Thrombotic microangiopathy (TMA) refers to a group of pathological disorders that are characterized by hemolytic anemia, thrombocytopenia, and widespread microvasculopathy, with or without thrombi.4
Clinical manifestations of TMA reflect ischemic injury of the affected organs. In some patients neurological deficits predominate; in others, renal failure is severe. This clustering provided a convenient basis for defining thrombotic thrombocytopenic purpura (TTP) and the hemolytic uremic syndrome (HUS). However, this classification has been misleading, since some patients have both neurological deficits and renal failure, and others may have predominant neurological deficits or renal failure on different occasions.
Thrombotic microangiopathy may appear in a variety of conditions such as pregnancy, inflammation, malignancy, or exposure to such drugs as thienopyridines or calcineurin inhibitors. These conditions might be the cause of acquired TTP, HUS, or HELLP syndrome (hemolysis, elevated liver enzymes, low platelets), or the trigger in individuals with a genetic predisposition to ADAMTS-13 or complement factor H deficiency.
While patients with congenital TTP and acquired immune TTP attributed to low ADAMTS-13 activity demonstrate a good response to plasma infusion or plasma exchange (PEX), other clinical forms of TMA occur in the absence of severe ADAMTS-13 deficiency, and this may be the reason why patients with the other clinical forms of TTP do not respond to plasma therapy.26
The diagnosis of TMA can be very difficult, as there is a clinical overlap between various TMAs. Since in untreated cases mortality may approach 90%, the availability of ADAMTS-13 activity and anti-ADAMTS-13 antibody assays is crucial for the differentiation between the TMAs, accurate diagnosis, and urgent initiation of the appropriate treatment.
Thrombotic Thrombocytopenic Purpura
Thrombotic thrombocytopenic purpura (TTP) is rare, with a reported incidence of 4–6 cases per million per year and with a female-to-male ratio of 3:2.27,28
In spite of major progress in early detection and modern therapies, early death still occurs: approximately half of the deaths in the regional UK TTP registry occurred within 24 hours of presentation.27
Thrombotic thrombocytopenic purpura is characterized by microvascular platelet clumping, resulting in microangiopathic hemolytic anemia, fragmented erythrocytes (schistocytes), consumptive thrombocytopenia, renal dysfunction, and neurological symptoms. However, TTP can present without the full pentad; up to 35% of patients do not have neurological signs at presentation, and renal abnormalities and fever are not prominent features. The revised diagnostic criteria state that TTP must be considered in the presence of thrombocytopenia and microangiopathic hemolytic anemia alone.29 The diagnosis of TTP remains based on clinical history, examination of the patient, and the blood film. Assays for ADAMTS-13 help to confirm the diagnosis, differentiate TTP from other TMA forms, and monitor the efficacy of treatment. They are also helpful in consideration of the need for additional or alternative therapy.
In general, congenital TTP is defined by ADAMTS-13 deficiency, while acquired TTP is defined by the presence of ADAMTS-13 neutralizing autoantibodies. During an acute episode, before starting therapy, ADAMTS-13 activity level of <5% supports the TTP diagnosis.
Congenital TTP: Upshaw–Schulman Syndrome
This very rare condition with a prevalence of about 0.05–0.4 per 100,000 is transmitted by autosomal recessive inheritance.30,31
Neonates with severe phenotype typically have major neonatal jaundice. Blood film examination may show schistocytes together with red cell anisocytosis.32
More frequently, the diagnosis is made later in infancy or childhood,33
typically with thrombocytopenia, microangiopathic hemolytic anemia, jaundice, and elevated lactate dehydrogenase (LDH), although some children may only have an isolated thrombocytopenia. Neurological symptoms, such as hemiparesis, hemiplegia, or seizures, occur in 35% of cases.34
Patients presenting during adulthood tend to have milder clinical courses.31 However, the clinical course in individual patients can be highly variable.30 The presence of an affected sibling or a therapeutic response to a plasma-containing blood product may propose the diagnosis.35
The diagnosis of congenital TTP is dependent on detecting ADAMTS-13 activity of <5% during an acute episode, in the absence of antibodies to ADAMTS-13. Over the last few years, molecular analysis has been used to confirm the diagnosis, and either a homozygous or compound heterozygote defect in ADAMTS-13 could be found. Testing of siblings and other first-degree relatives at risk should be considered.36
Mutations affecting the highly conserved N-terminal domains of ADAMTS-13 are associated with lower residual ADAMTS-13 activity and a more severe clinical phenotype in an allelic dose-dependent manner.37,31 Mutations located in the C-terminal part of ADAMTS-13 are associated with a less severe clinical expression.
A mutation located in the TSP1–7 domain, p.Arg1060Trp, is specifically associated with an adult onset of congenital TTP and found with a very high prevalence in women in whom TTP events are associated with pregnancy.38
Patients with congenital TTP have persistently low levels of ADAMTS-13, but they can be asymptomatic until a further precipitating event results in an acute TTP episode. Events include febrile episodes, infections, vaccinations, excess alcohol intake, and in females mostly pregnancy.39–41
Rarely, patients with a “late-onset phenotype” may not develop symptoms until their 50s or 60s with isolated cerebral events or renal disease.42 Asymptomatic male cases are usually detected because they have affected siblings.
Acquired Thrombotic Thrombocytopenic Purpura
Acquired TTP is a rare, autoimmune disease characterized by antibodies, usually IgG, directed against ADAMTS-13, with an annual incidence of 0.2–1 per 100,000.43
In its most common, characteristic form, TTP begins abruptly and virulently, occasionally after a febrile, viral-like prodrome; a minor infection or pregnancy may be the trigger.44,45
Thrombocytopenia and fragmentation hemolysis are severe, and central neurologic signs exist at presentation or supervene quickly, out of proportion to renal signs. Dialysis-requiring renal failure is rare. Without immediate recognition and intervention, death, often precipitated by seizures and arrhythmias, may come rapidly and suddenly. Before the advent of modern therapy, mortality was about 90%. One-third of TTP survivors experience relapses over the course of years, especially soon after initial presentation.46,47
Some have persistent cognitive and central neurologic impairments, other chronic health problems, or die prematurely even when TTP is inactive.48–50
About 5%–10% of patients later in their course manifest systemic lupus erythematosus.50
Hemolytic Uremic Syndrome
Hemolytic uremic syndrome (HUS) is a TMA defined by thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure with elevated serum creatinine levels, low glomerular filtration rates, microscopic hematuria, and subnephrotic proteinuria.51
The most frequent form is associated with infections by Shiga-like toxin-producing bacteria (Shiga-HUS). Atypical form of HUS (aHUS) is associated with defects in the immunological complement pathway.
Shiga toxins (Stx)-1 and Stx-2, produced by enterohemorrhagic E. coli, stimulate rapid and profuse secretion of UL-VWF from endothelial cells, in particular glomerular microvascular endothelial cells.53 Platelets immediately adhere to the secreted UL-VWF, and the rate of platelet–VWF string cleavage by ADAMTS-13 is delayed in the presence of Stx-1 or Stx-2. This may explain the glomerular microvascular occlusion and acute renal failure.52
Hemolytic uremic syndrome usually occurs as a single episode, except for rare individuals who have a familial, recurrent type of the disease.1,23 In these patients, often children, with aHUS, the level of the plasma complement control protein, factor H, is abnormally low most of the time. The result is over-activation of complement component 3 (C3), which causes permanent glomerular endothelial activation and obstruction of the glomerular microvasculature by platelet–fibrin thrombi.23
Shiga Toxin-induced HUS
About 10%–20% of symptomatic infections lead to HUS.23,53
Shiga toxin-induced HUS (Shiga-HUS) is the commonest TMA, most prevalent in children under the age of 5 years, with an annual incidence of 6 per 100,000.54
Severe thrombocytopenia, fragmentation hemolysis, renal failure, and hyper-tension are characteristic.
The diagnosis of Shiga-HUS depends on the detection of E. coli O157:H7 and other Stx-producing bacteria and their products in stool cultures.51
In extreme cases, the brain and other organs may be involved. The condition is a medical emergency with a short-term mortality of about 5%–10% without urgent therapy. Renal function recovers in 70% to over 90% of cases.35
Approximately 5% of HUS cases in children are not associated with Stx-producing bacteria and result from infection by neuraminidase-producing Streptococcus pneumoniae.51
Cases of atypical HUS (aHUS) are rare, one-tenth as frequent as Shiga-HUS.54
The first presentations are most of the time in children, including neonates, but may not occur until later in life. About 20% are familial phenomena. Infections and pregnancy may trigger an acute episode.54
The end-organ presentation is predominantly renal, but cardiac, neurologic, and more rarely large artery obstruction may occur. The prognosis before recent treatment advances was poorer than for Shiga-HUS, with over half of cases progressing to end-stage renal failure and one-quarter of patients dying of the disease.35
Atypical HUS is the result of excessive alternative complement pathway activation.
Prominent causes of aHUS are a heterozygous mutation of the complement factor H gene, or homozygous deletion in genes for the factor H-related proteins or autoantibody-mediated inhibition of factor H deficiency.
Other mutations associated with aHUS include heterozygous loss-of-function mutations of complement factor I, membrane co-factor protein or CD46 or thrombomodulin, heterozygous gain-of-function mutations in C3 or complement factor B.
Excessive alternative complement pathway activity in aHUS results in severe damage of renal endothelial cells, leading to renal failure.19
Lately, treatment with eculizumab has been approved for aHUS. Eculizumab is a humanized monoclonal antibody to terminal complement protein C5 that prevents activation of the terminal complement pathway by binding C5 and inhibiting generation of pro-inflammatory C5a and the lytic C5b-9 membrane attack complex. Before administering eculizumab therapy for an acute episode of aHUS, there is a need to rule out TTP which is proved by normal levels of ADAMTS-13 activity (>30%), without the presence of anti-ADAMTS-13 antibodies.
Pre-eclampsia and HELLP syndrome are serious TMA complications in pregnancy. In these events, the hypoxic placenta releases receptors for angiogenic factors, like soluble VEGF receptor-1. These circulating soluble angiogenic receptors contribute to the progressive renal dysfunction and hepatic necrosis in pregnancy TMAs.55
Nevertheless, pregnancy is a hypercoagulation state with very high levels of VWF and UL-VWF released from endothelial cells and the placenta, and can trigger TTP (acquired or congenital), aHUS, or other TMAs.
Pregnancy is the initiating event for approximately 5%–25% of TTP cases, which are late-onset adult congenital TTP or acute idiopathic TTP.27,36
Thrombosis occurs in the placenta in untreated TTP pregnancies, resulting in fetal growth restriction, intrauterine fetal death, and pre-eclampsia. There is a continued risk of relapse during subsequent pregnancies. However, there are some reports demonstrating that women with normal pre-pregnancy levels of ADAMTS-13 have a lower risk of relapse.56,57 Differentiating TTP from more common pregnancy-related TMAs is difficult. In these suspected cases, measurement of ADAMTS-13 activity and anti-ADAMTS-13 antibodies can advance the differentiation. Low ADAMTS-13 activity and the presence of anti-ADAMTS-13 antibodies can distinguish congenital and acquired TTP, respectively, from other pregnancy-associated TMAs. Although in pre-eclampsia and HELLP syndrome ADAMTS-13 activity is reduced (median 31%, range 12%–43%), in an acute TTP episode the ADAMTS-13 activity levels are below 10%. In addition, presence of anti-ADAMTS-13 antibodies supports the diagnosis of acquired TTP.36
TMA Due to Drugs
Thienopyridines (ticlopidine and clopidogrel) are the most frequent TMA-causing drugs reported to the United States Food and Drug Administration. Ticlopidine, now infrequently prescribed, produced the highest incidence, 1 in 1,600 to 5,000 patients. About 90% of cases occurred between 2 and 12 weeks of therapy. Clopidogrel causes TMA less frequently, about 1 in 80,000 patients.58,59
Other drug causes are the calcineurin inhibitors (cyclosporine and tacrolimus), the mTOR inhibitors (sirolimus and everolimus), anti-neoplastic agents (mitomycin and gemcitabine, both in a cumulative, dose-dependent manner), and quinine.35
Drugs appear to be responsible for <15% of all TTP cases. Ticlopidine therapy increases the risk of developing ADAMTS-13 inhibitors 200- to 300-fold.60,61
Some chemotherapy agents, such as gemcitabine, bleomycin, and mitomycin-C, can cause HUS but not TTP.36
Transplant and Malignancy-associated TMA
Transplant-associated TMA is a microangiopathy hemolytic anemia with thrombocytopenia that occurs after bone marrow transplantation. It may reflect endothelial toxicity associated with chemotherapy, infections, immunosuppressives, and graft-versus-host disease (GVHD).35,62
Thrombotic microangiopathy occurs in association with a variety of malignancies, especially adeno-carcinomas.63 Presentation may be either at an early stage of cancer or associated with disseminated disease.
The ADAMTS-13 activity is not significantly reduced in transplant and malignancy-associated TMA,64 and this might explain the inefficiency of PEX therapy in these patients. Some suggest that due to endothelial damage associated with malignancy, chemotherapy, and bone marrow transplantation, there is an extreme release of UL-VWF which even normal ADAMTS-13 level cannot cleave, and this may lead to TMA events. Future drugs targeting the VWF-platelet interaction could be efficient in transplant and malignancy-associated TMA.