Reduced surface expression and binding of fibronectin by thrombin-stimulated thrombasthenic platelets.

171

To assess the hemostatic consequences and antithrombotic effectiveness of blocking the platelet glycoprotein (GP) IIb/ila receptor for fibrinogen and other adhesive glycoproteins in vivo, well characterized murine monoclonal antibodies against the platelet GP Jib/lila complex, AP-2 and LJ-CP8, were infused intravenously into baboons. Four animals each received doses of 0.2, 0.4, and 1.0 mg/kg of purified AP-2 IgG, and three animals were given 1.0 mg/kg of the F(ab)2 fragment of AP-2. Five additional animals were given 10 mg/kg LJ-CP8 IgG. At the highest dose, radiolabeled AP-2 IgG bound to an average of 33,000 sites on the circulating platelets. Serial measurements included platelet count, bleeding time, platelet aggregation (induced by ADP, collagen, and 'y-thrombin), and "1In-platelet deposition onto Dacron vascular grafts. Bleeding times were markedly prolonged after injection of 1.0 mg/kg AP-2 IgG (19.2±3.4 min), 1.0 mg/kg AP-2 F(ab)2 (16.5±1.8 min), and 10 mg/kg LJ-CP8 (> 30 min) vs. control studies (4.6±0.2 min), and remained prolonged for 48 h. With each antibody platelet aggregation was initially reduced or absent, with partial recovery over 48 h in a manner that was inversely related to dose. AP-2, both whole IgG and F(ab)2 fragment, but not LJ-CP8, caused a dose-dependent reduction (20-46%) in the circulating platelet count over 24 h. Neither AP-2 nor LJ-CP8 caused a reduction in intraplatelet platelet factor 4, B-thromboglobulin, or I'4Ciserotonin. Graft-associated platelet thrombus formation was reduced by 73% (1.0 mg/kg AP-2 IgG and 10 mg/kg LJ-CP8) and 53% (1.0 mg/kg AP-2 F(ab)2) relative to control values. In contrast, neither heparin (100 U/kg) nor aspirin (32.5 mg/kg twice a day) showed antithrombotic efficacy in this model. Thus, antibodies that functionally alter the platelet GP JIb/lIla complex may produce immediate, potent, and transient, antihemostatic, and antithrombotic effects.

Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Effects of monoclonal antibodies against the platelet glycoprotein IIb/IIIa complex on thrombosis and hemostasis in the baboon.

Hanson

Pareti²,

Ruggeri³

et al. 1988

171

“…Also, a recently reported platelet alloantigen system, Yuk, which was the causative factor of several cases of NATP in Japan (13,14) has turned out to be identical to the Pen system (Aster, R. H., and Y. Shibata, unpublished observations In the presence of calcium ions, GPIIIa is complexed with GPIIb constituting a receptor site not only for fibrinogen (27) but also for fibronectin (28) (6) also reported autoantibodies against the GPIIb-IIIa complex in patients with the same disorder. Also, isoantibodies directed against components of the GPIIb-IIIa complex have been described in plasma from polytransfused patients with Glanzmann's thrombasthenia (9, 10, and this study).…”

Section: Discussionmentioning

confidence: 95%

On the association of the platelet-specific alloantigen, Pena, with glycoprotein IIIa. Evidence for heterogeneity of glycoprotein IIIa.

Furihata

Nugent²,

Bissonette³

et al. 1987

128

“…In addition, the GP I~b-IIla complex appears to be a site for the binding of Factor VIII and fibronectin to thrombin-stimulated platelets (9)(10)(11) and may also provide a site for the binding of the cytoskeletal protein network to the platelet membrane (12). Absence or decreased amount of the platelet GP Ilb-IIa complex characterizes the inherited bleeding disorder thrombasthenia, and platelets from thrombasthenic patients show decreased fibrinogen binding and impaired aggregation (1-8, 12, 13).…”

Section: Introductionmentioning

confidence: 99%

A monoclonal antibody to human platelet glycoprotein IIIa detects a related protein in cultured human endothelial cells.

Thiagarajan¹,

Shapiro²,

Levine³

et al. 1985

119