Prescribed medications can have some pretty strange effects. Perhaps you have yet to hear of drug-induced thrombotic microangiopathy (DITMA). This under-reported condition often flies under the radar—and is potentially lethal.

A 2015 systematic review published in Blood (and a 2018 update) detailed the drugs that cause this condition.

Al-Nouri ZL, Reese JA, Terrell DR, et al. Drug-induced thrombotic microangiopathy: a systematic review of published reports. Blood. 2015;125(4):616–618.

 

Saleem R, Reese JA, George JN. Drug-induced thrombotic microangiopathy: An updated systematic review, 2014-2018.American Journal of Hematology. July 9, 2018.

 

In recent years, experts have looked into potential causes. Diagnosis and treatment are important in such cases.

 

 

What is DITMA?

Microangiopathic hemolytic anemia, thrombocytopenia, and microvascular thrombosis with characteristic vessel wall abnormalities are all syndromes of thrombotic microangiopathy. They have multiple causes including prescription drugs, vaccines, alternative medicines, beverages, and toxins.

Some cases involve idiosyncratic, acute immunologic reaction while others indicate a direct toxic effect, which could be acute dose-related toxicity or chronic dose and duration-dependent toxicity. Severe kidney injury, including hemolytic-uremic syndrome, is another DITMA presentation.

Symptoms due to immune-mediated reactions are typical of acute onset following the initiation of a drug. Those arising from dose-related toxicity could manifest acutely or develop gradually, and often include kidney failure, according to the aforementioned Blood study. 

 

Drugs that cause DITMA

The list of drugs that cause DITMA is considerable and growing. Here are some examples:

• Chemotherapy agents. These agents were the first to be identified as leading to DITMA, with mitomycin and gemcitabine tied to dose-related DITMA. Combinations of chemotherapy with other drugs can cloud the etiology; nevertheless, there are many clear-cut relationships.

• Multiagent chemotherapy. DITMA occurs in children with acute lymphoblastic leukemia and adults with solid tumors who receive multi-agent chemo. Again, the use of multiple agents makes identification of single offenders difficult.

• Proteasome inhibitors. These agents, predominantly used to treat multiple myeloma, have been linked to DITMA.

• Monoclonal antibodies. The first monoclonal antibody linked to DITMA was emicizumab, which is used to treat hemophilia A. Monoclonal antibodies targeting tumor necrosis factor alpha have also been implicated, including adalimumab, golimumab, and certolizumab pegol.

• Opioids. Extended-release oxymorphone and oxycodone tablets with polyethylene oxide have been associated with DITMA in various cases. Recreational use of cocaine and ecstasy has also been linked.

• Neuro drugs. Through 2018, Interferon beta 1-a and 1-b, which are disease-modifying treatments for multiple sclerosis, as well as the anticonvulsant valproic acid, were the only neuro drugs related to DITMA. More recently, alemtuzumab, which is indicated for the treatment of relapsing-remitting MS, was also linked.

• Infectious agents. Drugs used to treat infections have been linked to DITMA. The most notable example is quinine, used to treat malaria.

It can be hard to flesh out whether direct or indirect relationships are responsible for DITMA. In the systematic review published in Blood,among the 78 drugs evaluated as suspected of causing DITMA, a definite association could be established for only 29%.

 

Treatment of DITMA

The only way to definitively manage DITMA is to discontinue use of the offending agent. Plasma exchange and immunosuppressive therapy also may benefit. The monoclonal antibody eculizumab may be useful in patients with non-immune DITMA, as well as in those who decompensate after discontinuation of the offending agent and despite supportive care, and in those who may be at risk for kidney failure.

 

Unmet clinical need

DITMA represents an unmet clinical need that warrants increased awareness. As noted by the authors of a report published in Frontiers in Medicine, the distinctive presentations and characteristics of DITMA should be on the radar of treating physicians in certain specialties.

Chatzikonstantinou T, Gavriilaki M, Anagnostopoulos A, et al. An update in drug-induced thrombotic microangiopathy. Front Med (Lausanne). 2020;7:212.

 

 

 

“Hematologists are largely involved in the administration of the majority of these drugs, along with other internal medicine specialties,” the authors wrote. “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.”