Sera from patients with heparin-induced thrombocytopenia generate platelet-derived microparticles with procoagulant activity : an explanation for the thrombotic complications of heparin-induced thrombocytopenia

Drug-induced thrombocytopenia should be suspected in any patient with acute thrombocytopenia of unknown cause Although the incidence is low, more than 100 drugs have been implicated in thrombocytopenia, including quinine, sulfonamides, abciximab, carbamazepine, and vancomycin, as well as herbal remedies and several nonprescription drugs This review summarizes the current understanding of pathogenesis and provides a guide for diagnosis and management of this potentially dangerous disorder

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Drug-Induced Immune Thrombocytopenia

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1538-7836.2009.03360.x

Drug-induced immune thrombocytopenia: pathogenesis, diagnosis, and management

Drug disposition and drug hypersensitivity.

http://pathology.ucla.edu/workfiles/Education/Transfusion%20Medicine/9-9-DIHAreviewGarratty-39113603.pdf

Immune hemolytic anemia associated with drug therapy.

Platelets coated with quinine- or quinidine-induced antibodies form rosettes around protein A-Sepharose beads and normal platelets form rosettes about protein A-Sepharose beads coated with these antibodies. These reactions occurred only in the presence of sensitizing drug. Platelets also formed rosettes about protein A-Sepharose beads coated with an anti-PIA1 antibody, but drug was not required. Formation of rosettes between antibody-coated platelets and protein A-Sepharose was inhibited by F(ab')2 fragments of goat antibody specific for the Fc portion of human IgG, while rosette formation between antibody-coated protein A-Sepharose and platelets was inhibited by F(ab')2 fragments directed against the F(ab')2 portion of the IgG molecule. Since binding of IgG to protein A is known to occur via the Fc region, these findings suggest that binding of drug-induced antibodies to platelets occurs at the Fab domains of the IgG molecule.

/pdf/fab-mediated-binding-of-drug-dependent-antibodies-to-28lxia6oc2.pdf

Fab-mediated binding of drug-dependent antibodies to platelets in quinidine- and quinine-induced thrombocytopenia.

Summary

Quinine- and quinidine-dependent antiplatelet antibodies are generally believed to bind to the membrane glycoprotein complex, GPIb/IX. However, we and others have found that some drug-dependent antibodies bind to platelets from patients with the Bernard-Soulier syndrome which lack these glycoproteins. We therefore studied the reactions of a group of these antibodies with normal and Bernard-Soulier platelets and their membrane proteins.



As indicated by rosette formation of the sensitized platelets around protein A-Sepharose beads, two quinine- and two quinidine-dependent antibodies reacted with both normal and Bernard-Soulier syndrome platelets at a high (300 μM) concentration of drug. At a pharmacologic drug concentration (10 μM), all four antibodies reacted with normal platelets, but only the two quinine-induced antibodies reacted with Bernard-Soulier platelets.



Immunoprecipitation studies with solubilized, tritiumlabelled normal platelets, at both high and low drug concentrations, showed that each of the four antibodies precipitated proteins corresponding to GPIb and GPIX. Fainter bands corresponding to glycoproteins IIb and IIIa, which do not label well with tritium, were also detected. With radioiodinated normal platelets, it was found that each of the four antibodies was capable of precipitating GPIIb/IIIa, but only in the presence of drug.



The four antibodies also promoted drug-dependent precipitation of GPIIb and GPIIIa from lysates of radioiodinated Bernard-Soulier platelets. The two quinine-dependent antibodies precipitated these glycoproteins at both high and low drug concentrations, while the quinidine-dependent antibodies reacted much more strongly at the higher drug concentration. Precipitation of GPIb/IX was not observed with BSS platelets.



Absorption of a quinine-induced antibody with Bernard-Soulier platelets in the presence of drug eliminated its ability to precipitate GPIIb and GPIIIa. However, the absorbed antibody retained the ability to precipitate GPIb from solubilized normal platelets. Thus, at least two drug-dependent antibodies were present, one specific for GPIb/IX and the other for GPIIb/IIIa.



These findings indicate that glycoproteins IIb and/or IIIa, in addition to the GPIb/IX complex, can serve as targets for drug-dependent antibodies in both intact and detergent-solubilized platelet preparations.

Patrick C. Mullen

Papers

Fab-mediated binding of drug-dependent antibodies to platelets in quinidine- and quinine-induced thrombocytopenia.

Quinine- and quinidine platelet antibodies can react with GPIIb/IIIa.

Structural features of the quinidine and quinine molecules necessary for binding of drug-induced antibodies to human platelets