Recurrent Cerebral Hemorrhaging with Platelet Dysfunction Accompanied by Anti-glycoprotein VI Autoantibodies in a Patient with TAFRO Syndrome.

Thrombocytopenia, anasarca, fever, renal dysfunction, and organomegaly (TAFRO) syndrome is an inflammatory disorder with an unclear pathogenesis. We herein report a case of TAFRO syndrome in remission in a patient who experienced recurrent intracranial bleeding despite a normal platelet count and coagulation system. A further investigation suggested the presence of anti-glycoprotein VI (GPVI) autoantibodies in the plasma, which induced platelet dysfunction and bleeding tendency. No new bleeding or relapse of TAFRO syndrome occurred after immunosuppressive therapy was initiated. These findings may help elucidate the autoimmune pathogenesis of TAFRO syndrome.

C-type lectin-like receptor-2 in platelets mediates ferric chloride-induced platelet activation and attenuates ferroptosis of endothelial cells.

BACKGROUND: An iron overload status induces ferroptosis, an iron-dependent nonapoptotic cell death, in various pathological conditions. We previously reported that hemin (heme), protoporphyrin-IX with ferric iron, activates platelets via C-type lectin-like receptor-2 (CLEC-2) and glycoprotein VI/FcRγ, but protoporphyrin-IX alone blocks CLEC-2-dependent platelet activation. Therefore, we hypothesized that free iron has the ability to activate platelets. OBJECTIVES: This study aimed to elucidate platelet activation mechanisms of iron (ferric chloride), including the identification of signaling pathways and receptors, and to examine whether platelets regulate ferroptosis. METHODS: Platelet aggregometry, platelet activation marker expression, and protein phosphorylation were examined in ferric chloride-stimulated human and murine platelets. Inhibitors of platelet activation signaling pathways and receptor-deleted platelets were utilized to identify the responsible signaling pathway and receptor. The effect of platelets on ferroptosis of endothelial cells was investigated in vitro. RESULTS: Ferric chloride induced platelet activation dependent on Src family kinase pathways in humans and mice. Ferric chloride-induced platelet aggregation was almost lost in CLEC-2-depleted murine platelets and wild-type platelets preincubated with recombinant CLEC-2 proteins. Furthermore, coculture of wild-type platelets, but not CLEC-2-deficient platelets, attenuated ferroptosis of endothelial cells in vitro. CONCLUSION: Ferric chloride activates platelets via CLEC-2 and Src family kinase pathways, and platelets have a protective role in the ferroptosis of endothelial cells dependent on CLEC-2.

A role of platelet C-type lectin-like receptor-2 and its ligand podoplanin in vascular biology.

PURPOSE OF REVIEW: Platelets are essential for hemostasis and are also vital in lymphatic and lung development and the maintenance of vascular integrity. Platelet activation receptor C-type lectin-like receptor 2 (CLEC-2) and its endogenous ligand podoplanin (PDPN) in lymphatic endothelial cells (LECs) and other cells regulate these processes. This review aims to comprehensively summarize the roles of platelet CLEC-2 and PDPN. This review also focuses on discussing the underlying mechanisms by which platelet CLEC-2 and PDPN mediate blood/lymphatic separation. FINDINGS: CLEC-2/PDPN-induced platelet activation in the primary lymph sacs, developmental lymphovenous junctions, neonatal mesentery, and the site of tumor lymphangiogenesis prevents blood/lymphatic vessel misconnection. Further, CLEC-2/PDPN-induced platelet activation is essential for lung development. Mice deficient in CLEC-2 or PDPN show blood-filled lymphatics, lung malformations, and cerebrovascular abnormalities. CLEC-2 deletion in steady-state adult mice did not result in blood/lymphatic vessel mixing. In adulthood, CLEC-2 maintains vascular integrity and that of high endothelial venules in lymph nodes. CLEC-2 deletion in adulthood results in hemorrhage under inflammatory conditions, and hemolymph nodes. SUMMARY: The platelet CLEC-2/LEC PDPN interaction prevents blood/lymphatic vessel mixing at active remodeling sites of the blood/lymphatic system, but not in steady-state adult mice. This interaction also regulates vascular integrity when vascular permeability increases before and after birth.

Abnormalities in C-type lectin-like receptor 2 in a patient with Gorham-Stout disease: the first case report.

Background: Gorham-Stout disease (GSD) is a form of lymphangiomatosis of unknown etiology, characterized by abnormal distribution of lymphatic vessels. Platelets and lymphangiogenesis are closely related via C-type lectin-like receptor 2 (CLEC-2)/podoplanin. Key Clinical Question: Despite similarities between abnormal lymphatic vessels in CLEC-2-deficient mice and patients with GSD, whether CLEC-2 on platelets is involved in GSD pathogenesis is unknown. Clinical Approach: We examined CLEC-2 expression in platelets of a patient with lethal GSD. Most of the patient's platelets expressed aberrant CLEC-2 that was not detectable by certain monoclonal antibodies for human CLEC-2. Further, this population was not activated by a CLEC-2-activating snake venom, rhodocytin. Possible causes of abnormal CLEC-2 including anti-CLEC-2 autoantibodies, podoplanin binding to CLEC-2, and pathogenic CLEC1B gene alteration were excluded. Conclusions: We believe that this is the first report of a patient with structurally and functionally abnormal CLEC-2. CLEC-2 abnormality may be associated with dysregulated lymphangiogenesis in GSD.