A novel platelet aggregating factor found in a patient with defective collagen-induced platelet aggregation and autoimmune thrombocytopenia

Abstract

We found a novel platelet aggregating factor in a patient with steroid- responsive immune thrombocytopenic purpura that is associated with defective collagen-induced platelet functions. The aggregating factor and platelet functions were analyzed. The patient, a 58-year-old female, had purpura and prolonged bleeding time despite adequate platelet counts (greater than 140,000/microL) after steroid therapy. The patient's platelets responded normally to all agonists except collagen. Platelet adhesion to collagen fibrils was decreased. The patient's plasma induced irreversible aggregation and ATP release in normal platelet-rich plasma (PRP). This platelet aggregating factor was found in F(ab')2 fragments of the patient's IgG, which caused thromboxane B2 synthesis, elevation of cytoplasmic Ca2+ levels, and phosphorylation of 40 kDa protein in normal platelets. Platelet aggregation by the patient's IgG was inhibited by prostacyclin, dibutyryl cAMP, diltiazem, disodium ethylenediaminetetraacetate, and antimycin A plus iodoacetate, but ADP scavengers, cyclo-oxygenase inhibitors, and heparin had little or no effect. The aggregating activity of the patient's IgG absorbed to and eluted from normal platelets. The patient's Fab fragments did not induce platelet aggregation in eight of ten normal PRP but specifically inhibited aggregation induced by collagen and by the patient's IgG. The major component of an immunoprecipitate made with the patient's IgG from radiolabeled membrane proteins of normal platelet extract had a 62 kDa mol wt, while no such precipitate appeared in extracts of the patient's platelets. These results indicated that platelet aggregation by the patient's IgG was induced by the reaction of an antibody with a specific antigen on the normal platelet membrane through stimulus- response coupling. This antigen may be a collagen receptor on the platelet, most likely a polypeptide of 62 kDa under reducing condition. The defect of collagen-induced aggregation of the patient's platelets seemed to be due to alteration of the membrane protein related to this putative collagen receptor.

Iron Oxide Nanoparticles Carrying 5-Fluorouracil in Combination with Magnetic Hyperthermia Induce Thrombogenic Collagen Fibers, Cellular Stress, and Immune Responses in Heterotopic Human Colon Cancer in Mice

“…The distinct short-term cellular stress and injury induced by the combined thermo-chemotherapeutic tumor treatment was visible by the enrichment of protein pathways belonging to GP6 signaling pathway and coagulation system, which is in agreement with the high impact of this therapy modality on the tumor volume. GP6 is the major signaling receptor for the extracellular matrix protein, collagen [19], and it plays a critical role in hemostasis and thrombosis through integrin activation, supporting adhesion and the initial stages of platelet aggregation [20][21][22]. In agreement with this, collagen fibers, which are being destroyed by magnetically induced heating, are the most thrombogenic macromolecular components of the extracellular matrix [23].…”

Platelet Inhibition by Low-Dose Acetylsalicylic Acid Reduces Neuroinflammation in an Animal Model of Multiple Sclerosis

“…GPVI is one of the most essential platelet collagen receptors involved in atherothrombosis, and soluble GPVI is rapidly proteolytically cleaved by TxA 2 -induced MMP [38,53]. Since GPVI expression is restricted to platelets and megakaryocytes, it is another potential antithrombotic target [54,55], and in line, patients with a GPVI deficiency do not exhibit symptoms other than a mild bleeding tendency [56][57][58][59][60][61][62][63]. In the present study, the reduction of soluble GPVI plasma levels was not found in low-dose ASA-treated mice compared to control mice.…”

Progress toward a Glycoprotein VI Modulator for the Treatment of Thrombosis

“…The first piece of epidemiological evidence validating GPVI as an antiplatelet target was reported in 1987 via the identification of a GPVI deficient patient . Since then numerous cases of acquired (anti-GPVI autoantibodies) and congenital GPVI deficiency (GPVI is not expressed or is not functioning as normal) have been reported and were summarized by Arthur et al in 2007 (Table ).…”