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Inoculation of Bothrops jararaca snake venom (BjV) induces thrombocytopenia in humans and various animal species. Although several BjV toxins acting on hemostasis have been well characterized in vitro, it is not known which one is responsible for inducing thrombocytopenia in vivo. In previous studies, we showed that BjV incubated with metalloproteinase or serine proteinase inhibitors and/or anti-botrocetin antibodies still induced thrombocytopenia in rats and mice. Thus, herein we identified and characterized BjV toxins responsible for inducing thrombocytopenia. Initially, by filtering BjV on ultrafiltration systems, proteins with molecular masses between 30 and 50 kDa were shown to induce thrombocytopenia in mice, but they were not associated with hemorrhagic or coagulating activities. The 50 kDa ultrafiltrate was chromatographed, and two proteins (named fraction D and fraction E) induced thrombocytopenia in mice. However, neither fraction D nor fraction E induced platelet aggregation in platelet-rich plasma or whole blood from humans or mice. By mass spectrometry analysis, fraction E was identified as jararaca glycoprotein Ib (GPIb)-binding protein. Injection of these fractions caused thrombocytopenia in control or Vwf−/− mice, showing that the axis platelet GPIb – von Willebrand factor is not involved in their biological action in vivo. New studies are necessary to understand how these proteins act in vivo. [ABSTRACT FROM AUTHOR]

Hemolysis is associated with thrombosis and vascular dysfunction, which are the pathological components of many diseases. Hemolytic products, including hemoglobin and hemin, activate platelets (PLT). Despite its activation, the effect of hemolysis on platelet clearance remains unclear, It is critical to maintain a normal platelet count and ensure that circulating platelets are functionally viable. In this study, we used hemin, a degradation product of hemoglobin, as a potent agonist to treat platelets and simulate changes in vivo in mice. Hemin treatment induced activation and morphological changes in platelets, including an increase in intracellular Ca2+ levels, phosphatidylserine (PS) exposure, and cytoskeletal rearrangement. Fewer hemin-treated platelets were cleared by macrophages in the liver after transfusion than untreated platelets. Hemin bound to glycoprotein Ibα (GPIbα), the surface receptor in hemin-induced platelet activation and aggregation. Furthermore, hemin decreased GPIbα desialylation, as evidenced by reduced Ricinus communis agglutinin I (RCA- I) binding, which likely extended the lifetime of such platelets in vivo. These data provided new insight into the mechanisms of GPIbα-mediated platelet activation and clearance in hemolytic disease. [ABSTRACT FROM AUTHOR]

High-altitude polycythemia (HAPC) can occur in individuals who are intolerant to high-altitude hypoxia. In patients with HAPC, erythrocytosis is often accompanied by a decrease in platelet count. Chronic hypoxia can increase the incidence of arteriovenous thrombosis and the risk of bleeding during antithrombotic treatment due to thrombocytopenia; therefore, understanding the cause of thrombocytopenia can reduce the risk of treatment-related bleeding. In this study, we examined platelet production and apoptosis to understand the cause of thrombocytopenia in patients with HAPC. The classification of myeloid-derived megakaryocytes (MKs) in HAPC patients was mainly granular MKs rather than mature MKs, suggesting impaired differentiation and maturation. However, the total number of MKs and newly generated reticulated platelets in the peripheral blood increased, indicating sufficient platelet generation in HAPC thrombocytopenia. Increased platelet apoptosis may be one of the causes of thrombocytopenia. Platelet activation and GP1ba pathway activation induced by thrombin and von Willebrand factor can lead to platelet apoptosis. Platelet production was not reduced in patients with HAPC, whereas platelet apoptosis was associated with thrombocytopenia. These findings provide a rationale for considering the bleeding risk in HAPC patient while treating thrombotic diseases. [ABSTRACT FROM AUTHOR]

Objective: To describe the clinical presentation, clinical course, and successful management of noncompressible, abdominal hemorrhage with recombinant human factor VIIa (rFVIIa) in 2 postoperative patients. Case Summary: A 14‐year‐old neutered female Border Terrier and a 9‐year‐old neutered male domestic shorthair were treated with rFVIIa to treat noncompressible abdominal hemorrhage in the postoperative period. The dog presented for a septic abdomen following endoscopic intestinal biopsies 10 days prior and was found to have a jejunal perforation along with a fractured liver lobe and hepatic lymphoma at the time of exploratory laparotomy. The cat presented for a spontaneous hemoabdomen associated with hepatic amyloidosis. Clinically significant hemorrhage occurred in the perioperative and postoperative period and both patients received massive transfusions and antifibrinolytic therapy. Despite these interventions, the patients continued to have ongoing abdominal hemorrhage and surgical attempts at hemostasis were not attempted due to the friable nature of the liver at the time of surgery. Both patients received rFVIIa intravenously every 3 hours at a dose between 70 and 90 μg/kg as indicated by the clinical picture, which subsequently decreased transfusion requirements. New or Unique Information Provided: This case report describes the use of rFVIIa in a cat and a dog with severe, noncompressible abdominal hemorrhage in combination with standard hemostatic interventions. [ABSTRACT FROM AUTHOR]

High-altitude polycythemia (HAPC) can occur in individuals who are intolerant to high-altitude hypoxia. In patients with HAPC, erythrocytosis is often accompanied by a decrease in platelet count. Chronic hypoxia can increase the incidence of arteriovenous thrombosis and the risk of bleeding during antithrombotic treatment due to thrombocytopenia; therefore, understanding the cause of thrombocytopenia can reduce the risk of treatment-related bleeding. In this study, we examined platelet production and apoptosis to understand the cause of thrombocytopenia in patients with HAPC. The classification of myeloid-derived megakaryocytes (MKs) in HAPC patients was mainly granular MKs rather than mature MKs, suggesting impaired differentiation and maturation. However, the total number of MKs and newly generated reticulated platelets in the peripheral blood increased, indicating sufficient platelet generation in HAPC thrombocytopenia. Increased platelet apoptosis may be one of the causes of thrombocytopenia. Platelet activation and GP1bα pathway activation induced by thrombin and von Willebrand factor can lead to platelet apoptosis. Platelet production was not reduced in patients with HAPC, whereas platelet apoptosis was associated with thrombocytopenia. These findings provide a rationale for considering the bleeding risk in HAPC patient while treating thrombotic diseases. What is the context? Platelets are essential in the process of blood clotting; hence, low platelet count increases the risk of bleeding. Thrombocytopenia is present in patients with high-altitude polycythemia Hypoxia can lead to platelet activation and increase in procoagulant factors, while at the same time increase the risk of thrombosis due to erythrocytosis and blood stasis. Antithrombotic therapy should be administered when thrombosis occurs in patients with high altitude polycythemia; however, due to the low platelet count, risk of bleeding must be considered. What is new? In this study, we found that platelet production was not decreased in patients with high-altitude polycythemia. One cause of thrombocytopenia is apoptosis, which is associated with platelet activation, especially GP1bα activation. Inhibition of GP1bα binding to ligand decreased the level of platelet apoptosis. What is the impact? This study provides novel insights into antithrombotic therapy for patients with high-altitude polycythemia complicated by thrombosis. Thrombocytopenia is associated with excessive apoptosis. Interfering with GP1bα targets may have a dual benefit, both in inhibiting thrombosis and avoiding thrombocytopenia. [ABSTRACT FROM AUTHOR]

In vivo gene therapy is rapidly emerging as a new therapeutic paradigm for monogenic disorders. For almost three decades, hemophilia A (HA) and hemophilia B (HB) have served as model disorders for the development of gene therapy. This effort is soon to bear fruit with completed pivotal adeno-associated viral (AAV) vector gene addition trials reporting encouraging results and regulatory approval widely anticipated in the near future for the current generation of HA and HB AAV vectors. Here we review the clinical development of AAV gene therapy for HA and HB and examine outstanding questions that have recently emerged from AAV clinical trials for hemophilia and other monogenic disorders. [ABSTRACT FROM AUTHOR]

Acquired von Willebrand syndrome (AVWS) is a rare hematologic disorder characterized by quantitative or qualitative defects of von Willebrand factor (vWF), a protein crucial for normal hemostasis. AVWS has been described in association with several pathologic entities with varied mechanisms. Among these, lymphoproliferative disorders are the most common, with monoclonal gammopathy of undetermined significance (MGUS) being the most frequently reported. AVWS in this setting is commonly associated with the development of bleeding that is clinically challenging to manage due to accelerated clearance of vWF, limiting the utility of many conventional treatment modalities such as DDAVP or vWF/FVIII. We report a case of a 43-year-old male who was sent to our institution for new-onset easy bruising and laboratories concerning for von Willebrand disease (vWD). Further diagnostic workup revealed evidence of an IgG monoclonal gammopathy and findings suggestive of vWF inhibition. Ultimately, he was found to have monoclonal gammopathy of clinical significance (MGCS)-associated AVWS refractory to conventional treatment but responsive to lenalidomide and dexamethasone. This case suggests that lenalidomide may be suitable for patients with AVWS secondary to MGCS. [ABSTRACT FROM AUTHOR]

Introduction and hypothesis: Pelvic organ prolapse (POP) is a common gynecological disease caused by defects in pelvic support tissue that manifests as the descent of the pelvic organs, significantly impacting patient quality of life. Transvaginal mesh (TVM) is an effective treatment (Grade A). However, postoperative pain in the groin and medial thigh is very common. Although the use of mesh for transvaginal POP repair has been prohibited or the indications for such use have been extensively limited in many places, it is still an alternative in some countries. Therefore, the safety of the use of mesh still needs to be discussed. The current research on postoperative pain has mainly focused on management. The pathophysiology is unclear. Methods: In this study, anterior TVM surgery was performed on ten frozen cadavers. The obturator area was carefully dissected. We explored the relative position of the polypropylene mesh to the internal segment of the obturator nerve in the obturator canal. Results: Four out of 20 obturator explorations were insufficient to allow conclusions to be drawn. We observed a small branch of the obturator nerve, which is a new anatomical finding that we named the obturator externus muscle branch. This structure terminated in the external obturator muscle in 6 out of the 16 successfully dissected obturator areas. The mean distance between the superficial mesh arm and this nerve branch was 7.5 mm. The mean distance between the deep mesh arm and the closest nerve branch was 5.5 mm. Conclusion: The path of the obturator externus muscle branch of the obturator nerve ran close to the mesh arm. It may provide a clinical anatomical basis explaining the observed postoperative pain. [ABSTRACT FROM AUTHOR]

Platelet adhesion to the site of vascular damage is a critical early step in hemostasis. The platelet glycoprotein (GP) Ib-IX-V plays a key role in this step via its interaction with immobilized von Willebrand Factor (VWF). In addition to its well-known role in adhesion, GPIb-IX-V is critical for platelets' survival in circulation and plays an important role in the regulation of platelet clearance. Several mechanisms of platelet clearance work in concert to maintain a normal platelet count and ensure that circulating platelets are functionally viable via removal of senescent or activated platelets. Furthermore, dysregulation of platelet clearance underlies several bleeding disorders. GPIb-IX-V is central to many physiological mechanisms of platelet clearance including clearance via glycan receptors, clearance of VWF-platelet complexes, and fast clearance of transfused platelets. GPIb-IX-V dependent clearance also underlies thrombocytopenia in several bleeding disorders, including von Willebrand disease (VWD) and immune thrombocytopenia. This review will cover physiological and pathological mechanisms of platelet clearance, focusing on the role of GPIb-IX-V. [ABSTRACT FROM AUTHOR]