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864 PART 7: Hematologic and Oncologic Disorders

study has demonstrated that the combination of plasma exchange, from baseline, no need for plasma therapy, and no new dialysis for
antibiotics including meropenem, ciprofloxacin, and rifaximin with 12 consecutive weeks). 209,210
azithromycin, and eculizumab, a fully humanized recombinant anti-
C5 monoclonal antibody, appeared to be highly effective in treatment ■ MANAGEMENT OF ORGAN FAILURE
of HUS associated with E coli O104 : H4 infection during the German AND TREATMENT-RELATED COMPLICATIONS
outbreak. 60,62 In rare cases, when E coli infection acts as a trigger in
patients with hereditary deficiency of ADAMTS13 activity or muta- Cardiac: Although clinical manifestations of cardiac abnormalities
tions in a complement regulator gene, plasma infusion or exchange were not clinically recognized in TTP patients, cardiac involvement
is beneficial. was found to occur in greater than 70% of autopsy cases in a small
series of patients. Even in Moschcowitz’s original case, widespread
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aHUS: The underlying mechanisms of aHUS are heterogeneous; thrombi were found within the microvasculature of the heart. One
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therefore, no single therapeutic modality has been consistently dem- review of cases with TTP found myocardial infarct, congestive failure,
onstrated to be effective. Plasma infusion or exchange appears to be arrhythmias, and sudden cardiac death as the most described car-
the logical initial treatment as the underlying mechanism of aHUS is diac events. In addition to these events, there were case reports of
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not known at the time of diagnosis. Plasma exchange of 1.5 × volumes cardiogenic shock due to TTP. One group reported coronary artery
(60-75 mL/kg) per session should be given as early as possible, pref- occlusion while the other group found no such lesions. However,
erably within 24 hours of presentation. 200,201 As in the case of TTP, both reports described extensive myocardial necrosis and microvas-
FFP is the replacement fluid. Plasma infusion (10-20 mL/kg) should cular thrombi at autopsy. 213,214 Therefore, careful cardiac monitoring
be given if the patient is not volume overloaded and/or hypertensive is essential for patients with TTP, but may be less critical for HUS.
and does not have cardiac failure. When disease severity is con-
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trolled by daily plasma exchange, tapering the frequency of treatment Pulmonary: TTP was also reported to involve the lungs and resulted in
should be considered for an additional 2 weeks. While plasma respiratory compromise. Several centers reported respiratory dysfunction as
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therapy appears to be effective in correcting the serum deficiency an initial presentation of TMAs. 215,216 The clinical presentation varied with
of the complement regulatory components or removing the mutated disease ranging from mild tachypnea and hypoxemia to fulminant ARDS.
proteins, it does not prevent the progression to renal failure requir- Early recognition and treatment with plasma exchange therapy were proven
ing dialysis. 114,203,204 Also, plasma exchange therapy has little effect on to be successful as one series reported improvement in lung injury in four
aHUS caused by mutations in the MCP gene due to its membrane out of six TTP patients 48 hours after initiation of plasma exchange. 217
localization. Therefore, the demonstration of MCP mutations allows Neurologic: Neurologic involvement is considered to be part of the clini-
prompt withdrawal of plasma therapy. Renal transplantation may cal manifestation of TTP, although less commonly seen in patients with
be beneficial for patients with MCP mutations as the risk of disease aHUS. Neurologic involvement varies from mild symptoms such as head-
recurrence after transplantation is relatively low (0%-20%). 205,206 This aches, waxing and waning mental status, to severe manifestations such
has not been the case in patients with the CFH, CFI, and C3 gene as coma. Seizures were reported in patients with TTP including status
mutations. The recurrences rate of posttransplant HUS approaches epilepticus. 218,219 One review of 20 patients with TTP reported seizures was
75% to 90% in patients with CFH mutations, 45% to 80% in patients with observed in 6 (30%) of patients and nonconvulsive status such as altered
CFI mutations, and 40% to 70% in patients with C3 mutations. 114,138,206 mental status in 2; the authors of this series suggested that patients with
Three patients with CFB mutations 113,115 and one patient with TM altered mental status and thrombotic microangiopathy should undergo
mutation lost the graft after transplantation because of recurrent continuous electroencephalography (EEG) monitoring. As there are not
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disease. Combined kidney and liver transplantation in aHUS patients a larger series evaluating the incidence of nonconvulsive status in TTP
with ESRF resulting from the mutations in CFH, CFI, C3, and CFB patients, the practice of continuous EEG monitoring in TTP patients has
should be considered. 202,207,208 This is logical because all of these three yet to become a standard of care. Treatment with plasma exchange and
complement components are synthesized in the liver. Kidney trans- antiepileptic medications often resulted in complete remission and recov-
plant alone does not correct the underlying deficiency of comple- ery of neurologic signs and symptoms. 218,219
ment regulatory genes.
The activation of C5 is essential for the development of aHUS and has Therapy-Related Complications: Prognosis in patients with TTP has
been recently proposed to play a central role in pathogenesis of HUS and been dramatically improved with early recognition and treatment of the
TTP. A humanized monoclonal antibody, eculizumab, targets the com- disorder. Emergency plasma exchange therapy should be initiated in all
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plement C5 to block the cleavage of C5 to C5b, thereby preventing the patients presenting with thrombocytopenia and MAHA without other
generation of the proinflammatory peptide C5b and the cytotoxic mem- explanations because the mortality rate is nearly 100% if left untreated.
brane attack complex C5b-9. Food and drug administration (FDA) in However, the risks and benefits of emergent plasma exchange must be
the United States approved eculizumab for the treatment of paroxysmal considered prior to initiation of therapy, as plasma exchange may be asso-
nocturnal hemoglobinuria (PNH). Its efficacy and good tolerance have ciated with serious complications, which include those related to central
been demonstrated in several hundreds of patients with this disease. venous catheter placement (such as hemorrhage, arrhythmia, pneu-
Eculizumab has now been approved by the FDA for the treatment of mothorax, air embolism, thrombosis, infection) and those associated
aHUS with excellent efficacy. All patients with aHUS are eligible for with plasma exchange (such as citrate toxicity), and the risks associated
eculizumab therapy. The dose and schedule used in adult patients are with plasma transfusion (such as allergic reaction, pulmonary edema,
the same as for the treatment of PNH (900 mg, intravenous infusion, and transfusion-related acute lung injury (TRALI). 216,221 Of a series of
weekly for 4 weeks, then 1200 mg for the fifth week, and every 14 days 249 patients treated over 12 years, 26% of patients had major complica-
for long-term maintenance treatment). To date, 24 patients with aHUS tions with plasma exchange and fatality rate was 2.8%. 11,216 Catheter-
202
including 11 children and 13 adults have been treated with eculizumab; related complications and systemic infections were the most common
21 patients have achieved complete remission. These patients showed major complications reported in this series. Patients with TTP have
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a prompt and complete resolution of hematological abnormalities and an increased risk of bleeding with catheter insertion due to profound
severe extra renal manifestations, including gangrene of the fingers thrombocytopenia. Platelet transfusion prior to catheter placement may
and toes in two patients and brain involvement in one patient. A retro- be considered as there was no difference in the mortality and morbid-
209
spective study of 15 young children with aHUS treated with eculizumab ity rates between TTP patients who received platelet transfusion and
was reported with 93% of patients achieving normal platelet count and those who did not. If available, ultrasound guidance should be used for
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80% are disease free (defined by no decrease in platelet count of >25% vascular access in this patient population. Another commonly reported

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