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Chapter 134 Thrombotic Thrombocytopenic Purpura and the Hemolytic Uremic Syndromes 1991

chronic relapsing TTP. Plasma exchange should be continued after death or severe neurologic events. The authors of the study concluded
splenectomy until the TMA resolves. that there was “uncertain evidence of harm” with platelet transfusion
in TTP. More recently however, this question has been revisited in a
study conducted over a 5-year period (2007–2011) using a large US
Other Modalities inpatient database (Nationwide Inpatient Sample that includes both
adults and children). Based on retrospective analysis of these data,
Antiplatelet Agents platelet transfusion was associated with a sixfold higher risk of arterial
The response rate to aspirin, dipyridamole, sulfinpyrazone, or ticlopi- (but not venous) thrombosis and a twofold higher risk of acute
dine as single antiplatelet agents approximates 10%, essentially myocardial infarction, after adjusting for age and gender in a popula-
indistinguishable from the natural history. Antiplatelet agents have tion with no reported prior history of thrombosis. In experienced
not been convincingly shown to increase the response to plasma hands, vascular access catheters for apheresis can safely be inserted
exchange and may promote bleeding in the setting of severe throm- even in the face of thrombocytopenia. Therefore based on accumulat-
bocytopenia and invasive procedures. ing evidence, platelet transfusion in TTP patients should be reserved
for those with life-threatening bleeding.
Immunosuppressive Agents
Cyclosporine has been used as an alternative to rituximab for decreas-
ing the risk of relapse and the time to achieve a durable remission. SHIGA TOXIN HEMOLYTIC UREMIC SYNDROME
There is evidence that cyclosporin reduces the incidence of TTP
relapse, decreases ADAMTS13 antibody levels and produces a paral- Clinical Manifestations
lel increase in ADAMTS13 activity. Cyclophosphamide and vincris-
tine were used before the advent of rituximab. However in current STEC-HUS is one of the main causes of acute renal failure in chil-
practice, they are used only in patients with critical illness that is dren. Patients generally present with the triad of hemolytic anemia,
unresponsive to treatment with plasma exchange, corticosteroids, and thrombocytopenia and acute renal injury. STEC-HUS occurs most
rituximab. Reports of responses to other immunosuppressive agents commonly after E. coli O157:H7–induced gastroenteritis, with rare
including azathioprine, mycophenolate mofetil, staphylococcal cases reported after infection of the urinary tract or skin, or after
protein A immunoadsorption and bortezomib also exist. infection with organisms other than E. coli. The clinical presentation
begins with the sudden onset of abdominal pain and watery diarrhea,
Intravenous Immunoglobulin on average 4 days (range, 2–12 days) after toxin exposure. Abdominal
The efficacy of intravenous immunoglobulin remains unclear. pain may be severe and precede the onset of diarrhea. In the absence
of fever, STEC-HUS may be difficult to differentiate from inflam-
Supportive Care matory bowel disease, appendicitis, ischemic colitis, or intussuscep-
Starting low-dose aspirin (81 mg daily) once the platelet count tion. Bloody diarrhea generally ensues on the second day, accompanied
exceeds 50,000/µL has been recommended in the 2003 guidelines of in some cases by nausea and vomiting; though up to one-third of
the British Committee for Standards in Haematology. Folate supple- patients do not report blood in the stool. Fever is typically absent or
mentation and administration of the hepatitis B vaccine should be mild. Colonoscopy reveals edematous colonic mucosa with occasional
considered routine components of supportive care. Platelet transfu- ulceration and pseudomembrane formation.
sion in patients with TTP should be restricted to patients with life- E. coli–associated hemorrhagic gastroenteritis is complicated by
threatening bleeds (see discussion later). HUS in 8% to 18% of sporadic cases, and in over 20% in certain
epidemic outbreaks. Therefore, the disease should be suspected in a
patient who presents with characteristic clinical manifestations after
Blood Product Transfusion in Thrombotic an episode of bloody diarrhea, although the prototypic history of a
preceding hemorrhagic gastroenteritis may be absent in up to 30%
Microangiopathy of cases. Young children and older adults are at greatest risk. HUS
typically develops 7 days (range, 5–13 days) after the onset of diar-
Red Blood Cells rhea. Patients often present with oliguria or other evidence of renal
Patients with TTP often develop symptomatic anemia because of impairment; 50% of patients require dialysis, at least temporarily.
bleeding and partially compensated hemolytic anemia. Packed red The severity of MAHA varies considerably, but many affected indi-
blood cells can be transfused safely in this setting. In older adults and viduals require red cell transfusion. Thrombocytopenia is common,
in those with impaired cardiac function, it may be prudent to provide with a median platelet count of 30,000/µL in one study, but may be
an additional margin of safety when choosing a threshold for mild or absent in up to 30% of cases at presentation. Up to 25% of
transfusion. patients develop neurologic manifestations, which may include irri-
tability and somnolence and less commonly, confusion, paresis, and
Platelet Transfusion seizures. The mortality rate is estimated at 3% to 5%.
Historically, platelet transfusions have not been recommended for
patients with TTP because they have been hypothesized to provoke
fatal thrombotic events. This is based on two observations. First, there Epidemiology
are anecdotal reports of a close temporal relationship between platelet
transfusion and adverse outcomes. In these cases, there was clinical STEC-HUS accounts for at least 90% of cases of infection associated
deterioration within 1–24 hours of allogeneic platelet transfusion. HUS. In one study conducted in the United States, the median age
Second, postmortem examination in such patients revealed wide- of patients with STEC-HUS was 4 years; 55% of patients were
spread microthrombi involving the brain, heart, lung, kidney, and younger than 5 years of age, 33% between 5 and 17 years, 6%
multiple other organs. Furthermore, clinical deterioration after between 18 and 44 years, and 6% older than 45 years of age. The
5
platelet transfusion has also been reported in patients with other annual incidence of STEC-HUS is estimated to be 2–3 per 10 in
TMAs (HUS, STEC-HUS and drug-induced TMAs). Rarely, sudden children under age 5. STEC accounts for 80% to 86% of cases in
death has occurred in patients who responded to plasma therapy with the United States and Europe. The most common serotype of E. coli
a rapid rise in the platelet count. associated with HUS is O157:H7, although other serotypes including
Data from the Oklahoma TTP-HUS registry challenge this O26:H11, O103:H2, O111:NM, O21:H19, O145:NM and
dogma. Thus none of 33 platelet transfusions administered to a O104:H4 have been reported. The major reservoir of STEC is
cohort of 54 consecutive TTP patients (of whom 47 had ADAMTS13 domestic cattle; approximately 2% to 3% harbor STEC in their
activity <10%) was associated with an increase in the incidence of gastrointestinal tract at the time of slaughter, and meat can become