Patients who initiate early chemotherapy have a better prognosis, with a considerably higher survival rate and a good quality of life. Plasmapheresis could be useful if antibody-mediated TMA is suspected 10,142. A cross-sectional multicentre study 143 showed that patients with TiTMA, when compared with those with idiopathic TMA, had a longer duration of symptoms, including some atypical ones, such as bone pain and wasting. To sum up, even if no etiological role has been recognized with certainty in patients with HSCT-TMA, it is clear the association between endothelial damage and complement overactivation, both in early and terminal pathways.
Pregnancy
These data provide the best current summary of drugs documented to cause thrombotic microangiopathy. These data, including the analyses of all 387 articles reporting patients with suspected DITMA,(3) are available on our website (/platelets). 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).
3 Infection Associated TMAs
Once STEC is in the intestines, it attaches to the epithelium where it produces Shiga toxin which translocates through to the blood stream. The Shiga toxin travels through the vasculature attached to blood cells such as leucocytes and platelets. It is a recombinant humanized monoclonal antibody to the C5 complement protein, preventing the cleavage of C5 into C5a and C5b.50 It has revolutionized the treatment of patients with complement‐mediated aHUS and is also thought to be safe in pregnancy. Complement‐mediated aHUS can be caused by genetic mutations and autoantibodies. TTP is rare in the United Kingdom with an annual incidence of six per million.3 TTP may be either acquired (aTTP) or congenital (cTTP).
List Of TMAs
- Carboplatin has very few cases reported, mostly in coadministration with drugs like gemcitabine, docetaxel or trastuzubam 51, 52, 53.
- Furthermore, patients previously diagnosed with TA-TMA using the criteria from Jodele and Cho were reevaluated according to the recent revised criteria.
- DITMA Review Methods – Methods of assessment of reports of DITMA and determination of scores designating the level of evident for a causal association of the drug with TMA.
- In summary, other studies are needed to confirm a potential role of TFE and RTX in DITMA.
After withdrawal of eculizumab, remission was stable over an observation period of 47 months and 15 months, respectively. Our data show that eculizumab is effective in treating chemotherapy-induced TMA. Discontinuation of eculizumab is feasible once the complement-activating condition is controlled and the trigger is eliminated.
Secondary Hemolytic Uremic Syndrome
One such adverse effect is TMA which constitutes microangiopathic hemolytic anemia (MAHA), thrombocytopenia, intravascular thrombosis, and ischemia-induced end-organ damage. This disease, now known as thrombotic thrombocytopenic purpura (TTP), is one of the most extensively studied subtypes of TMA. Primary TMAs mainly include hereditary or acquired forms of TTP and primary atypical hemolytic uremic syndrome (aHUS). Their pathogeneses are well-understood, and their respective diagnosis and treatment are well-developed. Drugs (including chemotherapy), pregnancy, malignant hypertension, autoimmune rheumatic diseases, infection, transplant, and malignancy constitute the secondary TMAs (Figure 1). Example published cases of type I (chemotherapy) and type II (targeted therapy) antineoplastics are presented along with therapeutics explored and outcomes where available.
- When you suffer from TMA your blood will have deformed red blood cells (called schistocytes) and no platelets.
- Both cases resolved after drug cessation; the first patient received also therapeutic plasma exchange.
- It seems reasonable to treat with anti-complementary therapy, particularly those patients with signs of complement activation.
- In addition, novel reports have unraveled potential new mechanisms that might contribute to a targeted therapy of this syndrome.
- To date, several cases of the use of eculizumab in chemotherapy-induced TMA have been reported, most of them regarding gemcitabine (summarized in Table 1).
- The establishment of a nationwide disease registry in Germany with a biobank would now be desirable.
Infectious Diseases
Numerous drugs are described in scientific literature as causative of TMA, mostly as little case series, and the number is rapidly increasing (see Table 1). The drugs reported as causative of TMA are heterogeneous in terms of mechanism of action. Some drugs are more frequently used in clinical activity, as antibiotics or antiplatelet therapy, some others in more restricted contexts, such as IO-anti-VEGF.
5 Genetic Complement‐mediated AHUS
On the other hand, it’s been observed that arterial wall changes are more specific for malignant hypertension (HTN) or scleroderma renal crisis, whereas glomerular changes are more specific for CM-TMA. Therefore, a biopsy should be considered when the clinical picture is ambiguous, there is no response to definitive therapy, the degree of reversibility of kidney injury is unclear, or a second pathology is suspected. For this study we included all patients enrolled through 2014 with their first episode of clinically suspected acquired TTP (475 patients) and also all patients in whom TMA was first identified by a kidney biopsy (12 patients). Not included in this study were the 12 patients who were enrolled at the time of a recurrent episode of TTP.
1 Heterogeneity Of Etiopathogenesis For DITMA Classification: Description And Limitations
A popular 3-hit hypothesis suggests that hit 1 is an underlying predisposition (eg, genetic variant or prior endothelial injury), hit 2 is new endothelial injury (eg, HSCT conditioning regimen), and hit 3 is complement activating triggers described above. Here we use Primary TMA (complement-mediated, replacing the older term Atypical HUS) and Secondary TMA (triggered by another disease), as suggested by our region’s expert Dr. Anuja Java in a recent book (Fig 1). Interestingly, there is a long history of trades between these teams, with multiple players having played for both sides. Indeed, the presence of a complement mutation may not become significant without the stress of a clinical trigger.
Drug withdrawal and supportive care are the only therapeutic approaches available. The response to plasmapheresis is poor, and red blood cells (RBC) transfusions could exacerbate TMA 21,23. Some reports suggest improvement in survival and kidney function with rituximab 24,27 and eculizumab 28,29.
Malignant hypertension, which is sudden, abnormally high blood pressure, is also a known contributor to 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.
Close monitoring of renal function and hematological parameters after eculizumab withdrawal is mandatory; however, there are no evidence-based data about the reliability of a specific parameter and the optimal frequency of testing 33. These include the retrospective design, the limited number of patients treated, and their highly heterogeneous clinical presentation including the presence of both pediatric and adult cases. However, given the difficulties or the impossibility in promoting prospective control trials, real-world data are of paramount importance to understand the clinical potential of innovative treatment proposals in such a rare and often fatal disease.
Immediately after the first dose of eculizumab, we observed a rapid and dramatic improvement of neurological symptoms. Eculizumab was administered 6 times over a period of 5 weeks (Figure 1A). Breast-conserving surgery was performed 7 weeks after termination of eculizumab, followed by radiation therapy. During 47 months of follow-up, renal function continued to improve (eGFR 68 mL/min), and no relapse of TMA has occurred (Figure 1A) (Table 2).
