Page 2252 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 134 Thrombotic Thrombocytopenic Purpura and the Hemolytic Uremic Syndromes 1999

relatively quickly to plasma exchange. Spontaneous relapses may the nonpregnant setting, pregnancy-associated aHUS is closely tied
occur. In contrast, 90% of patients exposed to clopidogrel but only to complement AP activation, particularly factor H, and thus may
10% of patients exposed to ticlopidine develop a syndrome character- respond to complement inhibitors, such as eculizumab.
ized primarily by MAHA and renal insufficiency, without severe HELLP syndrome complicates approximately 0.5% to 0.9% of
thrombocytopenia; these individuals have normal levels of pregnancies and approximately 10% to 20% of cases of preeclampsia.
ADAMTS13, usually develop disease within the first 2 weeks of The pathogenesis is attributed to aberrant placental development, but
exposure, and may require several weeks of plasma exchange to the details remain unclear. Patients often present with abdominal pain
achieve remission. Whether plasma exchange actually improves the and/or gastrointestinal symptoms, and concomitant hypertension
clinical outcome is uncertain. Spontaneous relapses are uncommon. and proteinuria. Seventy percent of cases occur before delivery and
the majority of the postpartum cases occur within 48 hours of par-
turition. Diagnosis is based on evidence microangiopathic changes
HIV-Associated Thrombotic Microangiopathy on the blood smear, thrombocytopenia and abnormal liver function
studies. The differential diagnosis is broad, and includes acute fatty
An association between HIV infection and TMA has been recognized liver of pregnancy, TTP, aHUS, vasculitis, DIC, and infection. The
since 1984. TMA occurred in up to 7% of patients hospitalized with timing of development of symptoms may assist in the diagnosis
HIV infection. Conversely, the incidence of HIV infection in patients because TTP tends to occur earlier in pregnancy, whereas aHUS often
with TMA varied from 15% to 50% in endemic areas. In contrast, occurs postpartum. Initial management is to stabilize the patient,
TMA is rare in HIV patients who are treated with highly active treat hypertension and prepare for delivery—delivery is considered
antiretroviral therapy. The mechanism of disease remains unclear, but curative for HELLP syndrome.
endothelial injury is hypothesized. Coexisting opportunistic infections
may be a contributing cofactor. TMA that occurs in patients with
advanced or untreated HIV often responds quickly to the initiation FUTURE DIRECTIONS
of antiretroviral therapy and can relapse if therapy is discontinued.
In some patients with HIV infection, the associated immune Thrombotic microangiopathic syndromes are uncommon, but their
dysfunction may predispose to the formation of autoantibodies associated morbidity and mortality are significant. Over the last 10
against ADAMTS13. This can lead to severe ADAMTS13 deficiency years, dramatic progress has been made in our understanding of the
and TTP, despite adequate treatment for HIV. These patients may pathogenesis of these syndromes, and these discoveries are being
respond to plasma exchange. translated into effective therapeutic interventions. A phase I trial of
recombinant ADAMTS13 for treatment of congenital TTP has been
initiated. Targeted disruption of the vWF-GP1b interaction may
Pregnancy-Associated Thrombotic Microangiopathy prevent microvascular occlusion in TTP, and a phase II trial of a
targeted therapy with caplacizumab has been completed. Expanded
The differential diagnosis of MAHA associated with gestation is use of anti-CD20 and other immunomodulatory approaches may
complex. TMA may be difficult if not impossible to distinguish from reduce relapses and induce durable remissions. Drugs that block the
other causes of MAHA unique to pregnancy, such as preeclampsia, action of Stx may be the most promising approach to ameliorating
acute fatty liver associated with DIC, and HELLP syndrome. The STEC-HUS. A tetravalent peptide has been shown to be effective in
severity of the renal and neurologic abnormalities and the time during animal models. Alternatively, generation of highly neutralizing
gestation at which the signs and symptoms of TMA first appear may anti–Stx-2 antibody may provide passive immunity and a mechanism
provide the clues needed to prevent critical delays in therapy. to interrupt outbreaks of STEC-HUS.
Approximately 10% of cases of idiopathic TTP occur in associa- Complement factor H concentrates have received orphan drug
tion with pregnancy. In one series, 40 of 45 cases of TTP in pregnancy designation in Europe. Eculizumab and other complement inhibitors
were diagnosed antepartum at a mean gestational age of 23.5 weeks. may convert aHUS from a progressive disorder that often culminates
Additional studies have confirmed that TTP frequently develops in in chronic renal failure or death to a manageable chronic disease.
the second trimester, although some studies report more common Better biomarkers are needed to aid in the diagnosis of aHUS and to
occurrence in the third trimester or immediately postpartum. monitor patients on eculizumab. Such biomarkers indicate early
ADAMST13 levels fall progressively during pregnancy, but severe response before organ functional changes can be identified, allow
deficiency (<10%) is seen only in women with TTP. In the absence better understanding of the optimal duration of therapy, and define
of appropriate therapy, maternal and fetal mortality approach 90%, who might not require life-long anticomplement therapy to prevent
and TTP during pregnancy is associated with a high risk of fetal loss. aHUS relapse.
Pregnancies in women with congenital ADAMTS13 deficiency have The factors that trigger onset and relapse of TMAs remain to be
been carried to term with prophylactic plasma infusion, sometimes elucidated. It is unclear why some patients with acquired TTP have
combined with aspirin and low-molecular-weight heparin. The multiple relapses while others do not. Although Stx triggers acute
prognosis of pregnancy-associated autoimmune TTP has improved episodes of STEC-HUS, other factors must account for the fact that
dramatically since the advent of plasma exchange, and continuing some individuals with congenital deficiency of ADAMTS13 present
pregnancy does not impair response. There is no evidence that uterine in early childhood, while others develop the disease in the fifth or
evacuation leads to resolution. Many patients carry to term success- sixth decades of life, if at all. Why is the penetrance of aHUS only
fully, although the overall risk for fetal loss remains significant. Up 50% in the presence of a complement inhibitor gene mutation
to 20% of patients with chronic, relapsing TTP have recurrences known to predispose to disease? Clearly, a better understanding of
during subsequent pregnancies, whereas recurrence occurs in almost genetic susceptibility factors is essential, but equally important is
all women with inherited ADAMTS13 deficiency. identification of the environmental agents that incite disease, about
aHUS also occurs with increased frequency in association with which we currently have little information.
pregnancy. The disorder primarily affects primiparas who present
with MAHA, thrombocytopenia, renal insufficiency and hyperten-
sion beginning at a mean of approximately 26 days after delivery in SUGGESTED READINGS
one series—this later onset may help to distinguish HUS from other
causes of pregnancy-associated MAHA and thrombocytopenia, such Ardissino G, Tesla S, Possenti I, et al: Discontinuation of eculizumab main-
as preeclampsia and HELLP, which occur late in gestation or soon tenance treatment for atypical hemolytic uremic syndrome: a report of
after parturition. The outcome of aHUS associated with pregnancy 10 cases. Am J Kidney Dis 64:633–637, 2014.
is poor with mortality rates up to 50% and an additional 15% are Bitzan M, Schaefer F, Reymond D: Treatment of typical (enteropathic)
left with chronic renal insufficiency. Recent studies suggest that as in hemolytic uremic syndrome. Semin Thromb Hemost 36:594, 2010.