Despite the increased worldwide awareness, over the last decade, of the platelet-type von Willebrand Disease (PT-VWD), many uncertainties remain around this rare platelet bleeding disorder. This report aims to correctly identify and study the phenotype of new patients and highlights the diagnostic and therapeutic challenges this disease remains to pose. We describe four PT-VWD cases confirmed by genetic analysis in which either the diagnosis and/or the treatment posed challenge. We provide the details of the clinical presentation, laboratory analysis, and the treatment and the responses in each case. We show that in addition to type 2B VWD, PT-VWD can be misdiagnosed as idiopathic thrombocytopenic purpura, neonatal alloimmune thrombocytopenia, and unexplained gestational thrombocytopenia. The disease can be diagnosed as early as 1 year of age and with phenotypically normal parents. Bleeding in some patients can be managed successfully using Humate P and DDAVP combined with tranexamic acid with no significant thrombocytopenia. We provide for the first time an evidence of an efficient response to rFVIIa in PT-VWD. Anaphylactic reaction to VWF preparations may be related to PT-VWD and the development of HLA antibodies is not uncommon. Progressive thrombocytopenia with normal VWF levels can be seen with PT-VWD and the platelet count was normalized at 2.5 weeks postpartum in one case. We conclude that these studies represent a record of clinical observations/interventions that help improve diagnoses/management of PT-VWD, highlight the variations in age and clinical presentations, laboratory diagnostic approaches, the importance of genetic testing for accurate diagnosis and consideration of therapeutic alternatives.
Background: Management of bleeding in hemophilia patients that develop inhibitors remains a challenging clinical problem. Current bypassing agents are expensive, not universally effective and have pro-thrombotic potential. New approaches, including bispecific antibodies and others have shown potential but still require additional testing in clinical trials. As such, there is a clear need for alternative therapeutic options. The inflammatory reflex is an endogenous neuro-immune pathway that monitors and regulates systemic inflammation via the vagus nerve. The afferent vagus nerve can inform the brain of increased peripheral inflammation. The brain then down-regulates systemic inflammation via increased efferent vagus nerve signaling to the spleen, a mechanism referred to as the cholinergic anti-inflammatory pathway (KJ Tracey, Nat Rev Imm 9(6), 2009). Our previous work has demonstrated that activation of the cholinergic anti-inflammatory pathway via direct electrical vagus nerve stimulation (VNS) or by systemic administration of a pharmacological cholinergic agonist inhibits proinflammatory cytokine production and protects against lethal systemic inflammation (JR Fritz, Bioelectron Med 1(1), 2014). While studying the cholinergic anti-inflammatory pathway in mice, we observed that cholinergic stimulation reduces traumatic hemorrhage. To explore this observation further, we developed a porcine model of soft tissue trauma and hemorrhage. Electrical stimulation of the cervical vagus nerve significantly reduces total blood loss and bleeding time in pigs. Electrical vagus nerve stimulation also significantly increases local thrombin generation at the site of injury, whereas systemic thrombin concentrations remain unchanged (CJ Czura, Shock 33(6), 2010). Aim: To evaluate the beneficial hemostatic effects of cholinergic stimulation on tail hemorrhage in a mouse model of hemophilia A. Methods: Male 8-12-week-old, factor VIII knockout mice (B6;129S-F8<tm1Kaz>/J, Jackson Labs) receive either electrical cervical vagus nerve stimulation (1 V, 30 Hz, 2 ms pulse for 5 minutes) or sham stimulation under anesthesia (ketamine/xylazine 140/16 mg/kg, ip) five minutes before 2 mm distal tail transection. In separate experiments, nicotine (2 mg/kg, ip) or saline is administered 17 minutes before injury. Mouse tails are placed into a 37¡ÆC normal saline bath for five minutes prior to injury. After injury, tails are placed into 50 mL conical tubes filled with 37¡ÆC normal saline and allowed to bleed freely for a total of ten minutes. Total shed blood volume and active bleeding time are recorded, and systemic and local thrombin generation (thrombin-antithrombin complex) is measured via ELISA. Complete blood counts are measured via standard clinical assay. Results: Vagus nerve stimulation significantly reduces total blood loss and bleeding time by 75% and 18%, respectively. Administration of nicotine significantly reduces total blood loss and bleeding time by 79% and 41%, respectively (Fig. 1). Nicotine significantly increases local thrombin generation compared with vehicle controls, whereas systemic thrombin generation is unchanged. There are no differences in circulating platelet counts or hematocrit levels. Conclusions: Cholinergic stimulation results in rapid and specific improvements in hemostasis during traumatic hemorrhage in a mouse model of hemophilia A. The molecular mechanisms of localized thrombin generation remain an active area of research. Future clinical trials are necessary to determine if cholinergic stimulation is an efficacious, safe and cost-effective therapy for hemophilia A patients. Figure 1. Vagus nerve stimulation (A) and nicotine administration (B) significantly reduce blood loss following traumatic hemorrhage in hemophilia A mice. Figure 1. Vagus nerve stimulation (A) and nicotine administration (B) significantly reduce blood loss following traumatic hemorrhage in hemophilia A mice. Figure 2. Nicotine administation significantly increases thrombin generation specifically at the site of injury and not systemically. Figure 2. Nicotine administation significantly increases thrombin generation specifically at the site of injury and not systemically. Disclosures No relevant conflicts of interest to declare.
Deficiency of coagulation factor VIII in hemophilia A disrupts clotting and prolongs bleeding. While the current mainstay of therapy is infusion of factor VIII concentrates, inhibitor antibodies often render these ineffective. Because preclinical evidence shows electrical vagus nerve stimulation accelerates clotting to reduce hemorrhage without precipitating systemic thrombosis, we reasoned it might reduce bleeding in hemophilia A. Using two different male murine hemorrhage and thrombosis models, we show vagus nerve stimulation bypasses the factor VIII deficiency of hemophilia A to decrease bleeding and accelerate clotting. Vagus nerve stimulation targets acetylcholine-producing T lymphocytes in spleen and α7 nicotinic acetylcholine receptors (α7nAChR) on platelets to increase calcium uptake and enhance alpha granule release. Splenectomy or genetic deletion of T cells or α7nAChR abolishes vagal control of platelet activation, thrombus formation, and bleeding in male mice. Vagus nerve stimulation warrants clinical study as a therapy for coagulation disorders and surgical or traumatic bleeding.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.