Drug-Induced Immune Thrombocytopenia
Stacey Bidigare Weldon, M.D.

Aster RH, Bougie DW.
Drug-induced immune thrombocytopenia.
N Engl J Med.
Aug 2007;357(6):580-587.

Thrombocytopenia is a potentially deadly disorder that has a multitude of underlying causes. In acutely ill patients, a low platelet count is often attributed to various medical conditions, such as sepsis or disseminated intravascular coagulation. Despite these triggers, drug-induced thrombocytopenia is an equally devastating issue that cannot be overstated. Recognizing drug-induced thrombocytopenia is paramount since it has the potential to be reversed by withdrawing the offending agent, unlike thrombocytopenia due to medical conditions. Due to this, the American College of Emergency Physicians has highlighted a review in The New England Journal of Medicine on drug-induced thrombocytopenia in the lifelong learning and self-assessment series. This review article by Richard H. Aster, M.D., and Daniel W. Bougie, Ph.D., focuses on the common causative agents, theories about pathogenesis, diagnosis and treatment of drug-induced thrombocytopenia. For the purposes of this article, decreases in platelet counts due to dose-dependent suppression with chemotherapeutic and immunosuppressive agents, as well as heparin-induced thrombocytopenia are not discussed.

Background:

Drug-induced platelet destruction is most commonly thought to be caused by drug-induced antibodies, similar to the well-known phenomenon heparin-induced thrombocytopenia. However, several other mechanisms of platelet destruction have been postulated, yet are difficult to prove. The typical course begins approximately one week after a patient begins the offending medication, or this occurs intermittently over a longer period of time. In some cases, symptoms begin within 1 or 2 days of exposure to a drug. This can be explained by naturally occurring antibodies in patients taking platelet inhibitors like abciximab. Patients with drug-induced thrombocytopenia typically present with petechial hemorrhages and ecchymoses. They may also develop systemic symptoms such as lightheadedness, chills, fever, nausea, and vomiting prior to onset of bleeding. In more severe cases, florid purpura and bleeding from the nose, gums, gastrointestinal and urinary tract may occur. These symptoms typically develop with platelet counts of less than 20,000 per cubic millimeter.

Criteria for Diagnosis:

Since cases are either attributed to different causes or not reported at all, the incidence of drug-induced thrombocytopenia has not been well established. To date, more than 100 different medications have been implicated. Laboratory evidence of drug-dependent antibodies is often not available to definitively prove the diagnosis. One study performed in 2005, highlighted in the review article, used a set of clinical criteria to identify the cause-and-effect relationship between medications and cases of drug-induced thrombocytopenia. They are as follows:

Criteria and Level of Evidence for Establishing a Causative Relationship in Drug-Induced Thrombocytopenic Purpura

Criterion

  1. Therapy with the candidate drug preceded thrombocytopenia, and recovery from thrombocytopenia was complete and sustained after discontinuation of therapy.
  2. The candidate drug was the only drug used before the onset of thrombocytopenia, or other drugs were continued or reintroduced after discontinuation of therapy with the candidate drug, with a sustained normal platelet count.
  3. Other causes of thrombocytopenia were ruled out.
  4. Re-exposure to the candidate drug resulted in recurrent thrombocytopenia.
Level of Evidence
Definite-criteria......., 2, 3, and 4 are met

Probable-criteria....... 1, 2, and 3 are met

Possible-criterion......................1 is met

Unlikely-criterion................. 1 is not met

With an extensive list of possible causative agents, an exhaustive list cannot be included for the purposes of this article. Some of the more common medications implicated include quinine, quinidine, sulfonamides, herbal remedies, folk medicines, and common nonprescription drugs such as acetaminophen, vaccinations, foods, and even iodinated contrast. A current compendium of implicated agents is available at http://moon.ouhsc. edu/jgeaorge/ DITP.html. Although chemotherapeutic and immunosuppressive agents are known to cause thombocytopenia by suppressing hematopoesis, they can also induce immune-mediated thrombocytopenia. This is important to remember if patients develop an acute decrease in their platelet count after exposure. Another important cause to remember is vancomycin. Thrombocytopenia in patients on this medication may easily be attributed to the patient’s underlying illness, since many patients on vancomycin are acutely ill. Despite this, an immune-mediated cause is more likely the culprit.

Pathogenesis:

No predisposing genetic or environmental factors have been identified for drug-induced thrombocytopenia. The pathogenesis is poorly understood, possibly due to multiple underlying mechanisms with various agents.

Six postulated underlying mechanisms

  1. Hapten-dependent antibody – Hapten links covalently to membrane protein and induces drug-specific immune response.
  2. Quinine-type drug – Drug induces antibody that binds to membrane protein in presence of soluble drug.
  3. Fiban-type drug – Drug reacts with glycoprotein iib/iiia to induce a conformational change recognized by antibody.
  4. Drug-specific antibody – Antibody recognizes murine component of chimeric Fab fragment specific for platelet membrane glycoprotein iiia.
  5. Autoantibody – Drug induces antibody that reacts with autologous platelets in absence of drug.
  6. Immune complex – Drug binds to platelet factor 4, producing immune complexes for which antibody is specific; immune complex activates platelets through Fc receptors.
Diagnosis and Management:
Drug-induced thrombocytopenia should be suspected in any patient who presents with an acute drop in the platelet count of unknown cause. A careful medication history must be obtained, including over-the-counter and herbal remedies. The most common scenario would be a patient who was started on a medication for the first time, approximately 5 to 7 days prior to symptom onset. In this case, the presence of severe thrombocytopenia, with platelet counts less than 20,000 per cubic millimeter, increases the likelihood of the diagnosis. Specific drug antibodies are technically difficult to test for, and are not helpful in the immediate management of the patient. However, they can be useful in the documentation of the cause, and in determining which drugs cause this disorder. Unfortunately, even with a suggestive history of drug-induced thrombocytopenia, antibody tests may be negative. If a definitive diagnosis is needed and a drug-induced cause is suspected, a diagnostic challenge can be performed. After sensitization, as little as 1 to 2 mg of the suspected drug can cause a significant decrease in the platelet count. It is important to closely monitor the patient and increase the dose slowly, as the therapeutic dose can cause severe thrombocytopenia and bleeding. The most challenging aspect of this disorder is the diagnosis. Once drug-induced thrombocytopenia is suspected and the causative agent discontinued, symptoms usually resolve within 1 to 2 days, and platelet counts return to normal in less than one week. If any uncertainty exists, all medications should be discontinued, and pharmacological equivalents with different chemical structures should be substituted. Patients with only petechial hemorrhages and occasional ecchymoses require no other specific treatment. If they have severe thrombocytopenia with bleeding, platelet transfusions may be necessary to avoid potential devastating complications, such as intracranial or intrapulmonary hemorrhage. Corticosteroids, intravenous immune globulin, and plasma exchange have no proven benefit, but are often given in these cases. Once a drug-induced cause of thrombocytopenia has been established, the patient should be advised to permanently avoid the medication, as sensitivity persists indefinitely. Fortunately, antibodies tend to be specific, and patients usually tolerate pharmacological equivalents with similar chemical structures.




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Posted: Sunday, April 27, 2008