Treatment of drug-induced immune thrombocytopenias

Abstract

Several therapeutic agents can cause thrombocytopenia by either immune-mediated or non-immune-mediated mechanisms. Non-immune-mediated thrombocytopenia is due to direct toxicity of drug molecules to platelets or megakaryocytes. Immune-mediated thrombocytopenia, on the other hand, involves the formation of antibodies that react to platelet-specific glycoprotein complexes, as in classic drug-induced immune thrombocytopenia (DITP), or to platelet factor 4, as in heparin-induced thrombocytopenia (HIT) and vaccine-induced immune thrombotic thrombocytopenia (VITT). Clinical signs include a rapid drop in platelet count, bleeding or thrombosis. Since the patient's condition can deteriorate rapidly, prompt diagnosis and management are critical. However, the necessary diagnostic tests are only available in specialized laboratories. Therefore, the most demanding step in treatment is to identify the agent responsible for thrombocytopenia, which often proves difficult because many patients are taking multiple medications and have comorbidities that can themselves also cause thrombocytopenia. While DITP is commonly associated with an increased risk of bleeding, HIT and VITT have a high mortality rate due to the high incidence of thromboembolic complications. A structured approach to drug-associated thrombocytopenia/thrombosis can lead to successful treatment and a lower mortality rate. In addition to describing the treatment of DITP, HIT, VITT, and vaccine-associated immune thrombocytopenia, this review also provides the pathophysiological and clinical information necessary for correct patient management.

Figure 1.

Schematic representation of the pathophysiology of drug-induced thrombocytopenia (DITP), immune checkpoint inhibitor-induced thrombocytopenia (ICI-induced ITP), heparin-induced thrombocytopenia (HIT), and vaccine-induced immune thrombotic thrombocytopenia (VITT). Ab: antibody; PLT: platelet; GP: glycoprotein; Hep: heparin; PF4: platelet factor 4; CI: checkpoint inhibitor; PD-L1: like programmed death-ligand 1.

Figure 2.

Suggested algorithm to manage cases with suspected drug-induced thrombocytopenia (DITP). (Adapted from Arnold et al.⁸⁰).

Figure 3.

Management of patients with suspected heparin-induced thrombocytopenia (HIT) based on clinical assessment supported by complementary laboratory investigations. Screening platelet factor 4 (PF4)-dependent immunoassays are indicated for patients with at least intermediate probability of HIT. If the ELISA assay is positive, heparin should be stopped, an alternative anticoagulant should be started, and thromboembolic complications should be excluded. Next, functional assays should also be performed to confirm or refute a diagnosis of HIT. HIPA: heparin-induced platelet activation assay; SRA: serotonin release assay; FC: flow cytometric assay; DOAC: direct oral anticoagulants; Vit-K: vitamin K; DIC: disseminated intravascular coagulation. (Figure modified, with permission, from Bakchoul and Marini).

Figure 4.

Suggested approach to diagnosis and initial management of patients with suspected vaccine-induced immune thrombotic thrombocytopenia (VITT). FEU: fibrin equivalent units; PT: prothrombin time; aPTT: activated partial thromboplastin time; HIPA: heparin-induced platelet activation assay; SRA: serotonin release assay; PEA: P-selectin expression assay.