Presentations vary from petechia, bruising and bleeding from mucosal membranes eg, epistaxis , to potentially life-threatening intracranial haemorrhage. DITP is caused by drug-dependent antibodies that react with platelet membrane glycoproteins when the offending drug is present, resulting in platelet destruction 1.
This mechanism differs from thrombocytopaenia induced by some cytotoxic drugs that affect the bone marrow 2. The typical time to presentation of DITP is within one to two weeks of starting the medicine. Previously sensitised patients can experience rapid drops in platelet counts within one to two hours on repeat exposure 2. However, alternative anticoagulants are rarely used outside the niche indication of HIT, and many physicians have limited experience handling these drugs.
This may increase the risk for both bleeding and thrombotic events. Diagnostic algorithms that combine clinical features and results of laboratory testing are available for diagnosis of HIT.
A suggested example is shown in Figure 2. A suggested approach to diagnosis and initial management of patients with suspected HIT based on clinical assessment supported by complementary laboratory investigations. Screening PF4-dependent immunoassays is indicated for patients with at least intermediate probability of HIT.
FC, flow cytometer. In a prospective, randomized trial, danaparoid was shown to be efficient in preventing new, progressive, or recurrent thromboembolic complications including thrombotic death or limb amputation in HIT.
Fondaparinux is a synthetic pentasaccharide with potent indirect anti-Xa inhibitor properties that have been increasingly used off label for the management of HIT.
Argatroban is a synthetic direct thrombin inhibitor that reversibly binds to the thrombin active site. It is capable of inhibiting both free and clot-associated thrombin. Two multicenter trials showed that argatroban therapy reduces death, amputation, and thrombosis compared with historical controls.
Bivalirudin is another synthetic peptide composed of 2 short hirudin peptide fragments. It is the best investigated alternative anticoagulant in non-HIT patients with coronary disease, including acute coronary syndrome and that requiring coronary intervention.
Rivaroxaban, apixaban, and endoxaban directly inhibit activated factor X, whereas dabigatran is a direct thrombin inhibitor. Emerging evidence suggests the safety and efficacy of several direct oral anticoagulants in HIT. In a small multicenter, prospective study, rivaroxaban seemed to be safe and effective without occurrence of new thrombosis. Of particular importance seems to be the observed low trough levels of the drug, which might cause inadequate protection for HIT patients.
Accumulating evidence from case reports suggests that patients with prolonged thrombocytopenia refractory to standard treatment may benefit from IVIG therapy. Several advantages and disadvantages of nonheparin anticoagulants should be taken into consideration when selecting an agent Table 4.
Protamine is widely used in medicine as an additive to certain preparations of insulin delaying onset and prolonging duration of insulin action and as a rapidly acting antidote to heparin, particularly to neutralize the effects of high heparin concentrations needed for anticoagulation during cardiac surgical procedures.
Protamine and heparin form multimolecular complexes, which result in high rates of immunization in postcardiac surgery patients. Heparin has been shown to increase binding of antiprotamine antibodies compared with protamine alone. Platelet count recovered after starting argatroban, and no adverse events occurred.
Thrombocytopenia after drug administration can be associated with bleeding or thrombosis depending of the pathophysiology of platelet destruction.
Significant progress has been made during the last 2 decades in understanding the pathomechanisms of drug-associated thrombocytopenia. However, there are still numerous diagnostic and treatment challenges, especially in the critically ill patient, including the difficulty in distinguishing drug-associated thrombocytopenia from secondary thrombocytopenia caused by underlying disorders, like sepsis or tumor.
Current diagnostic test methods seem to have limited clinical added benefit in the management of patients suspected to have drug-associated thrombocytopenia.
These assays are not automated, they are time consuming, and they require high technical expertise. This makes them restricted to reference laboratories. Thus, in many cases, the diagnosis is made based on clinical features without laboratory conformation. In addition, the sensitivity of the serological testing for DDAbs is generally considered to be low.
In fact, negative test results are often obtained in patients with a clinical picture strongly suggestive of DITP. One possible reason is that available methods are not sufficiently sensitive due to the low avidity of DDAbs or the lack of the solubility of the target drug. Finally, the mechanism of thrombocytopenia could simply not be related to platelet destruction but rather, could be inhibited platelet production.
The implementation of megakaryocytes as test cells to investigate the binding of DDAbs and the impact of proplatelet production might improve the test sensitivity in DITP. In the absence of sensitive and easy-to-perform assays for DDAbs, physicians should stop drugs that are very likely responsible for thrombocytopenia, even if laboratory assays revealed negative test results.
Recently, important efforts have been made to improve the performance of the functional assays, including addition of PF4 to increase the sensitivity of SRA or flow cytometer-based assays. Although the results of these studies are promising, additional validation in multicenter laboratory workshops as well as clinical trials is needed before a final conclusion could be drawn. A better understanding of pathophysiology of the different drug-associated thrombocytopenias may help developing strategies to avoid complications induced by these drugs.
For instance, some drugs are able to induce conformational changes in platelet surface proteins, leading to increased binding avidity of DDAbs. Using new techniques, like circular dichroism spectroscopy and atomic force microscopy, to analyze protein changes in the presence of the drug could be helpful to predict the immunization risk in treated patients. Conflict-of-interest disclosure: T. Sign In or Create an Account. Sign In. Skip Nav Destination Content Menu. Close Abstract.
Drug-mediated thrombocytopenia. Alternative anticoagulants for HIT. Choice and duration of the anticoagulation. Article Navigation. Drug-associated thrombocytopenia Tamam Bakchoul , Tamam Bakchoul. This Site. Google Scholar. Irene Marini Irene Marini. Cite Icon Cite. Learning Objectives. Table 1. Drugs associated with nonimmune thrombocytopenia. Suspected impaired thrombopoiesis.
Suspected proapoptotic effect. View Large. Table 2. Mechanisms of DITP. Thrombocytopenia caused by platelet destruction, hypersplenism, or hemodilution. Hematology: Basic Principles and Practice. Philadelphia, PA: Elsevier; chap Review provided by VeriMed Healthcare Network. Editorial team. Drug-induced thrombocytopenia. There are two types of drug-induced thrombocytopenia: immune and nonimmune.
Decreased platelets may cause: Abnormal bleeding Bleeding when you brush your teeth Easy bruising Pinpoint red spots on the skin petechiae. The first step is to stop using the medicine that is causing the problem. For people who have life-threatening bleeding, treatments may include: Immunoglobulin therapy IVIG given through a vein Plasma exchange plasmapheresis Platelet transfusions Corticosteroid medicine.
Possible Complications.
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