Her test for gemcitabine-dependent, platelet-reactive antibodies was negative; this result was anticipated as her clinical course was consistent with a dose-dependent toxic mechanism. The ADAMTS13 activity of the patient with evidence supporting a definite association of TMA with pentostatin was 50%. She was not tested for pentostatin-dependent, platelet-reactive antibodies. Twenty-two of the 37 patients who did not have definite evidence supporting a causal association with the suspected drug, including 10 patients in whom the mechanism was postulated to be immune-mediated, had drug-dependent antibody tests; all were negative. Twenty-four of these 37 patients had ADAMTS13 activity measured; none were severely deficient (mean, 63%; range, 25–100%). In 475 (98%) of the 487 Oklahoma Registry patients included in this study, TMA was initially suspected from the clinical features of microangiopathic hemolytic anemia and thrombocytopenia; the etiology of TMA was attributed to a drug in 52 (11%) of these patients.
Immune Checkpoint Inhibitors
In our opinion, eculizumab discontinuation is feasible in carefully selected patients after permanent removal of the complement-activating condition. Further studies are needed to elucidate the role of genetic variants in complement-regulatory proteins in chemotherapy-induced TMA and to define parameters predictive of complement activation and likely TMA recurrence. Until then, the decision to withdraw eculizumab has to be made on an individual basis. Genetic mutations leading to dysregulation of the alternative complement pathway or autoantibodies against complement regulatory proteins are identified in ~ 50% of aHUS patients 4. However, genetic variants in complement regulatory proteins are also detected in patients with secondary, e.g., chemotherapy-induced, TMA 3. In such patients, the underlying dysregulation of the alternative complement system may be unmasked by the applied drug, acting as a complement-activating trigger.
- Moreover, if recognized, these forms showed to benefit more from the withdrawal of the causative drug, with a lower relapse risk and better survival rates than the systemic DITMA (Izzedine and Perazella, 2015).
- A 2016 review of research suggests that TMA originating from cancer treatment drugs may be more serious and that the prognosis is more encouraging when TMA develops as a result of the underlying cancer.
- Treatment for TMA may include blood transfusions, plasma exchange, and other treatments.
- The CP is activated by molecules such as immune complexes and the LP is triggered when microbial carbohydrates are detected.
- The secondary forms of TMA include an extensive range of causes, varying from infections to cancer, pregnancy, malignant hypertension, drugs, solid or hematopoietic transplantation, and autoimmune or metabolic diseases, etc.
Recent Activity
It is essential to distinguish proteasome inhibitors (PIs) kidney toxicity from complications of gammopathies 78. Blood pressure control is essential and renin-angiotensin system blockers are preferred, since VEGF inhibition induces renin secretion through tissue ischemia 64,67. Some case reports described the successful use of eculizumab, even while still administrating VEGFi 57,68. NCI defines targeted therapies as “drugs or substances that block growth and spread of cancers by interfering with specific molecules involved in tumor growth and progression”. In the last decade, there has been a revolution in the development of these anticancer drugs.
Alternative Pathway Of Complement Activation
Resolution or improvement of TMA is observed after the drug is stopped or dose reduced; however, discontinuation alone is often not enough to lead to clinical recovery and some degree of kidney injury can persist. In these patients, especially in case of advanced kidney disease, other therapies need to be considered. The poor understanding of the underlying etiopathogenetic mechanisms of DITMA and the absence of clinical trials on this topic are reflected in treatment guidelines not supported by strong scientific evidence. In summary, our report supports the role of complement-directed therapy with eculizumab as an effective therapeutic option in the management of refractory chemotherapy-induced TMA.
Symptoms of TMA depend primarily on the part of the body affected by the disease. For example, with low platelet counts, a person may be more likely to bruise and have bleeding problems. HUS often develops after a serious bowel infection, typically caused by the bacteria E. This type of TMA primarily affects the small blood vessels of the kidneys. Other people with TTP develop a type of autoimmune disorder that interferes with the activity of the ADAMTS13 gene.
Historical case reports of patients with TTP receiving either no treatment or non-specific treatment reveal a mortality of 72–94%. Current guidelines recommend plasma exchange within the first 4 to 8 hours if TTP is suspected (recommendation grade 1 B) (5, 12). Plasma exchange increases ADAMTS13 activity in the blood and should eliminate ADAMTS13 neutralizing antibodies. For aTTP, a combination with steroids is recommended to control antibody-producing B cells; however, this goal is not usually sustainable (recommendation grade I B) (5, 13).
Who Can Get TTP And HUS?
While immune-mediated damage generally shows acute onset within 2 – 3 weeks of drug exposure, the clinical manifestation of cytotoxic damage is either acute or slowly progressive with cumulative dose-dependent toxicity 5, 8, 9. Distinguishing cancer-related TMA as a consequence of cancer itself from cases of chemotherapy-induced TMA can be challenging. However, metastatic disease is more common in cancer-related TMA, whereas in chemotherapy-induced TMA, little or no active malignancy is detectable 10. While discontinuation of the offending drug and supportive care are the primary treatment options in drug-induced TMA, in some cases this intervention is unable to limit the already dysregulated complement activity and requires therapeutic complement inhibition. The term thrombotic microangiopathy describes an etiologically very heterogeneous group of diseases (table 1), which in the presence of endothelial damage can lead to thrombosis of small and micro vessels, both arterial and venous. Microangiopathy can lead to secondary consumption of platelets and mechanical hemolysis.
Eculizumab In Chemotherapy-induced Thrombotic Microangiopathy
However, if there was significant kidney damage, some kidney problems and high blood pressure may be more likely later on. A 2016 review of research suggests that TMA originating from cancer treatment drugs may be more serious and that the prognosis is more encouraging when TMA develops as a result of the underlying cancer. In most patients with TMA, a complement-activating trigger can be identified, and in 28% of patients with an activating trigger, a genetic risk mutation can be found 3. In agreement with others we found that TPE/plasma infusion was not effective in patients with chemotherapy-induced TMA 12, 13, 14, 15, 16, 17, 18. Thrombotic microangiopathy (TMA) encompasses a group of disorders presenting with microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and ischemic organ damage, most frequently of the kidneys and the central nervous system 1, 2.
There are other drugs that have been used in refractory cases, such as vincristine, bortezomib and azathioprine, and splenectomy has also been used. The mechanism is direct endothelial injury with release of von Willebrand factor multimers, which overwhelm ADAMTS13 capacity and activate coagulation-complement crosstalk. Preeclampsia results from abnormal placentation with production of anti-angiogenic (i.e., anti-VEGF) factors triggering complement activation. This typically occurs later in the pregnancy; helpful diagnostic tests are abnormal uterine doppler and elevated sFlt-1/PlGF ratios (the latter are not yet available in the United States).
Immune-mediated, Acquired Thrombotic Thrombocytopenic Purpura
Immune checkpoint inhibitors (CPIs) are part of this class of drugs, consisting of monoclonal antibodies that target inhibitory receptors expressed on T cells 85. Some authors reported favourable results using eculizumab in carfilzomib-induced TMA. In those cases, ADAMTS13 activity was normal, suggesting a pathophysiology similar to aHUS, with complement overactivation 83.
Epidemiology Of Cancer-Associated TMA
Positive testing in a child who has recently had bloody diarrhea will lead to a diagnosis of HUS. Normal blood has completely round red blood cells and plenty of tiny platelets. When you suffer from TMA your blood will have deformed red blood cells (called schistocytes) and no platelets.
- Although rituximab is not approved for treatment of TTP (off-label use), it is currently the drug of choice for the long-term control of immune-mediated aTTP (recommendation grade I B) (5).
- Despite the temporal correlation, true causality is difficult to establish, since the reported cases presented confounding factors, namely metastatic malignancy and other drugs related with TMA 85.
- Coaches and scouts (or you, our reader) can use several tests to evaluate the presence of functional complement dysregulation in addition to testing for genetic complement mutations (Figure 3).
- Notorious culprits include calcineurin inhibitors like tacrolimus, chemotherapy drugs like mitomycin C, VEGF inhibitors like bevacizumab, and tyrosine kinase inhibitors like sunitinib.
- A city with a population of 1 million will average only about 11 cases in a given year.
One additional report refers to a patient with a complement mutation 84. As expected, plasmapheresis showed no clear benefit in this setting 75. Treatment is based on immediate and permanent drug cessation 30,34 and recurrence has been described with repeated exposure 32. Despite the pathological mechanism, response to plasmapheresis is poor 30,34,35. Few case reports document successful use of rituximab 11,36,37 and eculizumab 35,38,39.
And “microangiopathy” is a medical situation affecting small blood vessels — specifically capillaries and arterioles. So TMA is a condition in which blood clots have formed in those blood vessels. Thrombotic microangiopathy (TMA) is a rare but potentially life threatening condition that affects the body’s small blood vessels. However, the presence of diarrhea is not sufficient to exclude other forms of TMA as ~ 30 – 40% of aHUS and TTP cases involve gastrointestinal symptoms, including bloody diarrhea 19, 20. A city with a population of 1 million will average only about 11 cases in a given year.
In STEC-HUS, Shiga toxin translocates from the gut, combines with glycolipid Gb3 in the circulation, enters endothelial cells via GB3 receptor, and creates havoc disrupting protein synthesis and egging on tissue factor and von Willebrand factor release. In a fascinating move, Shiga toxin can also bind to Factor H on endothelial surfaces, thus bringing complement into the game. Pathogenesis of Strep pneumo-HUS is attributed to pneumococcal neuraminidase, which cleaves sialic acid residues exposing a cell surface component called T-antigen and initiating complement activation. You notice thrombocytopenia, anemia, and an elevated reticulocyte count. You look for elevated lactate dehydrogenase (LDH), low haptoglobin, schistocytes on the peripheral smear, and increased reticulocytes. Direct antiglobulin (or Coombs test) is negative, excluding autoimmune hemolysis.
