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Recognize drug-induced thrombocytopenia

 Last Update: 2023-01-04
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Drug-induced thrombocytopenia (DITP), which also includes thrombocytopenia caused by beverages, foods and herbal remedies, is an important clinical problem
for hematologists.
DITP usually appears suddenly and can cause massive bleeding and death
.
In many patients, the cause of the drug is initially unknown
.
In hospitalized patients, unexpected thrombocytopenia may be due to complications such as sepsis
.
In previously asymptomatic patients, DITP is often misdiagnosed as immune thrombocytopenic purpura (ITP), leading to inappropriate
treatment.
Even considering the diagnosis of DITTP, the drug cause may not be obvious
.
Therefore, it is particularly important
to understand the pathogenesis, evaluation and prevention measures of drug-induced thrombocytopenia.
Platelets are small disc-shaped anucleated cells that exist in the blood circulation and play an important role
in physiological and pathological processes such as hemostasis, wound healing, inflammatory response, thrombosis, and organ transplant rejection.
The normal life span of platelets is 7~10d, about 1/3 of platelets are stored in the spleen, due to the different size of the spleen, so the number of platelets stored will change
。 There are many causes of thrombocytopenia, bacterial and viral infections, liver disease, kidney disease, alcoholism, pregnancy, surgery and drugs, etc.
can induce thrombocytopenia, of which drug-induced thrombocytopenia is one of the most common thrombocytopenia, lack of epidemiological data in China, epidemiological studies in Europe and the United States show that the annual incidence of drug-induced thrombocytopenia is 10 cases / 1 million people, and its annual incidence in the elderly and hospitalized patients may be higher
。 Drug-induced thrombocytopenia (DITP) refers to a disease in which the blood platelet count is reduced (< 100 × 10^9 / L) due to drugs, and causes symptoms such as bleeding, which is a secondary drug-induced blood system disease<b15>.
Thrombocytopenia, which also includes beverages, foods and herbal remedies, is an important clinical problem
for haematologists.
Pathogenesis of drug-induced thrombocytopenia Drug-induced platelet count reduction occurs mainly through 2 routes: (1) Inhibit the process of differentiation of hematopoietic stem cells to platelets, including inhibiting the differentiation and maturation of megakaryocytes and the maturation and shedding of platelets, and chemotherapy drugs mainly induce platelet count reduction through this pathway; There is a clear correlation between bone marrow transplantation and drug dose, which is generally reversible, and patients are treated with antineoplastic drugs, phenytoin, estrogen, and phenothiazines
.
The myelosuppressive effect of some drugs is not significantly related to the dose, which can make it difficult to recover from bone marrow suppression, resulting in persistent thrombocytopenia
.
(2) Immune thrombocytopenia, some drugs are antigenic, after entering the human body, the human body can produce drug-dependent antibodies, which act on platelets, identify glycoproteins on platelets, destroy platelets through immune reactions, resulting in a low
platelet count.
This process has little correlation with the patient's organ function, and may depend more on the patient's immune function, and the immune function of young patients is usually stronger than that of older and pediatric patients, so young patients are at high risk of
drug-induced thrombocytopenia.
In addition, there is also non-immune thrombocytopenia, some drugs will have a direct destructive effect on platelets, such as protamine sulfate used to neutralize the anticoagulant effect of heparin, which can form a complex with heparin, which will directly destroy circulating platelets, resulting in mild thrombocytopenia
.
A co-occurring feature in all drugs that cause immune-mediated thrombocytopenia is that thrombocytopenia occurs only in the presence of the
drug.
This indicates that thrombocytopenia will begin to subside within a few days of stopping the drug and clear from the circulation, and explains why patients may develop high titers of drug-dependent antiplatelet antibodies for many years without problems – until drug exposure
occurs again.
Drug-dependent antiplatelet antibodies usually occur 1 to 2 weeks after
exposure to the new drug.
Prolonged intermittent use of the drug may also produce drug-dependent antibodies
.
For unknown reasons, platelets are targets of drug-dependent antibodies much more frequently than neutrophils or red blood cells
.
The following questions should be considered in order regarding the evaluation and management of patients with suspected DITTP: 1.
When should DITP be suspected? 2.
Which of the multiple drugs (or drinks, foods or herbs) the patient is taking may cause thrombocytopenia? 3.
How to confirm the cause of the drug? 4.
What is the clinical course and appropriate management of DITTP? 5.
What is the doctor's responsibility to report the correlation between the drug and thrombocytopenia? When severe thrombocytopenia of unexpected occurrence of DITP should be suspected, it should always be a concern
for DITTP.
Patients with recurrent episodes of thrombocytopenia who recover rapidly should be presumed to be caused by drugs or beverages, foods, or herbs (eg, orange herbal tea).

In a cohort of 343 patients enrolled in ITP ^[1], the risk of DITP being misdiagnosed as ITP was clear; Of these, 28 (8%) patients were subsequently diagnosed with DITP
.
Three of the 28 patients underwent splenectomy before identifying DITP ; Splenectomy has no significant effect
on recurrence of thrombocytopenia with subsequent medical therapy.
Which drugs (or drinks, foods, herbs) can cause thrombocytopenia clinicians often focus on the efficacy of drugs, may ignore adverse drug reactions, and even when adverse drug reactions occur, they still think that patients have new clinical complications, regardless of the drug
.
Failure to detect or manage thrombocytopenia in a timely manner may lead directly to the death
of the patient.
Liu Yan ^[2] searched and consulted domestic medical journals included in CNKI and Wanfang Database from January 2005 to April 2016, and summarized and analyzed the case reports of drug-induced thrombocytopenia to provide
reference for clinical rational drug use 。 The results showed that 224 cases of drug-induced thrombocytopenia involved 19 classes and 105 kinds of drugs; Antibacterial drugs caused thrombocytopenia the most, with a total of 33 kinds, 97 cases (43.
30%); The top 3 were rifampicin in 26 cases (11.
61%), linezolid in 22 cases (9.
82%), and tirofiban in 15 cases (6.
70%)
.
See table 1
below.
Tang Qiaoyun et al^{.
[3]} searched the literature on drug-induced thrombocytopenia in the CNKI database from 2005 to 2015, and statistically analyzed
264 case reports reported in 175 articles that met the inclusion criteria.
The results showed that among the 264 patients with drug-induced thrombocytopenia, there were more male patients than female patients, with a male-to-female ratio of 1.
4:1
.
Young patients (18 – 44 years old) reported the highest number of cases (28.
03%)
.
Anti-infective drugs accounted for the largest proportion (40.
53%), and the occurrence time of ADR was mostly 2 ~ 7 days (41.
48%)
.
See table 2
.
Wu Dong ^[4] et al.
collected ADR reports with the name "thrombocytopenia" reported to the national ADR monitoring platform by his hospital from January 2012 to October 2018, and the results showed that 104 cases of DITP involved a total of 13 classes of drugs and 46 kinds, of which antitumor drugs were the most, unlike the above-mentioned Liu Yan and Tang Qiaoyun literature analysis reported the most
antibacterial drugs.
See table 3
.
Detection of drug-dependent antiplatelet antibodies is important
to confirm the cause of DITTP.
Because such tests are not widely available and take a significant amount of time, it is not feasible
to wait for test results before deciding whether to discontinue the potentially causative drug.
In addition, in patients who may have DITP the test result for drug-dependent antibodies may be negative because: (1) the sensitivity of the test method may not be sufficient to detect some antibodies; (2) Some drugs are relatively insoluble in water and difficult to be included in in vitro tests; (3) Metabolites formed in the body may be the cause of
thrombocytopenia.
In exceptional cases, the use of suspected drugs for diagnostic challenges
after recovery may be considered.
Clinical course and appropriateness of DITTPManagement of DITP usually occurs suddenly, severe thrombocytopenia, platelet count minimums are often less than 20,000/microliter, patients generally have typical bleeding symptoms, and there are reports of hemorrhagic death
.
From the perspective of onset time, patients generally have a history of medication for days, weeks or even months, and the onset time of patients will be different due to different drugs and their mechanisms of action, and patients with shorter time will develop the disease a few hours after medication, usually within 1~2 weeks after medication, and patients with a longer time may have several months later
.
Most patients with immune thrombocytopenia will occur within 24 hours and 1 week of medication, and a small number of drugs can remain in the body for a long time, so patients will have thrombocytopenia after weeks or even months Patients may require platelet transfusions to control overt bleeding, usually with corticosteroids, as the diagnosis
of ITP cannot be excluded.
When DITP is suspected, corticosteroid therapy
should be abruptly discontinued after platelet count returns to normal.
If thrombocytopenia recurs – and it is determined that the patient is not taking the suspect drug again – the diagnosis
of DITP is excluded.
Drug-dependent antibodies can last for many years, and patients must be advised to avoid taking drugs
that cause thrombocytopenia indefinitely.
For example, acute quinine-induced thrombocytopenia
can occur even if a patient has not taken quinine for more than 10 years.
What is the responsibility of the doctor to report the drug's association with thrombocytopenia When the drug is proven to be the cause of thrombocytopenia, it is important
for the doctor to report this experience.
First, adverse event reporting systems should be reported; Second, if there is no or little published evidence describing the drug as a cause of thrombocytopenia, case reports
should be published.
These reports are essential
to provide basic information and reference for future evaluation of patients with suspected DITTP.
Summary of drug-induced thrombocytopenia involves a wide variety of drugs, most of which are cured or improved after timely discontinuation and symptomatic treatment, and thrombocytopenia caused by some drugs is irreversible
.
In the process of clinical medication, the rational use of drugs should be strengthened, and the patient's medical history should be carefully asked before medication, and young patients, people with a history of drug-induced thrombocytopenia, bleeding risk, and the combination of two or more drugs that can cause thrombocytopenia should pay close attention to their platelet changes during medication, and adjust the dosing regimen in time to reduce the occurrence
of drug-induced thrombocytopenia.

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