In this review we use the term complement‐mediated aHUS to describe aHUS where there is dysregulation of the complement system (Figure 2). The clinical presentation of TMA can vary, and the differential diagnosis is wide, therefore laboratory tests are important alongside a thorough history and examination. Thrombocytopenia, MAHA, and end organ damage are the common elements of all TMAs.
Before the stem cell boost, this patient had gained an improved renal function but no response in terms of anemia, thrombocytopenia, and LDH. The stem cell boost induced a recovery from anemia and thrombocytopenia, but a fully normalized LDH value was documented only after 30 doses of narsoplimab. Risk factors for TA-TMA development such as GvHD and infections were present in a high proportion of patients. Before the diagnosis of TA-TMA and treatment with narsoplimab, 19 of the 20 patients (95%) were diagnosed with high-risk TA-TMA according to the consensus criteria in Schoettler et al. 7.
Oklahoma TTP-HUS Registry
Additionally, complications of acute infection have been described including macro thrombosis and AKI. Almost a third of patients can still develop thrombosis despite anticoagulation in this prothrombotic state.76 While C5 inhibition was proposed for to prevent these broader thrombotic events, a trial of ravulizumab in COVID‐19 was stopped due to lack of efficacy. Shiga toxin was first detected in Shigella dysenteriae and this remains an important cause of HUS in developing countries.
What Is The Treatment?
Nevertheless, several problems still need to be solved to clarify the role of complement in DITMA (as in other secondary TMA forms). Focusing on those patients with decreased serum complement factors, they all had positive IF staining. This concordance may help to identify, based on simple, inexpensive and widely available blood tests, a cluster of patients with an underlying complement hyperactivation.
ST-HUS (Shiga Toxin-related Hemolytic Uremic Syndrome)
Patients with acute GVHD after HSCT present high levels of plasma markers of endothelial injury, indicating a probable link between endothelial lesion and the development of both GVHD and HSCT-TMA 8,106,112. HSCT-induced TMA (HSCT-TMA) has a wide range of reported incidence (up to 80%), that may be explained by the retrospective nature of the studies, the simultaneous analysis of pediatric and adult populations and a lack of uniform diagnostic criteria. These are highly complex patients because of the procedure itself and its adverse effects, such as bone marrow ablation, toxic drug effects and immunological reactions against an allogenic graft.
Chemotherapy
- Both pathways form a different C3 convertase (C4b2a) composed from cleaved complement component C2 and C4.
- Among the 13 patients who responded to narsoplimab, 8 had acute GvHD with intestinal involvement of overall grade ≥ 2.
- In a series of 9 cases of TMA related with monoclonal gammopathies 149, all the patients presented with a kidney-limited TMA, with no confounding factors on presentation.
- TMA is a potential adverse effect when the targeted molecule interferes with endothelial homeostasis 61.
Most patients had already been diagnosed with cancer, although it can occasionally be a presenting sign of malignancy 89,140. Unlike other paraneoplastic syndromes, there is a high number of cases of TiTMA that occur with cancer recurrence, probably due to changes in tumor cells properties as a consequence of chemotherapy 141. The difficulty of histologic diagnosis led to the development of non-invasive clinical criteria for HSCT-TMA diagnosis.
Other nephrotoxins should be avoided any time close to the conditioning regimen 88, and platelet and RBC transfusion could be indicated 8. To add complexity to this issue beyond complement activation, Gavriilaki et al. recently suggested that neutrophil and coagulation cascade activation could also be of importance in HSCT-TMA pathophysiology 106. HSCT-TMA pathophysiology is complex and not fully understood, but endothelial dysfunction is probably independent of ADAMTS-13 activity 8,89,93.
Hemolytic Uremic Syndrome
Of the case reports, a subsequent TMA manifestation was observed in 31% (16/52) of patients after eculizumab discontinuation. Data from five clinical trials documented a relapse in 20% (12/61) of patients after cessation of therapy with eculizumab with a median follow-up of 24 weeks. Of note, relapse risk was independent of an identified genetic mutation, high-risk polymorphism, or autoantibody status.
- The common consequences are endothelial cell damage with consecutive thrombus formation and complement activation (16).
- Ever since its fall from grace for dabbing in drug induced-TMA, some US nephrologists are nostalgic for the days when this antimalarial agent was used as a remedy for leg cramps.
- Among these 177 patients, quinine was the most commonly reported drug (in 44 patients).
- There are other drugs that have been used in refractory cases, such as vincristine, bortezomib and azathioprine, and splenectomy has also been used.
- 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.
Thrombotic Microangiopathy (TMA) Region
Eculizumab is a monoclonal drug that inhibits C5-factor, thus not permitting the formation of the Complement Membrane Attack Complex, avoiding, the facto, cell lysis and death. All cases are summarized in Table 2 and referenced in Supplementary Material S18–S53. Criteria and levels of evidence for an association of a single drug with TMA were defined using criteria by Al-Nouri et al. (2015), previously adapted from drug-induced thrombocytopenia (George et al., 1998).
Tyrosine Kinase Inhibitors
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. Thrombotic microangiopathy is defined by the triad of Coombs-negative hemolytic anemia with evidence of schistocytes in the blood, thrombocytopenia (microangiopathic hemolytic anemia), and ischemic end-organ damage. Depending on the vascular systems involved, renal failure, neurological symptoms, cardiac complications, respiratory failure, visual disturbances, pancreatitis, intestinal ischemia, and (less commonly) skin changes may occur (1, 2). Mortality is high if untreated, with reports published prior to the advent of effective therapy of 72–94% (3, 4).
In children, TTP is rare, and PE has a more side effects, therefore, complement inhibitors are first line.47 PE remains the only treatment in countries where access to complement inhibitors is restricted due to cost. 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.
Table II presents the results of reassessing the status of the 58 patients in the Oklahoma Registry who had previously been assigned to the drug-induced category, 1989–2014. Using the evaluation criteria developed for our previous assessment of published reports, 21 patients (37%) had evidence supporting a definite association of the suspected drug with their episode of TMA. In 19 (90%) of these 21 patients, the etiology was attributed to quinine; 12 of the 19 patients with quinine-induced TMA has been reported previously;(8) the other seven patients with evidence supporting a definite association were diagnosed following this report.
The establishment of a nationwide disease registry in Germany with a biobank would now be desirable. HELLP is a more severe form of the disease spectrum, which can lead to a glomerular endotheliosis. There is known endothelial dysfunction thought to be due to greater circulating levels of the soluble form of the vascular endothelial growth factor receptor (sFlt‐1), syncytiotrophoblast‐derived antiangiogenic factors and soluble endoglin. 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).
Anecdotal reports suggest that TMA-2 is a highly unpredictable and dose-sensitive substance that can produce uncomfortable amounts of body load, nausea, overstimulation, and inconsistencies between experiences. Thrombotic microangiopathies are rare, life-threatening diseases whose care involves physicians from multiple specialties. The past five years have seen major advances in our understanding of the pathophysiology, classification, and treatment of these conditions. An autoimmune disorder may require the use of immune suppression therapies.
