Carbonic Anhydrase Inhibitors suppress platelet procoagulant responses and in vivo thrombosis

Agbani, Ejaife O.; Zhao, Xiaojuan; Williams, Christopher M.; Aungraheeta, Riyaad; Hers, Ingeborg; Swenson, Erik R.; Poole, Alastair W.

doi:10.1080/09537104.2019.1709632

Cited by 10 publications

(11 citation statements)

References 29 publications

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“…A promising target is the water channel aquaporin‐1, as animals lacking this channel have impaired platelet procoagulant function but maintain adequate coagulation 89 . The blockade of the chloride entry into platelets has also been considered as a therapeutic target as the diuretic acetazolamide reduces platelet procoagulant activity without impairing granule secretion, in vitro and in vivo 90 …”

Section: Platelet Procoagulant Function In Bleeding Disordersmentioning

confidence: 99%

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Update on platelet procoagulant mechanisms in health and in bleeding disorders

Bourguignon

Tasneem

Hayward

2022

Int J Lab Hematology

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Platelet procoagulant mechanisms are emerging to be complex and important to achieving haemostasis. The mechanisms include the release of procoagulant molecules from platelet storage granules, and strong agonist-induced expression of procoagulant phospholipids on the outer platelet membrane for tenase and prothrombinase assembly. The release of dense granule polyphosphate is important to platelet procoagulant function as it promotes the activation of factors XII, XI and V, inhibits tissue factor pathway inhibitor and fibrinolysis, and strengthens fibrin clots. Platelet procoagulant function also involves the release of partially activated factor V from platelets. Scott syndrome has provided important insights on the mechanisms that regulate procoagulant phospholipids expression on the external platelet membrane, which require strong agonist stimulation that increase cystolic calcium levels, mitochondrial calcium uptake, the loss of flippase function and activation of the transmembrane scramblase protein anoctamin 6. There have been advances in the methods used to directly and indirectly assess platelet procoagulant function in health and disease. Assessments of thrombin generation with platelet rich plasma samples has provided new insights on how platelet procoagulant function is altered in inherited platelet disorders, and how platelets influence the bleeding phenotype of a number of severe coagulation factor deficiencies. Several therapies, including desmopressin and recombinant factor VIIa, improve thrombin generation by platelets.There is growing interest in targeting platelet procoagulant function for therapeutic benefit. This review highlights recent advances in our understanding of plateletdependent procoagulant mechanisms in health and in bleeding disorders.

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Section: Platelet Procoagulant Function In Bleeding Disordersmentioning

confidence: 99%

“…89 The blockade of the chloride entry into platelets has also been considered as a therapeutic target as the diuretic acetazolamide reduces platelet procoagulant activity without impairing granule secretion, in vitro and in vivo. 90…”

Section: Factor V and Other Coagulation Factor Deficienciesmentioning

confidence: 99%

Update on platelet procoagulant mechanisms in health and in bleeding disorders

Bourguignon

Tasneem

Hayward

2022

Int J Lab Hematology

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“…Unfortunately, there are still no AQP1‐specific inhibitors. Carbonic anhydrase (CA) inhibitors, such as acetazolamide and methazolamide, are clinically used as mild diuretics, and may be potent anti‐procoagulant agents 58 . Acetazolamide and methazolamide attenuate intracellular Cl – entry and suppress the procoagulant response of activated platelets in vitro and thrombosis in vivo .…”

Section: Therapeutic Applications Of Procoagulant Plateletsmentioning

confidence: 99%

Procoagulant platelets: Generation, characteristics, and therapeutic target

Chu

Han

Zhang

et al. 2021

Clinical Laboratory Analysis

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Platelets play a pivotal role in hemostasis. Activated platelets are classified into two groups, according to their agonist response: aggregating and procoagulant platelets. Aggregating platelets consist of activated integrin αIIbβ3 and stretch out pseudopods to further attract platelets to the site of injury by connecting with fibrinogen. They mainly gather in the core of the thrombus and perform a secretory function, such as releasing adenosine diphosphate (ADP). Procoagulant platelets promote the formation of thrombin and fibrin by interacting with coagulation factors and can thus be considered as the connector between primary and secondary hemostasis. In addition to their functions in blood coagulation, procoagulant platelets play a proinflammatory role by releasing platelet microparticles and inorganic polyphosphate. Considering these important functions of procoagulant platelets, this subpopulation warrants detailed study to analyze their potential in preventing human diseases. This review summarizes the generation and important characteristics of procoagulant platelets, as well as their potential for preventing the adverse effects associated with current antiplatelet therapies.

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“…It is also possible that different AQP subtypes are simultaneously involved in a given procoagulation mechanism. A series of studies by Agbani et al [14,[41][42][43][44][45] revealed the spatiotemporal dynamics and drivers of the morphological transformation that platelets undergo during thrombosis and hemostasis. The mechanism of platelet procoagulant remodeling was shown to involve a coordinated fluid entry system of Na + , Cl − and water influx, together with a regulated disruption of the platelet microtubule network [45].…”

Section: Role Of Aquaporins In Platelet Procoagulationmentioning

confidence: 99%

Aquaporins in platelet function

Agbani

Poole

2021

Platelets

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Structurally, aquaporins (AQPs) are small channel proteins with monomers of ~ 30 kDa that are assembled as tetramers to form pores on cell membranes. Aquaporins mediate the conduction of water but at times also small solutes including glycerol across cell membranes and along osmotic gradients. Thirteen isoforms of AQPs have been reported in mammalian cells, and several of these are likely expressed in platelets. Osmotic swelling mediated by AQP1 sustains the calcium entry required for platelet phosphatidylserine exposure and microvesiculation, through calcium permeable stretch-activated or mechanosensitive cation channels. Notably, deletion of AQP1 diminishes platelet procoagulant membrane dynamics in vitro and arterial thrombosis in vivo, independent of platelet granule secretion and without affecting hemostasis. Water entry into platelets promotes procoagulant activity, and AQPs may also be critical for the initiation and progression of venous thrombosis. Platelet AQPs may therefore represent valuable targets for future development of a new class of antithrombotics, namely, antiprocoagulant antithrombotics, that are mechanistically distinct from current antithrombotics. However, the structure of AQPs does not make for easy targeting of these channels, hence they remain elusive drug targets. Nevertheless, thrombosis data in animal models provide compelling reasons to continue the pursuit of AQP-targeted antithrombotics. In this review, we discuss the role of aquaporins in platelet secretion, aggregation and procoagulation, the challenge of drugging AQPs, and the prospects of targeting AQPs for arterial and venous antithrombosis. History

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Carbonic Anhydrase Inhibitors suppress platelet procoagulant responses and in vivo thrombosis

Cited by 10 publications

References 29 publications

Update on platelet procoagulant mechanisms in health and in bleeding disorders

Update on platelet procoagulant mechanisms in health and in bleeding disorders

Procoagulant platelets: Generation, characteristics, and therapeutic target

Aquaporins in platelet function

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