Deficiency of intact thrombospondin and membrane glycoprotein Ia in platelets with defective collagen-induced aggregation and spontaneous loss of disorder

Abstract

Platelets from a patient with a severe lifelong bleeding tendency, which later spontaneously disappeared, lacked intact thrombospondin and glycoprotein (GP) Ia. Before disappearance of the bleeding disorder, results of coagulation studies and platelet aggregation in response to adenosine diphosphate (ADP), arachidonic acid, thrombin, A23187, epinephrine, and ristocetin were normal. In contrast, aggregation only occurred in the presence of collagen or wheat germ agglutinin at unusually high doses of these agonists. The platelets adhered normally to purified bovine and human type I collagen, and they did not spread in the presence of methylated type I collagen. No collagen-induced clot retraction was observed. Two-dimensional gel electrophoretic analyses of platelet proteins and immunologic studies showed that intact thrombospondin and GP Ia were absent. Aggregation in response to collagen could be restored by adding thrombospondin. Disappearance of the bleeding tendency occurred at the onset of menopause; subsequent analyses revealed that thrombospondin and GP Ia were present in platelets and that collagen-induced platelet aggregation was normal. These results suggest that both thrombospondin and GP Ia are essential in collagen-induced platelet aggregation. The spontaneous disappearance of the bleeding tendency may have been related to hormonal influences.

Rare bleeding disorders

“…Abnormalities of the platelet receptors for adhesive proteins include abnormalities of the GP Ib‐V‐IX complex (Bernard‐Soulier syndrome, characterized macrothrombocytopenia and absent platelet agglutination induced by ristocetin, and Platelet‐type von Willebrand disease, associated with gain of function phenotype of the platelet GPIbα, increased avidity for VWF, leading to the binding of the largest VWF multimers to resting platelets and their clearance from the circulation) and Glanzmann thrombasthenia, caused by defects of GPIIb/IIIa, which in activated platelets binds the adhesive glycoproteins that bridge adjacent platelets, securing platelet aggregation [4]. Other, less‐frequent abnormalities include abnormalities of GP Ia/IIa, or GPVI, both characterized by selective impairment of platelet responses to collagen [5–7].…”

The primary structure of the VLA-2/collagen receptor alpha 2 subunit (platelet GPIa): homology to other integrins and the presence of a possible collagen-binding domain.

“…Resolution of this discrepancy suggests that there may be another VLA heterodimer that resembles VLA-2 in size but has a different amino acid sequence. V LA-2 is an c~/~/-subunit cell surface heterodimer strongly implicated as receptor for collagen because (a) VLA-2 has been shown to be identical (61) to a 150,000/ll0,000-Mr structure recognized by the mAb P1H5, which specifically blocks human fibrosarcoma cell (66) and platelet (31) attachment to collagen; (b) patients deficient in platelet protein Ia (or subunit of VLA-2) also lacked responsiveness to collagen (27,41); and (c) the mAb 12F1 was used to identify VLA-2 as a 160,000/130,000-Mr (nonreduced) platelet protein complex that mediates Mg2+-dependent adhesion to collagen (51,52). Also in this regard, antigens that strongly resemble VLA-2 in size have been implicated in hepatocyte cell attachment to type I collagen (14).…”

Detection and Effects on Platelet Function of Anti-Platelet Antibody in Mule Foals with Experimentally Induced Neonatal Alloimmune Thrombocytopenia

“…35 Most antibodies are directed against platelet Gp IIb-IIIa, the most abundant and immunogenic platelet-surface Gp. 35 Other antibodies are directed against Gp Ib, 22 Gp Ia-IIa, [36][37][38][39] and Gp IV. 22,35 Many react with more than 1 Gp.…”