The Differential Diagnosis and Treatment of Thrombotic Microangiopathies
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Background: 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. Their timely diagnosis and prompt treatment can save lives.
Methods: This review is based on pertinent articles published up to 17 December 2017 that were retrieved by a selective search of the National Library of Medicine’s PubMed database employing the terms “thrombotic microangiopathy,” “thrombotic thrombocytopenic purpura,” “hemolytic-uremic syndrome,” “drug-induced TMA,” and “EHEC-HUS.”
Results: The classic types of thrombotic microangiopathy are thrombotic thrombocytopenic purpura (TTP) and typical hemolytic-uremic syndrome (HUS), also known as enterohemorrhagic Escherichia coli–associated HUS (EHEC-HUS). There are a number of further types from which these must be differentiated. The key test, beyond a basic hematological evaluation including a peripheral blood smear, is measurement of the blood level of the protease that splits von Willebrand factor, which is designated ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motif, member 13). The quantitative determination of ADAMTS13, of ADAMTS13 activity, and of the ADAMTS13 inhibitor serves to differentiate TTP from other types of thrombotic microangiopathy. As TTP requires urgent treatment, plasmapheresis should be begun as soon as TTP is suspected on the basis of a finding of hemolysis with schistocytes and thrombocytopenia. The treatment should be altered as indicated once the laboratory findings become available.
Conclusion: Rapid differential diagnosis is needed in order to determine the specific type of thrombotic microangiopathy that is present, because only patients with TTP and only a very small percentage of those with atypical hemolytic-uremic syndrome (aHUS) can benefit from plasmapheresis. The establishment of a nationwide registry in Germany with an attached biobank might help reveal yet unknown genetic predispositions.
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). Recognizing thrombotic microangiopathy and initiating plasmapheresis within 4 to 8 hours is essential for successful therapy (recommendation grade 1 B) (5). Plasmapheresis helps to reduce mortality of thrombotic thrombocytopenic purpura (TTP) to approximately 10–20% (3, e1). A diagnostic and therapeutic algorithm, as well as a classification of thrombotic microangiopathies, are shown in Figure 1, Table 1, eTable 2, and eTable 3, and the relevant differential diagnoses, in eTable 1. The establishment of a nationwide disease registry in Germany with a biobank would now be desirable.
A selective literature search in the PubMed (NLM) database was carried out up to (and including) December 17, 2017, based on the following keywords: “thrombotic microangiopathy,” “thrombotic thrombocytopenic purpura,” “hemolytic uremic syndrome,” “drug-induced TMA,” and “EHEC-HUS.”
The ultimate outcome of all thrombotic microangiopathies is ischemia in the terminal vascular bed of organs. In 1926, Elias Moschkowitz first reported a fatal thrombotic microangiopathy in a 16-year-old female patient who presented with anemia, fever, hemiparesis, and coma (6). This case is recognized as the first description of a TTP. Autopsy revealed multiple intravascular thrombi especially in the heart, but also in the kidneys and brain. Because of the important role of the von Willebrand factor (vWF)–cleaving protease ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motif, member 13), TTP is diagnosed by detection of thrombotic microangiopathy—that is, the presence of schistocytes (red blood cell fragmentation) in blood, hemolysis, and thrombocytopenia—with simultaneously reduced levels of ADAMTS13 and, if necessary, detection of anti-ADAMTS13 antibodies (5). The latter inhibits the vWF-cleaving protease and leads to uncontrolled thrombosis of small and micro blood vessels in almost all organs. This results in the clinical picture of an immune-mediated, acquired thrombotic thrombocytopenic purpura (aTTP) (Figure 2). In contrast, in hemolytic uremic syndrome (HUS), thrombus formation almost always occurs in the kidneys, although it may affect other organs in some patients. Further, in HUS, endothelial damage with complement activation and increased vWF release results in vascular occlusion. However, ADAMTS13 levels are normal in HUS (7).
Typically, microangiopathic hemolytic anemia is characterized by reduced levels of haptoglobin, reticulocytosis, and greatly increased concentrations of lactate dehydrogenase (LDH). Detection of schistocytes in a blood smear is easy to perform and is the most important laboratory test for diagnosis, which should always be initiated promptly, even at night, if thrombotic microangiopathy is suspected (recommendation grade 1 A) (Table 2) (5). Tests essential for differentiating TTP from other forms of thrombotic microangiopathies are quantitative detection of the vWF-cleaving protease ADAMTS13 and measurement of the activity levels of ADAMTS13 and the ADAMTS13 inhibitor. ADAMTS13 activity is determined in citrated blood samples prior to any treatments with plasma therapy or blood transfusion (recommendation grade I B) (5). As the results of the ADAMTS13 diagnosis are generally not available within hours, TTP must be suspected from a constellation of hemolysis with schistocytes and thrombocytopenia, due to the urgency of initiating plasmapheresis. A diagnosis of TTP is confirmed if the ADAMTS13 level is <10% (5).
Thrombotic thrombocytopenic purpura (TTP)
Immune-mediated, acquired thrombotic thrombocytopenic purpura
Clinically, patients with TTP often present with non-specific prodromes, such as flu-like symptoms or diarrhea. The highly variable clinical features range from general weakness to stroke or sudden cardiac death. Amarosi et al. (4) described the symptom pentad of TTP, the incidence of which was analyzed in a registry study of 78 patients (8): fever (10%), neurological disorders (headache, confusion, neurological deficits, and seizures; up to 80%), hemolytic anemia (100%), and thrombocytopenia (100%). On the other hand, renal impairment (≥ stage 3) is relatively rare (9%) (8). Severe hemolysis and marked thrombocytopenia with clinical symptoms usually only appear a certain time after disease onset, when a large cross-section of vessels have been affected by consumption of platelets and mechanical hemolysis. Therefore, thrombogenesis in a few organs relevant for end-organ perfusion, such as in the brain stem, can lead to severe neurological symptoms very early in the course of the disease. If ADAMTS13 levels and inhibitor titer are measured repeatedly, the effectiveness of immunosuppressive therapies in chronic recurrent disease can be monitored (9). In immune-mediated acquired aTTP, the risk of recurrence is associated with low levels of ADAMTS13; however, at an individual patient level, having a low level of ADAMTS13 cannot predict recurrence. The interindividual variations in protease levels are very high (10). Thus, in addition to low levels of ADAMTS13, additional factors are needed to trigger a clinical manifestation of aTTP.
Congenital thrombotic thrombocytopenic purpura (Upshaw–Schulman syndrome)
In addition to the acquired form of TTP, an extremely rare form of congenital thrombotic thrombocytopenic purpura (cTTP) exists, termed the Upshaw–Schulman syndrome, in which the levels of ADAMTS13 are genetically reduced. In other words, the liver makes less ADAMTS13. More than 100 mutations have been described for this. Depending on the underlying mutation, the patients can become clinically symptomatic in early childhood (about 50–60% of cases) or first in adulthood, in their third to fourth decade of life, despite having low levels of ADAMTS13 for years (11).
Therapy of thrombotic thrombocytopenic purpura
Historical case reports of patients with TTP receiving either no treatment or non-specific treatment reveal a mortality of 72–94%. In a randomized, non–placebo controlled study, a Canadian working group (3) compared plasma infusion with plasmapheresis and demonstrated that plasmapheresis is superior in terms of 6-month mortality (with 37% mortality after plasma infusion compared to 22% after plasmapheresis). 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). Compared to historical controls, rituximab (4 × 375 mg/m2) shortens the duration of treatment, reduces the risk of recurrence (10% versus 57%), and increases the duration of remission (with a median of 27 months versus 18 months) (14). 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).
As with aTTP, patients with cTTP (Upshaw–Schulman syndrome) require plasmapheresis—possibly followed by long-term treatment with repetitive plasma infusions—if they sustain organ damage. Asymptomatic patients with no signs of hemolysis and normal platelet counts may undergo watchful waiting without plasma infusions (15). Immunosuppressive therapy is not useful in cTTP, as there are no autoantibodies to be targeted.
Hemolytic uremic syndrome
Thrombotic microangiopathy with a primary finding of kidney failure is termed hemolytic uremic syndrome (HUS). The most common form is HUS following infection with Shiga toxin–producing Escherichia coli (STEC), which is typically accompanied by bloody diarrhea (Table 1). This form is called EHEC-HUS (enterohemorrhagic E. coli, EHEC) or STEC-HUS. HUS following a respiratory infection with Streptococcus pneumoniae (SP-HUS) is very rare. If none of these infections is present, there is a suspicion of an atypical hemolytic uremic syndrome (aHUS), also referred to as complement-mediated HUS (cmHUS) (7). In children, about 80–90% of all HUS cases are EHEC-induced, with only about 5–10% of cases attributable to aHUS (16). SP-HUS is even rarer, accounting for less than 5% of the cases (16).
Pathophysiologically, all forms of HUS have complement-mediated endothelial cell damage, which mainly affects the capillary area of the kidney. If HUS is due to a transient trigger, such as Shiga toxin of enterohaemorrhagic Escherichia coli, an infection with Streptococcus pneumoniae, or medications, spontaneous remission generally occurs with supportive therapy after the trigger has been removed. However, in the cases of a genetic defect or an acquired dysregulation of the complement or coagulation system, thrombotic microangiopathy may lead to damage of the affected organs (usually the kidney) even after the trigger (infection, surgical intervention, use of medication) has been controlled or in the absence of a trigger. Examples for this include complement-regulatory defects due to mutations of factor H, factor I, factor B, C3, or membrane cofactor protein (MCP), or to autoantibodies to factor H (1). Under physiological conditions, asymptomatic mutations of the complement regulatory genes can lead to clinical manifestation of thrombotic microangiopathy following a triggering event. Triggers can include for instance malignancy, pregnancy, stem cell transplantation, use of medication, or infection. In rare cases, mutations are present in genes involved in the coagulation system, such as those for diacylglycerol kinase E (DGKE) and thrombomodulin, or involved in cobalamin (B12) metabolism, leading to defects described predominantly in children (<1 year) (1, 16).
Typical hemolytic uremic syndrome
In 1955, Conrad Gasser coined the term hemolytic uremic syndrome (HUS) for patients with renal failure following bloody diarrhea (17). In the 1970s, an association between HUS and Shigella infections was described (18). The most common Shiga toxin–producing pathogen is EHEC of serotypes O157:H7 and O104:H4 (16). In an intestinal infection, the Shiga toxin passes the gut wall and enters the bloodstream. Shiga toxin binds to endothelial cells of the kidney via CD77 (cluster of differentiation, CD; also called globotriaosylceramide, Gb3), causing the cells to die and release vWF. Thrombosis of the renal vessels (as well as in other vascular areas in some patients) leads to the end-organ damage characteristic for thrombotic microangiopathy. The complement system is activated in the process, such that further endothelial cells are destroyed. Renal failure requiring dialysis is common, with a rate of up to 50% (19, 20). A proportion of patients (20%) experience permanent renal insufficiency (RI), although end-stage RI is rare (3%) (19, 20). Therapy is limited to treating kidney failure and management of fluid balance. Antibiotic therapy is controversial (16).
In Streptococcus pneumoniae–associated HUS (SP-HUS), neuraminidases induce exposure of the Thomsen-Friedenreich antigen of erythrocytes, causing thrombotic microangiopathy (16).
Atypical hemolytic uremic syndrome
A small proportion of patients with HUS (5–10%) do not have bloody diarrhea. In these cases, there is a suspicion of an atypical hemolytic uremic syndrome (aHUS), also called complement-mediated HUS (cmHUS). Diagnosis of aHUS requires exclusion of both STEC-HUS (typical HUS, with Shiga toxin detection in stool or blood) and ADAMTS13-mediated thrombotic microangiopathy (TMA) (TTP, with ADAMTS13 levels <10%) (Figure 1). Diagnostically indicative is finding evidence of thrombotic microangiopathy in renal biopsy. Pathophysiologically, aHUS is based on a dysregulation of the alternative complement pathway (eFigure). Inherited defects in complement regulation occur more frequently than acquired changes, with the most common being factor H mutations (20–30% of all aHUS patients) (19). Because of these mutations, a trigger such as infection or pregnancy can activate the alternative complement signaling pathway. Acquired forms of aHUS are very rare and can involve an antibody against factor H (6–10% of all aHUS patients). The treatment of choice for aHUS is the complement inhibitor eculizumab, a monoclonal antibody against C5 (eFigure). Binding of eculizumab to C5 disrupts the terminal pathway of complement signaling and thereby reduces endothelial injury (21). In both of two prospective phase 2 trials, renal function improved (≥ 1 stage, 45–65%) and hematologic parameters (88–90%) normalized, after 26 weeks of eculizumab therapy in patients with aHUS (22). Meningococcal vaccination is obligatory prior to initiating therapy with eculizumab.
Secondary hemolytic uremic syndrome
In addition to these now well-defined entities, there are a number of diseases that are less clearly classified. These diseases are referred to as secondary thrombotic microangiopathies or secondary HUS. The common consequences are endothelial cell damage with consecutive thrombus formation and complement activation (16). Triggers are tumors, stem cell transplantation, use of medications, pregnancy, autoimmune diseases, kidney disease, or malignant hypertension (eTable 2).
Drug-induced hemolytic uremic syndrome
Drugs can trigger thrombotic microangiopathy in two ways: i) dose-independent antibody formation, for instance against platelets and endothelial cells with quinine (23), against thrombocytes with oxaliplatin (11), and against ADTTS13 with ticlopidine resulting in TTP (24); and ii) associated with a dose-dependent toxic endothelial damage after use of gemcitabine, bevacicumab, mitomycin C, interferon, cyclosporin A, or tacrolimus. Gemcitabine is the only drug for which both mechanisms are described (25). Treatment of drug-induced TMA (DI-TMA) is to avoid exposure to the drug. If antibodies against ADAMTS13 are detected, therapy as for aTTP is indicated.
Transplant-associated thrombotic microangiopathy
Thrombotic microangiopathy that occurs after stem cell transplantation is referred to as transplantation-associated thrombotic microangiopathy (TA-TMA). Pathophysiologically, complement activation is suspected. Causes likely include endothelial cell damage due to conditioning, drug side effects (calcineurin inhibitors), chronic graft-versus-host (GvHD) response, and infections. TA-TMA has an unfavorable prognosis, with no standard treatment established and plasmapheresis not indicated (recommendation grade 1 A) (5, 26).
Thrombocytopenia associated with elevated LDH levels in pregnancy can potentially be caused by one of the common pregnancy-related conditions: the HELLP syndrome (hemolysis, elevated liver enzyme levels, and low platelet levels), acute pregnancy-induced fatty liver, or pre-eclampsia. Pregnancy is a much less frequent trigger for aHUS (1:25 000 pregnancies) or for TTP (1: 200 000 pregnancies) (27, 28). While aHUS usually occurs postpartum (80%), TTP occurs equally in both pre- and postpartum (28). Assessment of a peripheral blood smear is mandatory. Schistocytes indicate a pregnancy-induced thrombotic microangiopathy. If schistocytes are not present and if other findings indicate a pregnancy-related disease, an immediate cesarean delivery is indicated. If a thrombotic microangiopathy is confirmed, plasmapheresis initiation should not be delayed to wait for the ADAMTS13 result. However, the ADAMTS13 result can subsequently differentiate between TTP and aHUS. Both diseases may be congenital; pregnancy may merely be the trigger (28).
Cancer-associated thrombotic microangiopathies
In advanced cancer, drug-induced thrombotic microangiopathy may occur, such as after use of bevacicumab, mitomycin C, or gemcitabine. In case of extensive metastasis to the bone marrow and/or drainage of tumor cells into the vasculature, thrombotic microangiopathy may develop, sometimes accompanied by hyperfibrinolysis. The prognosis is unfavorable, with a median overall survival of only 4 to 5 months (29). To ensure the diagnosis, a bone marrow histology can be performed. Plasmapheresis is ineffective (recommendation grade 1 A) (5).
Autoimmune diseases with thrombotic microangiopathy or similar clinical pictures
In antiphospholipid syndrome, arterial and venous thrombosis occurs in young patients, often in pregnancy. Prolonged activated partial thromboplastin time (aPTT) and the detection of antibodies to phospholipid-binding proteins are typical. Uncontrolled thrombogenesis in the so-called catastrophic antiphospholipid syndrome has features of microangiopathic hemolytic anemia. Some data also suggest an uncontrolled activation of the classical complement pathway with potential efficacy of complement inhibitors (30). Renal diseases associated with vasculitis, such as mesangioproliferative glomerulonephritis/C3 glomerulopathy and anti-neutrophil cytoplasmic antibodies (ANCA), may also be associated with thrombotic microangiopathy and must be diagnosed serologically and bioptically (7).
In severe hypertension, thrombotic microangiopathy may result from endothelial cell damage. Distinguishing between primary thrombotic microangiopathy with subsequent hypertension, and malignant hypertension with subsequent thrombotic microangiopathy, is difficult. Control of hypertension often improves thrombotic microangiopathy (7).
Conflict of interest statement
Dr. Bommer has received consultant honoraria and study support (third-party funds) for clinical studies from Ablynx and speaking honoraria from Alexion Pharmaceuticals and Sanofi Genzyme.
Dr. Wölfle-Guter has received study support (third-party funds) for clinical studies from Ablynx.
Dr. Kuchenbauer and Dr. Bohl declare that no conflict of interests exists.
Manuscript submitted on 4 September 2017, revised version accepted
on 14 February 2018.
Translated from the original German by Veronica A. Raker, PhD
PD Dr. med. Martin Bommer
Klinik für Hämatologie, Onkologie, Palliativmedizin
73035 Göppingen, Germany
For e-references please refer tor:
Alb-Fils-Kliniken, Göppingen, Germany: PD Dr. med. Martin Bommer, Dr. med. Manuela Wölfle-Guter, PhD
Department of Internal Medicine III, Ulm University, Ulm, Germany:
Dr. med. Stephan Bohl, PD Dr. Dr. med. Florian Kuchenbauer
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