is now clear that the intrinsic coagulation factor XII (FXII) and FXI play a functional role in thrombus formation and stabilization during stroke: their deficiency or blockade protects from cerebral ischemia without overtly affecting hemostasis. Based on the accumulating evidence that thrombus formation and hemostasis are not inevitably linked, new concepts for prevention and treatment of ischemic stroke may eventually emerge without the hazard of severe bleeding complications. This review discusses recent advances related to antithrombotic strategies in experimental stroke research.

scholarly journals Diacylglycerol kinase ζ is a negative regulator of GPVI-mediated platelet activation

2019 ◽  
Vol 3 (7) ◽  
pp. 1154-1166 ◽  
Author(s):  
Alyssa J. Moroi ◽  
Nicole M. Zwifelhofer ◽  
Matthew J. Riese ◽  
Debra K. Newman ◽  
Peter J. Newman
Keyword(s):  
Platelet Activation ◽  
Bleeding Time ◽  
Thrombus Formation ◽  
Negative Regulator ◽  
Platelet Surface ◽  
Rotational Thromboelastometry ◽  
Surface Receptors ◽  
Glycoprotein Vi ◽  
Granule Secretion

Abstract Diacylglycerol kinases (DGKs) are a family of enzymes that convert diacylglycerol (DAG) into phosphatidic acid (PA). The ζ isoform of DGK (DGKζ) has been reported to inhibit T-cell responsiveness by downregulating intracellular levels of DAG. However, its role in platelet function remains undefined. In this study, we show that DGKζ was expressed at significant levels in both platelets and megakaryocytes and that DGKζ-knockout (DGKζ-KO) mouse platelets were hyperreactive to glycoprotein VI (GPVI) agonists, as assessed by aggregation, spreading, granule secretion, and activation of relevant signal transduction molecules. In contrast, they were less responsive to thrombin. Platelets from DGKζ-KO mice accumulated faster on collagen-coated microfluidic surfaces under conditions of arterial shear and stopped blood flow faster after ferric chloride–induced carotid artery injury. Other measures of hemostasis, as measured by tail bleeding time and rotational thromboelastometry analysis, were normal. Interestingly, DGKζ deficiency led to increased GPVI expression on the platelet and megakaryocyte surfaces without affecting the expression of other platelet surface receptors. These results implicate DGKζ as a novel negative regulator of GPVI-mediated platelet activation that plays an important role in regulating thrombus formation in vivo.

scholarly journals Prevention of vascular graft occlusion and thrombus-associated thrombin generation by inhibition of factor XI

Blood ◽  
2009 ◽  
Vol 113 (4) ◽  
pp. 936-944 ◽  
Author(s):  
Erik I. Tucker ◽  
Ulla M. Marzec ◽  
Tara C. White ◽  
Sawan Hurst ◽  
Sandra Rugonyi ◽  
...  
Keyword(s):  
Thrombin Generation ◽  
Thrombus Formation ◽  
Coagulation Factor ◽  
Flow Chamber ◽  
Factor Vii ◽  
Bleeding Complications ◽  
Factor Xii ◽  
Graft Occlusion ◽  
Factor Xi ◽  
Thrombosis Model

Abstract The protease thrombin is required for normal hemostasis and pathologic thrombogenesis. Since the mechanism of coagulation factor XI (FXI)–dependent thrombus growth remains unclear, we investigated the contribution of FXI to thrombus formation in a primate thrombosis model. Pretreatment of baboons with a novel anti–human FXI monoclonal antibody (aXIMab; 2 mg/kg) inhibited plasma FXI by at least 99% for 10 days, and suppressed thrombin-antithrombin (TAT) complex and β-thromboglobulin (βTG) formation measured immediately downstream from thrombi forming within collagen-coated vascular grafts. FXI inhibition with aXIMab limited platelet and fibrin deposition in 4-mm diameter grafts without an apparent increase in D-dimer release from thrombi, and prevented the occlusion of 2-mm diameter grafts without affecting template bleeding times. In comparison, pretreatment with aspirin (32 mg/kg) prolonged bleeding times but failed to prevent graft occlusion, supporting the concept that FXI blockade may offer therapeutic advantages over other antithrombotic agents in terms of bleeding complications. In whole blood, aXIMab prevented fibrin formation in a collagen-coated flow chamber, independent of factor XII and factor VII. These data suggest that endogenous FXI contributes to arterial thrombus propagation through a striking amplification of thrombin generation at the thrombus luminal surface.

New agents for thromboprotection

2015 ◽  
Vol 35 (04) ◽  
pp. 338-350 ◽  
Author(s):  
L. Labberton ◽  
E. Kenne ◽  
T. Renné
Keyword(s):  
Current Knowledge ◽  
Thrombus Formation ◽  
Coagulation Cascade ◽  
Factor Xii ◽  
Bleeding Tendency ◽  
New Agents ◽  
Mechanistic Basis ◽  
Normal Hemostasis ◽  
Coagulation Pathway

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.

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
Keyword(s):  
Ischemic Stroke ◽  
Targeted Delivery ◽  
Vascular Malformations ◽  
Thrombus Formation ◽  
Developed Countries ◽  
Coagulation Cascade ◽  
Vascular Targeting ◽  
Systemic Delivery ◽  
Vessel Occlusion ◽  
Vessel Patency

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.

scholarly journals Targeting coagulation factor XII provides protection from pathological thrombosis in cerebral ischemia without interfering with hemostasis

2006 ◽  
Vol 203 (3) ◽  
pp. 513-518 ◽  
Author(s):  
Christoph Kleinschnitz ◽  
Guido Stoll ◽  
Martin Bendszus ◽  
Kai Schuh ◽  
Hans-Ulrich Pauer ◽  
...  
Keyword(s):  
Thrombus Formation ◽  
Coagulation Factor ◽  
Artery Occlusion ◽  
Factor Xii ◽  
Intrinsic Pathway ◽  
Fibrin Formation ◽  
Vessel Injury ◽  
Normal Hemostasis ◽  
A Site

Formation of fibrin is critical for limiting blood loss at a site of blood vessel injury (hemostasis), but may also contribute to vascular thrombosis. Hereditary deficiency of factor XII (FXII), the protease that triggers the intrinsic pathway of coagulation in vitro, is not associated with spontaneous or excessive injury-related bleeding, indicating FXII is not required for hemostasis. We demonstrate that deficiency or inhibition of FXII protects mice from ischemic brain injury. After transient middle cerebral artery occlusion, the volume of infarcted brain in FXII-deficient and FXII inhibitor–treated mice was substantially less than in wild-type controls, without an increase in infarct-associated hemorrhage. Targeting FXII reduced fibrin formation in ischemic vessels, and reconstitution of FXII-deficient mice with human FXII restored fibrin deposition. Mice deficient in the FXII substrate factor XI were similarly protected from vessel-occluding fibrin formation, suggesting that FXII contributes to pathologic clotting through the intrinsic pathway. These data demonstrate that some processes involved in pathologic thrombus formation are distinct from those required for normal hemostasis. As FXII appears to be instrumental in pathologic fibrin formation but dispensable for hemostasis, FXII inhibition may offer a selective and safe strategy for preventing stroke and other thromboembolic diseases.

Influence of platelet count on the expression of platelet collagen receptor glycoprotein VI (GPVI) in patients with acute coronary syndrome

2009 ◽  
Vol 101 (05) ◽  
pp. 911-915 ◽  
Author(s):  
Boris Bigalke ◽  
Konstantinos Stellos ◽  
Dimitrios Stakos ◽  
Thomas Joos ◽  
Oliver Pötz ◽  
...  
Keyword(s):  
Acute Coronary Syndrome ◽  
Platelet Count ◽  
Thrombus Formation ◽  
Surface Expression ◽  
Platelet Surface ◽  
Glycoprotein Vi ◽  
Coronary Syndrome ◽  
Symptomatic Coronary Artery Disease ◽  
Artery Disease ◽  
Collagen Receptor

SummaryPlatelets play a key role in the development of an acute coronary syndrome (ACS) and contribute to cardiovascular events. Platelet collagen receptor glycoprotein VI (GPVI) contributes significantly to platelet adhesion and thrombus formation in ACS. We consecutively investigated both the platelet count and the platelet surface expression of GPVI in 843 patients with a symptomatic coronary artery disease verified by coronary angiography. Four hundred fourteen patients presented with stable angina pectoris and 429 patients with ACS. Platelet surface expression of GPVI and CD62P was determined by flow cytometry and platelet count with a coulter counter, plasmatic soluble GPVI was measured by ELISA. Platelet GPVI expression in patients with ACS was compared to platelet count. Patients with ACS showed significantly elevated GPVI expression levels in the first and second quartiles of platelet count compared to patients with higher platelet count [mean fluorescence intensity (MFI) ± standard deviation): 1st vs. 4th: 20.44 ± 6.1 vs. 18.62 ± 3.7; p=0.012; 2ndvs.3rd:21.2±8.5vs.18.76±3.7;P=0.03; 2ndvs.4th: 21.2±8.5vs.18.62±3.7;P=0.004], which was paralleled in trend for the CD62P expression [MFI: 1st vs. 4th: 11.2 ± 6.8 vs. 12.3 ± 9; p=0.057; 2nd vs. 3rd: 16.3 ± 16 vs.12.7 ± 5.3; p=0.138; 2nd vs. 4th: 16.3 ± 16 vs.11 ± 4.4; p=0.043]. In a subgroup of 48 patients with ACS, determination of soluble GPVI showed similar results [plasma GPVI (ng/ml): 1stvs.4th: 1.6 ± 0.6 vs. 1.2 ± 0.4; p=0.046; 1st vs. 3rd: 1.6 ± 0.6 vs. 1.1 ± 0.5; p=0.038; 2nd vs. 3rd: 1.9 ± 0.8 vs. 1.1 ± 0.5; p=0.04; 2nd vs. 4th: 1.9 ± 0.8 vs. 1.2 ± 0.4; p=0.056]. Thus, a lower platelet count comes along with a higher GPVI surface expression and plasma concentration in patients with ACS, which potentially reflects increased activation and enhanced recruitment of platelets to the site of vascular injury.

scholarly journals Platelets in Thrombo-Inflammation: Concepts, Mechanisms, and Therapeutic Strategies for Ischemic Stroke

2020 ◽  
Vol 40 (02) ◽  
pp. 153-164 ◽  
Author(s):  
Philipp Burkard ◽  
Timo Vögtle ◽  
Bernhard Nieswandt
Keyword(s):  
Ischemic Stroke ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Pharmacological Intervention ◽  
Kinin System ◽  
Platelet Surface ◽  
Surface Receptors ◽  
Recent Developments ◽  
Inflammatory Processes ◽  
Brain Artery

AbstractPlatelets are anucleate cells known for their essential function in hemostasis and formation of thrombi under pathologic conditions. In recent years, strong evidence emerged demonstrating the critical involvement of platelets in inflammatory processes including acute ischemic stroke (AIS), which is one of the leading causes of death and disability worldwide. Recanalization of the occluded brain artery to reconstitute cerebral blood flow is the primary goal in the treatment of stroke patients. However, despite successful reperfusion many patients show progression of infarct sizes, a phenomenon referred to as ischemia/reperfusion injury (I/RI). Cerebral I/RI involves both thrombotic as well as inflammatory pathways acting in concert to cause tissue damage, defining AIS as a prototypic thrombo-inflammatory disease. Currently used antiplatelet drugs applied to AIS patients eventually increase the risk of partially life-threatening hemorrhages, making more targeted pharmacological intervention necessary. Experimental evidence indicates that inhibition of platelet surface receptors that regulate initial platelet adhesion and activation might be suitable targets in thrombo-inflammatory settings, while inhibitors of platelet aggregation are not. In this review, we will summarize the recent developments in elucidating the role of the main platelet receptors in AIS and discuss their potential as pharmaceutical targets. Furthermore, we will also briefly discuss the important platelet-triggered intrinsic coagulation pathway with the pro-inflammatory kallikrein–kinin system in the context of ischemic stroke.

scholarly journals In vivo roles of factor XII

Blood ◽  
2012 ◽  
Vol 120 (22) ◽  
pp. 4296-4303 ◽  
Author(s):  
Thomas Renné ◽  
Alvin H. Schmaier ◽  
Katrin F. Nickel ◽  
Margareta Blombäck ◽  
Coen Maas
Keyword(s):  
Thrombus Formation ◽  
Coagulation Factor ◽  
Special Focus ◽  
Factor Xii ◽  
Excessive Bleeding ◽  
Charged Surfaces ◽  
Factor Xiia ◽  
Knockout Model

Abstract Coagulation factor XII (FXII, Hageman factor, EC = 3.4.21.38) is the zymogen of the serine protease, factor XIIa (FXIIa). FXII is converted to FXIIa through autoactivation induced by “contact” to charged surfaces. FXIIa is of crucial importance for fibrin formation in vitro, but deficiency in the protease is not associated with excessive bleeding. For decades, FXII was considered to have no function for coagulation in vivo. Our laboratory developed the first murine knockout model of FXII. Consistent with their human counterparts, FXII−/− mice have a normal hemostatic capacity. However, thrombus formation in FXII−/− mice is largely defective, and the animals are protected from experimental cerebral ischemia and pulmonary embolism. This murine model has created new interest in FXII because it raises the possibility for safe anticoagulation, which targets thrombosis without influence on hemostasis. We recently have identified platelet polyphosphate (an inorganic polymer) and mast cell heparin as in vivo FXII activators with implications on the initiation of thrombosis and edema during hypersensitivity reactions. Independent of its protease activity, FXII exerts mitogenic activity with implications for angiogenesis. The goal of this review is to summarize the in vivo functions of FXII, with special focus to its functions in thrombosis and vascular biology.

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