Page 2286 - Williams Hematology ( PDFDrive )

2260 Part XII: Hemostasis and Thrombosis Chapter 132: Thrombotic Microangiopathies 2261

THERAPY plasma exchange, with 90 percent alive and dialysis free after several
Plasma Exchange years (see Table 132–2). 138,139
Treatment with eculizumab is associated with sustained resolu-
For patients without a previous diagnosis of aHUS, plasma exchange tion of thrombotic microangiopathy, improvement in renal function
should be started at 1 to 2 volumes daily for adults or 50 to 100 mL/kg and prevention of relapses. The platelet count normalizes in approxi-
for children. Plasma exchange can induce responses at least tran- mately 50 percent of patients by day 7 and in 80 to 90 percent of patients
141
siently for patients with deficiency of plasma complement proteins or by week 26. Earlier initiation of eculizumab is associated with greater
autoantibodies to CFH but not for deficiency of the membrane protein improvement in renal function. 137
MCP. If an isolated MCP mutation is identified, plasma exchange can Most patients are likely to need lifelong treatment to prevent
be stopped.
recurrent thrombotic microangiopathy and progressive renal failure.
Eculizumab Some patients with aHUS and no remaining renal function may still
After excluding severe ADAMTS13 deficiency, STEC and secondary benefit from eculizumab to prevent the progression of neurologic or
causes of thrombotic microangiopathy, plasma exchange can be stopped other extrarenal injury. Patients with MCP mutations can have a rel-
and eculizumab started for presumptive aHUS at 900 mg intravenously atively mild course with normal renal function and long intervals
every week for 4 weeks, followed by 1200 mg in week 5 and every other between exacerbations; they may not need chronic prophylaxis with
week thereafter, in many cases indefinitely. For patients younger than eculizumab. 138,139
18 years of age, doses are adjusted based on body weight. Supplemen- DGKE mutations are associated with the development of nephrotic
140
tary doses are recommended during plasma exchange or infusion, syndrome, which is otherwise uncommon in aHUS. Case reports sug-
137
but concurrent plasma exchange and eculizumab is not beneficial and gest that aHUS caused by DGKE mutations is associated with comple-
should be avoided. ment activation and can respond to plasma therapy. 145,146 The efficacy of
Adverse reactions to eculizumab during the treatment of aHUS eculizumab is not known. HUS has not recurred after renal transplanta-
have included infections, fever, hypertension, headache, diarrhea, tion in children with DGKE mutations. 140,145,146
abdominal pain, nausea, and vomiting. Adverse reactions are common
but seldom require discontinuation of therapy. SECONDARY THROMBOTIC
Ideally, patients should be vaccinated against Neisseria meningiti-
des at least 2 weeks before treatment. If timely vaccination is not possible MICROANGIOPATHY
or the available vaccine does not cover prevalent strains, then antibiotic Secondary thrombotic microangiopathy occurs in patients with pre-
prophylaxis should be considered. Children also should be vaccinated disposing medical conditions such as metastatic cancer, malignant
for S. pneumoniae and Haemophilus influenzae type b. hypertension, systemic infection, solid-organ or hematopoietic stem
cell transplantation, vasculitis, catastrophic APS, radiation exposure,
Rituximab chemotherapy, certain other drugs, inherited or acquired metabolic dis-
Rituximab and glucocorticoids can be added to eculizumab for treat- orders, and various causes of disseminated intravascular coagulation.
ment of aHUS caused by autoantibodies to CFH. If the autoantibodies Endothelial injury may be a common cause, although the mechanism of
are eradicated, then eculizumab can be discontinued.
disease varies and in most cases is not understood.
Renal Transplantation The clinical features of secondary thrombotic microangiopathy
Patients with end-stage renal disease that does not improve on eculi- usually are dominated by the predisposing illness, and the most impor-
zumab may be treated by renal transplantation. Living related donors tant clinical intervention is correcting the underlying “primary” condi-
generally are not used because the donated kidney may be at risk for tion. The clinical history and laboratory testing can identify most causes
aHUS and the donor may have the same risk factors as the recipient and of secondary thrombotic microangiopathy. Severe ADAMTS13 defi-
develop aHUS after donation. ciency almost never occurs in secondary thrombotic microangiopathy,
Mutation screening should be performed before transplantation to and treatment with plasma exchange, rituximab, or eculizumab is not
guide subsequent therapy. Unless patients are treated preemptively with known to be beneficial.
eculizumab, aHUS recurs predictably in transplanted kidneys. Isolated
MCP deficiency is an exception because normal membrane-bound DISSEMINATED INTRAVASCULAR
MCP in the transplanted kidney protects it from complement attack. COAGULATION
HUS has not recurred after renal transplantation in children with
DGKE mutations. 141,144 Conditions resulting in disseminated intravascular coagulation some-
Liver transplantation or combined liver-kidney transplantation times cause microangiopathic changes and thrombocytopenia with lit-
can cure aHUS caused by deficiency of plasma complement proteins tle change in blood coagulation tests, which can suggest a diagnosis of
that are synthesized in the liver. However, the risk and complications TTP.
of liver transplantation can be avoided by prophylactic treatment with
eculizumab after renal transplantation. 141,144 INFECTIONS
Infections may trigger disease in patients with severe ADAMTS13 defi-
COURSE AND PROGNOSIS ciency, but infections typically cause secondary thrombotic microangio-
Treatment of aHUS with just plasma exchange and supportive care is pathy by other mechanisms. Secondary thrombotic microangiopathy
associated with up to 8 percent mortality during the first episode of dis- caused by infections may respond to antimicrobial or antiviral therapy,
ease and rapid progression to end stage renal failure in many survivors. but not to plasma exchange.
Mortality at 1 year appears substantially higher for children but progres- Thrombotic microangiopathy, often with acute renal failure, is a
sion to end-stage renal failure is more common for adults. MCP muta- rare complication of invasive infections with S. pneumoniae in chil-
tions are associated with a less-aggressive clinical course: patients may dren. A surveillance study in Atlanta, Georgia, identified HUS in 0.6
improve during plasma exchange but have similar outcomes without percent of pneumococcal infections in children younger than 2 years of

Kaushansky_chapter 132_p2253-2266.indd 2261 17/09/15 3:48 pm