Factor V Leiden (R506Q), Prothrombin G20210A, and MTHFR C677T Variants and Thrombophilia in Qatar Biobank Participants: A Case Control Study.

Thrombophilia, a predisposition to develop blood clots, is very common and can have serious sequelae. This study aimed to determine the prevalence of three thrombophilia-related genetic variants-factor V Leiden (FVL), prothrombin (F2) G20210A, and MTHFR C677T-in the Qatari population and their associations with self-reported thrombosis. We analysed samples from 408 Qatari participants [304 controls and 104 with self-reported thrombosis (deep vein thrombosis, pulmonary embolus, or ischaemic stroke)] from the Qatar Biobank.

Membrane procoagulation and N‑terminomics/TAILS profiling in Montreal platelet syndrome kindred with VWF p.V1316M mutation.

Background: The Montreal platelet syndrome kindred (MPS) with VWF p.V1316M mutation (2B-VWDMPS) is an extremely rare disorder. It has been associated with macrothrombocytopenia, spontaneous platelet clumping, mucocutaneous, and other bleeding, which can be largely prevented by von Willebrand factor (VWF) concentrate infusion.

Overexpression of facilitative glucose transporter-3 and membrane procoagulation in maternal platelets of preeclamptic pregnancy.

Background: Preeclampsia (PE) is a hypertensive disorder during pregnancy that results in significant adverse maternal and neonatal outcomes. Platelet activation is present in PE and contributes to the thrombo-hemorrhagic states of the disorder. However, the mechanisms that initiate and/or sustain platelet activation in PE are ill-defined.

Preeclampsia: Platelet procoagulant membrane dynamics and critical biomarkers.

A state-of-the-art lecture titled "Preeclampsia and Platelet Procoagulant Membrane Dynamics" was presented at the International Society on Thrombosis and Haemostasis (ISTH) Congress in 2022. Platelet activation is involved in the pathophysiology of preeclampsia and contributes to the prothrombotic state of the disorder. Still, it remains unclear what mechanisms initiate and sustain platelet activation in preeclampsia and how platelets drive the thrombo-hemorrhagic abnormalities in preeclampsia.

Natural history of antiplatelet nonresponders undergoing carotid artery stenting.

Objective: Routine antiplatelet responsiveness testing for patients undergoing carotid artery stenting procedures is not performed at most endovascular centers and remains a topic of controversy within the neurointerventional community. The objective of this study was to determine if nonresponsiveness to acetylsalicylic acid or clopidogrel was associated with the development of symptomatic thromboembolic events in patients undergoing carotid stenting procedures.

Methods: A prospective study was conducted at the Foothills Medical Centre in Calgary, Alberta, Canada, from August 2019 to July 2021.

Heightened Procoagulation after Post-Operative Thromboprophylaxis Completion in Patients with Metastatic Bone Disease from Primary Colorectal Cancer.

Background: Platelets play a role in venous thromboembolism (VTE) and in mediating colorectal cancer (CRC) progression. Still, platelets' role in hypercoagulability after surgical intervention for metastatic bone disease (MBD) is ill-defined.

Methods: In this quantitative observational study, we utilized a high-resolution imaging approach to temporally examine platelet procoagulant membrane dynamics (PMD) in four patients with MBD from primary CRC (CRC/MBD), before and after surgical intervention, over a 6-month period.

Hypercoagulability and Inflammatory Markers in a Case of Congenital Thrombotic Thrombocytopenic Purpura Complicated by Fetal Demise.

Background: Congenital thrombotic thrombocytopenic purpura (cTTP) is a rare disorder caused by an inherited genetic deficiency of ADAMTS13 and affects less than one per million individuals. Patients who are diagnosed with TTP during pregnancy are at increased risk of maternal and fetal complications including fetal demise. We present a case of a 32-year-old G3P0 (gravida 3, para 0) who presented at 20 weeks gestation with a new diagnosis of congenital TTP (cTTP) and fetal demise.

Illustrated State-of-the-Art Capsules of the ISTH 2022 Congress.

The ISTH London 2022 Congress is the first held (mostly) face-to-face again since the COVID-19 pandemic took the world by surprise in 2020. For 2 years we met virtually, but this year's in-person format will allow the ever-so-important and quintessential creativity and networking to flow again. What a pleasure and joy to be able to see everyone! Importantly, all conference proceedings are also streamed (and available recorded) online for those unable to travel on this occasion.

Proteomics and Metabolomics Profiling of Platelets and Plasma Mediators of Thrombo-Inflammation in Gestational Hypertension and Preeclampsia.

Platelets may be pivotal mediators of the thrombotic and coagulopathic complications of preeclampsia (PE), linking inflammation and thrombosis with endothelial and vascular dysfunction. Both PE and gestational hypertension (GH) fall within the spectrum of hypertensive complications of pregnancy, with GH being a risk factor for preeclampsia. However, it is unclear what biomarkers distinguish PE from GH.

Opposing Roles of GSK3α and GSK3β Phosphorylation in Platelet Function and Thrombosis.

One of the mechanisms by which PI3 kinase can regulate platelet function is through phosphorylation of downstream substrates, including glycogen synthase kinase-3 (GSK3)α and GSK3β. Platelet activation results in the phosphorylation of an N-terminal serine residue in GSK3α (Ser21) and GSK3β (Ser9), which competitively inhibits substrate phosphorylation. However, the role of phosphorylation of these paralogs is still largely unknown.

Aquaporins in platelet function.

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.

Carbonic Anhydrase Inhibitors suppress platelet procoagulant responses and in vivo thrombosis.

Carbonic anhydrase (CA) inhibitors have a long history of safe clinical use as mild diuretics, in the treatment of glaucoma and for altitude sickness prevention. In this study, we aimed to determine if CA inhibition may be an alternative approach to control thrombosis. We utilized a high-resolution dynamic imaging approach to provide mechanistic evidence that CA inhibitors may be potent anti-procoagulant agents and effective anti-thrombotics .

Aquaporin-1 regulates platelet procoagulant membrane dynamics and in vivo thrombosis.

In response to collagen stimulation, platelets use a coordinated system of fluid entry to undergo membrane ballooning, procoagulant spreading, and microvesiculation. We hypothesized that water entry was mediated by the water channel aquaporin-1 (AQP1) and aimed to determine its role in the platelet procoagulant response and thrombosis. We established that human and mouse platelets express AQP1 and localize to internal tubular membrane structures.

Procoagulant platelets: generation, function, and therapeutic targeting in thrombosis.

Current understanding of how platelets localize coagulation to wound sites has come mainly from studies of a subpopulation of activated platelets. In this review, we summarize data from the last 4 decades that have described these platelets with a range of descriptive titles and attributes. We identify striking overlaps in the reported characteristics of these platelets, which imply a single subpopulation of versatile platelets and thus suggest that their commonality requires unification of their description.

Membrane Ballooning in Aggregated Platelets is Synchronised and Mediates a Surge in Microvesiculation.

Human platelet transformation into balloons is part of the haemostatic response and thrombus architecture. Here we reveal that in aggregates of platelets in plasma, ballooning in multiple platelets occurs in a synchronised manner. This suggests a mechanism of coordination between cells, previously unrecognised.

The Phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) Binder Rasa3 Regulates Phosphoinositide 3-kinase (PI3K)-dependent Integrin αIIbβ3 Outside-in Signaling.

The class I PI3K family of lipid kinases plays an important role in integrin αβ function, thereby supporting thrombus growth and consolidation. Here, we identify Ras/Rap1GAP Rasa3 (GAP1) as a major phosphatidylinositol 3,4,5-trisphosphate-binding protein in human platelets and a key regulator of integrin αβ outside-in signaling. We demonstrate that cytosolic Rasa3 translocates to the plasma membrane in a PI3K-dependent manner upon activation of human platelets.

Coordinated Membrane Ballooning and Procoagulant Spreading in Human Platelets.

Background: Platelets are central to the process of hemostasis, rapidly aggregating at sites of blood vessel injury and acting as coagulation nidus sites. On interaction with the subendothelial matrix, platelets are transformed into balloonlike structures as part of the hemostatic response. It remains unclear, however, how and why platelets generate these structures.

Organelle-specific subunit interactions of the vertebrate two-pore channel family.

The organellar targeting of two-pore channels (TPCs) and their capacity to associate as homo- and heterodimers may be critical to endolysosomal signaling. A more detailed understanding of the functional association of vertebrate TPC1-3 is therefore necessary. We report here that when stably expressed in HEK293 cells, human (h) TPC1 and chicken (c) TPC3 were specifically targeted to different subpopulations of endosomes, hTPC2 was specifically targeted to lysosomes, and rabbit (r) TPC3 was specifically targeted to both endosomes and lysosomes.