Introduction
Drug-induced thrombotic microangiopathy (DITMA) is a life-threatening complication
that is often under-recognized and under-reported (1). Despite recent systematic reviews
published in 2015 (2) and 2018 (3), the list of drugs implicated in TMA continues
to expand (4–9). In addition, novel reports have unraveled potential new mechanisms
that might contribute to a targeted therapy of this syndrome. In this opinion article,
we aimed to summarize recent data on DITMA, categorizing drugs based on mechanisms
of actions and specialties.
Mechanisms of Action
Two decades ago, George et al. introduced the term “drug-induced thrombocytopenia.”
Clinically based criteria were proposed and levels of evidence were stratified in
order to solidify a definite, propable, possible, or an unlikely causal relationship
between a drug and thrombocytopenia (10). Although the mechanisms of endothelial injury
during DITMA still remain unknown; immune-mediated mechanisms or dose-dependent and
cumulative toxicity are implied (11). The hypothesis is based on the observation of
the timing of TMA occurrence, the pattern of disease, the exclusion of a better explanation
thorough investigation. DITMA suspicion is ampilified by TMA resolution when the drug
is withdrawn or recurrent endothelial injury during re-exposure to the drug.
During the last decade, laboratory criteria have been added to support the causal
relationship between a drug and TMA (2). Some examples of drugs in which antibody
mediated DITMA has been confirmed with identification of drug-dependent antibodies
to platelets or other cells as the pathophysiologic mechanism of TMA are quinine,
oxaliplatin, and vancomycin (12). On the other hand, the dose-dependent and cumulative
toxicity model seems to fit for opana's abuse, bevacizumab, levofloxacin, alemtuzumab,
and interferon's cases of DITMA (9, 13–15). It is important to exclude any other diagnosis
before attributing TMA to a drug. For example, in some cases such as these of ipilimumab,
pazopanib, ustekinumab, and golimumab severe ADAMTS13 deficiency was found, plasma
exchange was effective and no drug-dependent antibody inhibition of ADAMTS13 activity
was reported, making drug-indused causal relationship unlikely (7, 16–18). Figure
1 summarizes postulated mechanisms in DITMA.
Figure 1
Summary of postulated mechanisms in drug-induced thrombotic microangiopathy (DITMA).
ADAMTS13: a disintegrin and metalloproteinase with a thrombospondin type 1 motif,
member 13.
Hematology/Oncology
DITMA is caused by various drugs used in Hematology and Oncology.
Chemotherapy
Chemotherapeutic agents were the first to be implicated in causing DITMA. Mitomycin
and gemcitabine have numerous reports of dose-related DITMA, while one report describes
an immune-DITMA as a result of gemcitabine administration (19–26). Despite their use
as a combination with other drugs, which makes the direct causal relationship difficult
in some cases, many well-described cases support a clear-cut association (21, 27,
28).
Three reports have described DITMA caused by pentostatin, a purine analog used in
lymphoproliferative diseases (29). Docetaxel and vincristine have also been reported
to induce TMA (30, 31). Oxaliplatin has been implicated as a cause of DITMA in a review
by Al-Nouri et al. (2), although the authors of the original report described gemcitabine
as the causative factor (32). Renal-limited TMA has been reported in three patients
treated with pegylated liposomal doxorubicin (33) and in one patient receiving treatment
with a short interfering RNA targeted against Myc (DCR-MYC) (5).
Multiagent Chemotherapy
Drug-induced TMA has been reported in children with acute lymphoblastic leukemia (34,
35) and adults with solid tumors (36, 37), receiving multiagent chemotherapy. Jodele
et al. described 13 patients developing TMA after high-dose chemotherapy and autologous
stem cell transplantation for neuroblastoma (12 patients receiving carboplatin/etoposide/melphalan
and one cyclophosphamide/thiotepa) (38). Finally, a high incidence of TMA was observed
in melanoma patients receiving a lymphodepleting preparative chemotherapy regimen
with total body irradiation (TBI) prior to autologous T cell therapy (39). In all
cases, the co-administration of multiple drugs hinders the identification of the causative
agent.
Proteasome Inhibitors
Proteasome inhibitors are mainly used in multiple myeloma treatment and have been
associated with DITMA (bortezomib, carfilzomib, ixazomib). The majority of reports
have implicated bortezomib and cafilzomib (3, 40). Recent reports also support a causal
association of ixazomib with DITMA (41–43). Some authors report successful treatment
of carfilzomib-induced TMA with eculizumab (44, 45).
VEGF, Kinase and Immune Checkpoint Inhibitors
Vascular endothelial growth factor (VEGF) inhibitors are used for the treatment of
various malignancies. Many cases reported DITMA as a result of bevacizumab use, a
humanized monoclonal antibody directed against VEGF (46–49). In some, treatment with
eculizumab was successful (50). Ramucirumab, anti-VEGF receptor 2 monoclonal antibody,
and cetuximab, a monoclonal antibody against epidermal growth factor receptor (EGFR),
are also implicated in causing renal-limited TMA (51, 52).
Tyrosine kinase inhibitors (TKIs) are effective in the treatment of hematologic malignancies
and solid tumors. Sunitinib is a small-molecule TKI that targets VEGFR-2 and PDGFR-b.
Imatinib and ponatinib are small-molecule BCR-ABL TKIs, used mainly in the treatment
of chronic myeloid leukemia. Palbociclib inhibits the cyclin-dependent kinases CDK4
and CDK6. Cases reporting a link between the aforementioned TKIs and drug-induced
TMA have been described in literature (6, 53–56).
Two cases of TMA, one in a patient receiving the immune checkpoint inhibitor ipilimumab,
and one in a patient treated with multi-targeted receptor tyrosine kinase inhibitor
pazopanib have also been reported. However, these reports differ from other DITMAs,
due to the severe ADAMTS13 deficiency (7, 16).
Calcineurin and mTOR Inhibitors
Numerous reports implicate cyclosporine and tacrolimus in causing dose-dependent TMA
(2). Most of these reports described calcineurin inhibitor-induced TMA in patients
that have undergone hematopoeitic stem cell or solid organ transplantation (57). Calcineurin
inhibitor-induced TMA mostly affects the kidneys (58, 59). The inhibitors of the mechanistic
target of rapamycin (mTOR), can also cause DITMA, most frequently associated with
sirolimus or tacrolimus administration, than everolimus (60–62). Successful treatment
with complement inhibition has been described in several patients, since this condition
along with TA-TMA has been considered to resemble atypical hemolytic uremic syndrome
(aHUS) (63, 64).
Monoclonal Antibodies
The first reported case of monoclonal antibody-induced TMA described a patient treated
with anti-T cell monoclonal antibody muromonab-CD3 (OKT3) (65). Emicizumab, a monoclonal
antibody used in Hemophilia A, co-administered with high doses of activated prothrombin
complex concentrate (aPCC) has been linked with TMA in three patients (66). Discontinuation
of aPCC resulted in resolution of TMA, highlighting the fact that emicizumab monotherapy
may not be sufficient to cause DITMA.
Various monoclonal antibodies against tumor necrosis factor alpha (TNF-a), such as
adalimumab, golimumab, and certolizumab pegol have been reported to cause TMA in a
few cases (17, 18, 67). Another report describes a patient with psoriasis developing
TMA after treatment with methotrexate and ustekinumab, a monoclonal antibody that
blocks interleukin (IL)-12 and IL-23 (68). However, in the cases where ustekinumab
and golimumab were suspected to be the causative factor of DITMA, the authors reported
low levels of ADAMS13 (<5%) and an initial response to plasma exchange, making DITMA
diagnosis unlikely (17, 18).
In phase 1 study, moxetumomab pasudotox, an anti-CD22 immunotoxin used in the treatment
of childhood acute lymphoblastic leukemia, caused TMA in 13% of patients. In the majority
of cases, TMA resolved with drug discontinuation (69).
Opioids and Other Drugs of Abuse
Intravenous use of the extended-release opioid oxymorphone and oxycodone tablets reformulated
with polyethylene oxide (PEO) have been reported to cause DITMA in many patients (3).
Subsequently, intravenously administrated high molecular PEO was determined as the
causative factor (15). Cocaine and ecstasy have caused DITMA in recreational users
(70–72).
Neurology
One of the biggest challenges in neurology is the lack of disease-specific drugs that
contributes to the increasing global burden of neurological disorders (73). Traditionally,
epilepsy benefited from a wide variety of available medicines but during the last
decade numerus drugs were introduced at multiple sclerosis (MS) treatment raising
long-term safety considerations (74, 75). Until 2018, interferon beta 1-a and 1-b,
disease modifying treatments (DMTs) of MS and anticonvulsive valproic acid were the
only neurologic drugs associated with thrombotic microangiopathy (3).
Recently, alemtuzumab; which was approved by US Food and Drug Administration (FDA)
for treatment of relapsing-remitting MS (RRMS) at 2014; was associated for the first
time with DITMA (8, 9). Administration of alemtuzumab was known to rarely cause severe
renal adverse effects (76). Nevertheless, in that case report the causal relationship
of alemtuzumab with TMA is supported by the fact that (a) symptoms started immediately
after the first infusion and (b) the patient did not respond to plasma exchange (9).
Another DMT, fingolimod was linked with TMA in an induced-malignant hypertension animal
model; in contrast with control group in which fingolimod was not administrated (77).
Interferon (IFN) has also been correlated with TMA with a dose-dependent manner (14).
Further studies confirm that TMA is a severe complication of IFN-beta RRMS treatment.
Lately, five patients were reported to have IFN-induced TMA following long-term treatment
(78–80). Interestingly, renal function of three patients improved only after administration
of eculizumab, not after withdrawal of IFN (80). Clinical translation of those studies
raises awareness of neurologists for early recognition and management of TMA when
prescribing DMTs.
Infectious Diseases
An infection can be caused by a variety of organisms such as bacteria, viruses, parasites
or fungi. Many anti-infectives agents have been associated with DITMA in the past
(2); quinine, the treatment of malaria, was the most commonly reported (81).
Novel studies implicate a number of different drugs in causing DITMA. First of all,
a case report incriminates hydroxychloroquine, a synthetic derivative of quinine used
for rheumatoid arthritis and systemic lupus erythematosus, as a possible cause of
thrombotic thrombocytopenia purpura (TTP) (82). Disease progression was detrimental
and patient died in spite of drug withdrawal and plasma exchange. Moreover, for the
first time an antiretroviral treatment of human immunodeficiency virus consisting
of tenofovir/emtricitabine was found to have a causality relationship with immune
TTP (83). After the cessation of the drug and the initiation of corticosteroids and
azathioprine the patient recovered. Last but not least, several antibiotics such as
ciprofloxacin, penicillin, and metronidazole were reported with probable evidence
to cause DITMA (2). A new case report implicates again ciprofloxacin in drug-induced
TTP which resolved completely with plasma exchange (84). Another report, identified
a highly effective and frequently prescribed fluoroquinolone, levofloxacin as a new
potential suspect for DITMA (13). This case report described two patients who developed
microangiopathic hemolysis and thrombocytopenia following levofloxacin treatment of
respiratory tract infections. Both cases resolved after drug cessation; the first
patient received also therapeutic plasma exchange. In conclusion, a wide variety of
anti-infectives agents have been scarcely correlated with DITMA and unfortunately,
no one could predict or prevent its appearance; hence, it is of paramount importance
to be aware of that possibility in order to start the appropriate treatment promptly.
Therapeutic Potentials
The only proven intervention in the management of DITMA is discontinuation of the
offending agent. Plasma exchange and immunosuppressive therapy may be a reasonable
treatment option, especially when the diagnosis is uncertain. Although rarely described
in DITMA, patients with severe ADAMTS13 deficiency respond to plasma exchange (7,
16–18, 82–84). However, these reports should be interpreted with caution, since severe
ADAMTS13 deficiency indicates TTP as a more likely diagnosis. In true DITMA, plasma
exchange is ineffective (85). On the other hand, numerous reports have now confirmed
that complement inhibition with eculizumab shows efficacy in DITMA (22, 26, 44, 45,
50, 63, 80). Eculizumab is a first-in-class monoclonal antibody that blocks terminal
complement activation with proven safety and efficacy in complement-mediated TMAs
(86). Based on current literature, we would consider eculizumab administration in
three instances: in patients with non-immune DITMA, in those who deteriorate despite
discontinuation of the implicated drug and supportive care, and finally, in patients
at risk of kidney failure (87).
Conclusions and Future Perspectives
Our state-of-the-art report categorizes drugs that have been associated with DITMA,
summarized in Table 1. It also emphasizes on unique presentations and characteristics
of DITMA, that require increased awareness by treating physicians of relevant specialties.
Hematologists are largely involved in the administration of the majority of these
drugs, along with other internal medicine specialties. Since many patients have presented
with renal-limited complications, the role of nephrologists is also important. Therefore,
our report highlights an unmet clinical need of increased recognition and better understanding
of DITMA by treating physicians across different specialties.
Table 1
Summary of drugs involved in DITMA.
Drug
Type
Specialty
Docetaxel Doxorubicin DCR-MYC Gemcitabine Oxaliplatin Pentostatin Vincristine
Chemotherapy
Hematology/Oncology
Carboplatin + Etoposide + Melphalan Cyclophosphamide + Thiotepa
Multiagent chemotherapy
Bortezomib Carfilzomib Ixazomib
Proteasome inhibitors
Bevacizumab Ramucirumab Cetuximab Imatinib Ipilimumab Pazopanib Ponatinib Palbociclib
Ruxolitinib Sunitinib
VEGF, kinase and immune checkpoint inhibitors
Cyclosporine Rapamycin Tacrolimus
Calcineurin and mTOR inhibitors
Adalimumab Certolizumab pegol Emicizumab + aPCC Golimumab OKT3 Ustekinumab Moxetumomab
pasudotox
Monoclonal antibodies
Hematology/Oncology/ Rheumatology
Cocaine/ Ecstasy Oxymorphone/Oxycodone Polyethylene oxide (PEO)
Opioids / Drugs of abuse
Toxicology
Interferon beta 1-a /1-b Alemtuzumab Fingolimod
Disease modifying treatments for Multiple Sclerosis
Neurology
Valproic acid
Anticonvulsive
Tenofovir/Emtricitabine
Anti-infectives
Infectious diseases
Quinine/Hydroxychloroquine
Antimalarials
Ciprofloxacin Fluoroquinolone Metronidazole Penicillin
Antibiotics
Except for expanding the list of drugs associated with DITMA, future reports need
to take into account potential mechanisms. Identification of underlying etiology is
of utmost importance for proper management. Further mechanistic studies need to identify
the drugs or pathways involved in complement activation in order to early select patients
that would benefit from complement inhibition.
Author Contributions
EG conceived the manuscript concept. TC and MG wrote the manuscript. AA and EG edited
and approved the final manuscript.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial
or financial relationships that could be construed as a potential conflict of interest.