ESSENTIALS OF DIAGNOSIS
Microangiopathic hemolytic anemia and thrombocytopenia, without another plausible explanation, are sufficient for a presumptive diagnosis of thrombotic microangiopathy (TMA).
Fever, neurologic impairment, and kidney disease may occur concurrently but are not required for diagnosis.
Kidney injury is more common and more severe in hemolytic-uremic syndrome (HUS).
The TMAs include, but are not limited to, thrombotic thrombocytopenic purpura (TTP) and HUS. These disorders are characterized by thrombocytopenia due to the incorporation of platelets into fibrin thrombi in the microvasculature, and microangiopathic hemolytic anemia, which results from shearing of erythrocytes in fibrin networks in the microcirculation.
In idiopathic TTP, autoantibodies against ADAMTS-13 (a disintegrin and metalloproteinase with thrombospondin type 1 repeat, member 13), also known as the von Willebrand factor (vWF) cleaving protease (vWFCP), lead to accumulation of ultra-large vWF multimers. The ultra-large multimers bridge and aggregate platelets in the absence of hemostatic triggers, which in turn leads to the vessel obstruction and various organ dysfunctions seen in TTP. In some cases of pregnancy-associated TMA, an antibody to ADAMTS-13 is present. In contrast, the activity of the ADAMTS-13 in congenital TTP is decreased due to a mutation in the gene encoding the molecule. Classic HUS, called Shiga toxin–mediated HUS, is thought to be secondary to toxin-mediated endothelial damage and is often contracted through the ingestion of undercooked ground beef contaminated with Escherichia coli (especially types O157:H7 or O145).
Complement-mediated HUS (formerly called atypical HUS) is not related to Shiga toxin. Patients with complement-mediated HUS often have genetic defects in proteins that regulate complement activity. Mutations in complement genes (such as factor H, a complement regulator) account for the uncontrolled activation of complement that characterizes the condition. Damage to endothelial cells—such as the damage that occurs in endemic HUS due to presence of toxins from E coli (especially type O157:H7 or O145) or in the setting of cancer, hematopoietic stem cell transplantation, or HIV infection—may also lead to TMA. Certain drugs (eg, cyclosporine, quinine, ticlopidine, clopidogrel, mitomycin C, and bleomycin) are associated with the development of TMA, possibly by promoting injury to endothelial cells, although inhibitory antibodies to ADAMTS-13 have been demonstrated in some cases.
Microangiopathic hemolytic anemia and thrombocytopenia are presenting signs in all patients with TTP and most patients with HUS; in a subset of patients with HUS, the platelet count remains in the normal range. Only approximately 25% of patients with TMA manifest all components of the original pentad of findings (microangiopathic hemolytic anemia, thrombocytopenia, fever, kidney disease, and neurologic abnormalities) (Table 14–4). Most patients (especially children) with HUS have a recent or current diarrheal illness, often bloody. Neurologic manifestations, including headache, somnolence, delirium, seizures, paresis, and coma, may result from deposition of microthrombi in the cerebral vasculature.
Table 14–4.Presentation and management of thrombotic microangiopathies. ||Download (.pdf) Table 14–4. Presentation and management of thrombotic microangiopathies.
| ||TTP ||Complement-Mediated HUS ||Shiga Toxin–Mediated HUS |
|Patient population ||Adults ||Children (occasionally adults) ||Usually children, often following bloody diarrhea |
|Pathogenesis ||Acquired auto-antibody to ADAMTS-13 ||Some cases: heritable deficiency in function of complement regulatory proteins ||Bacterial (such as enterotoxogenic Escherichia coli; Shiga toxin) |
|Thrombocytopenia ||Typically severe, except in very early clinical course ||Variable ||May be mild/absent in a minority of patients |
|Fever ||Typical ||Variable ||Atypical |
|Kidney disease ||Typical, but may be mild ||Typical ||Typical |
|Neurologic impairment ||Variable ||Less than half of cases ||Less than half of cases |
|Laboratory investigation ||Decreased activity of ADAMTS-13; inhibitor usually identified ||Defects in complement regulatory proteins || |
Typically normal ADAMTS-13 activity
Positive stool culture for E coli 0157:H7 or detectable antibody to Shiga toxin
|Management || |
Hemodialysis for severe renal impairment
Caplacizumab (selected patients)
Platelet transfusions contraindicated unless TPE underway
Immediate TPE initially in most cases
Hemodialysis for severe renal impairment
Hemodialysis for severe kidney impairment
TPE rarely beneficial (exception: selected cases in adults)
Laboratory features of TMA include those associated with microangiopathic hemolytic anemia (anemia, elevated lactate dehydrogenase [LD], elevated indirect bilirubin, decreased haptoglobin, reticulocytosis, schistocytes on the blood smear, elevated reticulocyte count, and a negative direct antiglobulin test); thrombocytopenia; elevated creatinine; positive stool culture for E coli O157:H7 or stool assays for Shiga toxin; reductions in ADAMTS-13 activity with the presence (acquired TTP) or absence (inherited TTP) of ADAMTS-13 inhibitor; and mutations of genes encoding complement proteins (complement-mediated HUS; specialized laboratory assessment). Routine coagulation studies (prothrombin time [PT], activated partial thromboplastin time [aPTT], fibrinogen) are within the normal range in most patients with TTP or HUS.
Immediate administration of plasma exchange is essential in most cases because the TTP mortality rate is more than 95% without treatment. With the exception of children or adults with endemic diarrhea-associated HUS, who generally recover with supportive care only, plasma exchange must be initiated as soon as the diagnosis of TMA is suspected and in all cases of TTP. Plasma exchange usually is administered once daily until the platelet count and LD have returned to normal for at least 2 days, after which the frequency of treatments may be tapered slowly while the platelet count and LD are monitored for relapse. In cases of insufficient response to once-daily plasma exchange, twice-daily treatments can be considered. Fresh frozen plasma (FFP) may be administered if immediate access to plasma exchange is not available or in cases of familial TMA. Platelet transfusions are contraindicated in the treatment of TMA due to reports of worsening TMA, possibly due to propagation of platelet-rich microthrombi. In cases of documented life-threatening bleeding, however, platelet transfusions may be given slowly and after plasma exchange is underway. Red blood cell transfusions may be administered in cases of clinically significant anemia. Hemodialysis should be considered for patients with significant kidney injury. Caplacizumab, a bi-specific antibody that targets the A1 domain of vWF that prevents vWF interaction with the platelet glycoprotein Ib-IX-V receptor, can reduce the time to platelet count normalization and 30-day mortality. The role that caplacizumab will play in the treatment of TTP remains to be determined as many factors, including cost, must be considered.
In cases of TTP relapse following initial treatment, plasma exchange should be reinstituted. If ineffective, or in cases of primary refractoriness, second-line treatments including rituximab (which has shown efficacy when administered preemptively in selected cases of relapsing TTP), corticosteroids, IVIG, vincristine, cyclophosphamide, and splenectomy should be used. Since idiopathic TTP is an autoimmune disorder (antibody inhibitor to ADAMTS-13), immunosuppression, often with rituximab, is often needed to prevent or reduce relapse events; early use of rituximab is gaining favor.
Cases of complement-mediated HUS may respond to plasma infusion initially; however, once this diagnosis is strongly suspected, apheresis is typically stopped and serial infusions of the anti-complement C5 antibody eculizumab are provided, which have produced sustained remissions in some patients. If irreversible kidney disease has occurred, hemodialysis or kidney transplantation may be necessary.
Consultation by a hematologist or transfusion medicine specialist familiar with plasma exchange is required at the time of presentation. Patients with TMA require ongoing care by a hematologist.
All patients with newly suspected or diagnosed TMA should be hospitalized immediately.
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