Thrombotic microangiopathy

Introduction

Hematopoietic stem cell transplantation (HSCT) is a potentially curative therapy for patients with hematologic malignancies, bone marrow failure syndromes, immunodeficiency states, and metabolic disorders. Thrombotic microangiopathy (TMA) is a well-recognized potentially lethal complication of HSCT. It is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and multiple organ dysfunction. The etiologies of this syndrome are diverse, and it requires a high degree of clinical suspicion for diagnosis. The incidence ranges between 0.5% and 63.6%. This wide disparity in incidence rates is caused by the inability to obtain tissue biopsy in most circumstances and therefore diagnosis relies solely on clinical parameters. The etiology of posttransplant TMA is multifactorial, and its risk factors include high-dose chemotherapy, radiation therapy, unrelated bone marrow donor status, human leukocyte antigen (HLA) mismatch, exposure to calcineurin inhibitors (with or without concomitant exposure to mammalian target of rapamycin inhibitors, graft-versus-host disease [GVHD], and infections). Genetic abnormalities in the complement system also contribute in a subset of patients. Management of posttransplant TMA remains a therapeutic challenge mainly because of the diverse pathogenic mechanisms involved in this disorder and the limited treatment options.

Thrombotic microangiopathy—general background

TMA is a clinical syndrome of relative or absolute thrombocytopenia and microangiopathic hemolytic anemia. It leads to dysfunction of multiple organs, including the kidneys, resulting in acute kidney injury (AKI). In the past, the combination of TMA with severe AKI was simply referred to as hemolytic uremic syndrome ( HUS ). However, this classification scheme has been modified based on the understanding of the various pathogenic mechanisms underlying the development of TMA.

The primary site of injury in TMA is the endothelium, leading to microvascular thrombosis with fibrin and platelet-rich thrombi. Microthombi formation and fibrin stranding induce flow disturbances, leading to microangiopathic hemolytic anemia and thrombocytopenia. Kidney biopsy under light microscopy reveals arteriolar and/or intracapillary thrombosis with fragmented erythrocytes in the capillary lumens. On electron microscopy, there is separation of endothelium from the basement membrane with the accumulation of an electron-lucent material in the expanded subendothelial space. A newly formed thin basement membrane often follows the outline of the endothelial cells, leading to a “double contour” appearance ( Fig. 13.1 ).

The clinical syndrome of TMA can be broadly categorized into four major entities based on pathogenesis ( Table 13.1 ). All four types require the presence of absolute or relative (< 25% decrease from baseline) thrombocytopenia and microangiopathic hemolytic anemia (schistocytes on peripheral blood smear, elevated lactate dehydrogenase [LDH] levels, and decreased haptoglobin values). It is known that most types of TMA have a waxing and waning course, so that the absence of schistocytes on a single peripheral blood smear is not conclusive evidence that TMA is not present. Likewise, an elevated LDH level is not specific for hemolysis because it is increased in several other disorders, and, because haptoglobin is an acute-phase reactant, levels may not be reduced below normal values in the face of ongoing hemolysis. Dysfunction of numerous organs can develop with TMA, although the kidneys are typically the most severely affected.

Pathogenic mechanisms define the type of TMA and inform therapy. In patients who acquire an inhibitory autoantibody to the metalloproteinase enzyme ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) (or rarely have a genetic mutation in the protein), the inability to cleave large von-Willebrand factor leads to TMA. This disorder is referred to as thrombotic thrombocytopenic purpura ( TTP ) and is treated with therapeutic plasma exchange (TPE). The major benefit to TPE is the ability to infuse large volumes of fresh plasma to provide sufficient quantities of enzyme to overcome the autoantibody; removal of autoantibody with TPE plays a less significant role. It is impossible to differentiate TTP from other forms of TMA on clinical grounds alone, so it is mandatory that an ADAMTS-13 activity assay be tested before initiation of TPE. Patients with normal activity assays do not have TTP and will not benefit from plasma exchange. In fact, patients treated with TPE for TMA who have normal ADAMTS-13 activity, may show an improvement in both platelet counts and LDH levels, yet still experience a high rate of death and end-stage kidney disease.

Patients can develop TMA associated with bloody diarrhea and severe AKI. The etiology is classically associated with infection with a shiga-toxin producing bacteria (typically Escherichia coli H-O157:H7). This syndrome is referred to as shiga-toxin E. coli hemolytic uremic syndrome (STEC-HUS). The infection is associated with eating uncooked meat, although the most recent outbreak occurred after ingestion of contaminated bean sprouts with E. coli serotype O104:H4. The disease is usually self-limited and only supportive care is necessary; antibiotics prolong shedding of the toxin. Direct injury of the endothelium by toxin leads to TMA and therefore there is no indication for TPE.

The most common form of TMA is HUS secondary to numerous medications (including chemotherapy), infections (including pneumonia and diarrhea [non-STEC HUS]), systemic diseases, various cancers (particularly adenocarcinomas), pregnancy, malignant hypertension, and transplantation (especially kidney and bone marrow) ( Box 13.1 ). In most of these cases, the TMA is the result of direct endothelial injury or self-limited activation of the complement system and resolves with treatment of the underlying disorder or discontinuation of the triggering medication. Failure to improve after these measures may indicate that patients have an abnormality in the regulation of complement activation and actually have atypical HUS (aHUS) (vide infra). TPE does not address the pathogenic mechanism in cases of secondary HUS and is not indicated in these circumstances.

The final type of TMA is caused by continuous complement activation in patients with dysfunctional regulatory proteins, referred to as aHUS . Because of an inability to inhibit activated complement, unabated production of the membrane attack complex (C5b-9) directly injures the endothelium, leading to TMA. Untreated, 80% of patients either require permanent dialysis or have died at 3 years. TPE has no effect on clinical outcomes, although it can improve LDH levels and platelet counts in 60% to 70% of patients. Therefore hematologic response to TPE does not portend a good prognosis in such patients. Rather, treatment is directed at decreasing terminal complement activation with the anti-C5 monoclonal antibody, eculizumab. Because of the variable penetrance of the genetic abnormalities in the complement system, most patients with aHUS only present after a complement amplifying condition. Similar to the “two-hit” hypothesis, patients may have mild abnormalities in complement regulation and are disease free, but when complement is strongly stimulated, they are no longer able to stop activation and develop TMA. Key is the fact that most of the complement amplifying conditions that “unmask” aHUS can also cause secondary HUS. The clinical challenge in these scenarios is to determine whether the TMA is secondary to the underlying disease or medication, for example, a calcineurin inhibitor, or due to aHUS that has been unmasked by administration of the drug. There are no diagnostic tests to differentiate between the two. C3 levels are normal in 80% of aHUS cases; genetic testing takes too long and is negative in 30% of cases of aHUS. Therefore in such patients, treatment is directed toward the disease or drug associated with TMA. If TMA does not improve with appropriate therapy, aHUS should be suspected.

Pathogenesis of post bone marrow transplant thrombotic microangiopathy

Several factors have been implicated in the development of posttransplant TMA. These include conditioning regimens with high-dose chemotherapy, total body irradiation, infections, such as cytomegalovirus/human herpesvirus-6, use of calcineurin inhibitors, and GVHD. The exact pathogenesis of TMA after HSCT remains incompletely understood, which limits the identification of patients at highest risk and appropriate selection of therapy. Although most cases of posttransplant TMA are a form of secondary HUS, some patients have been shown to have dysregulation of the complement system consistent with aHUS. In these patients, the histopathologic findings of the kidneys are identical to those reported in other cases of aHUS, including deposition of complement component C5b-9. Several investigators have demonstrated a genetic predisposition for the development of aHUS in patients with abnormalities in complement inhibitory factor H (CFH). Jodele et al. identified a high prevalence of deletions in CFH-related genes 3 and 1 and CFH autoantibodies in patients with posttransplant TMA.

Risk factors

The risk factors for development of posttransplant TMA include female gender, African American ethnicity, older age, prior medical history of severe hepatic dysfunction, and advanced primary disease. Treatment associated risk factors included unrelated donor transplant, HLA-mismatched donors, fludarabine based nonmyeloablative conditioning regimen, and busulfan with total body irradiation myeloablative conditioning. The use of calcineurin inhibitors, as well as infections and GVHD, also increases the risk of developing posttransplant TMA.