Page 2251 - Hematology_ Basic Principles and Practice ( PDFDrive )

1998 Part XII Hemostasis and Thrombosis

The pathogenesis of cancer-associated TMAs is poorly understood. many experts suggest avoidance of plasma infusion because of the
Laboratory evidence of DIC is found in 25% to 80% of patients concern that there may be unintended infusion of IgM anti–T-F.
based on findings of elevated fibrin degradation products or more
sensitive measures of increased fibrinogen turnover. However, the
observation that TMA occurs in only 5% of patients with dissemi- Disordered Cobalamin Metabolism
nated malignancy and DIC suggests the involvement of additional
factors, such as microvascular occlusion, intimal proliferation induced An autosomal recessive TMA associated with disordered cobalamin-C
by tumor emboli within the pulmonary vasculature, or formation of metabolism can occur in individuals during the first weeks to months
an incompletely endothelialized tumor vasculature that predisposes of life. Deficiency of cobalamin-C may result in markedly elevated
to platelet adhesion, activation and aggregation. Severe deficiency of levels of homocysteine and methylmalonic acid, which may be
ADAMTS13 is not typical. Outcomes of patients who develop TMA responsible for vascular injury. Approximately one quarter of such
in the setting of chemotherapy or advanced cancer are poor because patients present with HUS. Although the majority of patients have
the TMA tends to be unrelenting and the co-morbidity of the a fulminant course leading to death, some present with a more
malignancy is significant. Survival is generally measured in weeks. chronic form of the disease later in childhood. One adult case was
The only effective therapy is reduction of the tumor burden, a goal reported. Therapy consists of treatment with hydroxycobalamin.
often not attainable. A role for plasma exchange has not been Neurologic sequelae are common, as is chronic hypertension.
established.
Specific cancer chemotherapeutic agents have also been implicated
in the development of TMA. Patients are often receiving therapy for Miscellaneous Drug-Associated
adenocarcinoma at the time TMA develops, making attribution to Thrombotic Microangiopathy
the neoplasm versus its therapy difficult to determine. However,
unlike cancer-associated TMA, most patients with chemotherapy- Although TMA has been associated with more than 75 drugs, the 9
associated TMA do not have a large tumor burden, and some may drugs that account for 75% of the cases include clopidogrel, estrogen/
be in remission. Implicated agents include mitomycin-C, gemcitabine, progesterone, gemcitabine, interferon, mitomycin, quinine, tacroli-
cis-platinum, bleomycin, docetaxel, 5-fluourouracil, deoxycoformy- mus and ticlopidine. The mechanisms by which these agents induce
cin, carboplatin, oxaliplatin, interferon-α and bevacizumab, either TMA may differ, as may the natural history and response to therapy.
alone or in combination. Whereas mitomycin C, gemcitabine, and cyclosporin appear to
Patients with chemotherapy-associated TMA generally present induce TMA in a cumulative dose-dependent manner, quinidine and
with moderate to severe MAHA, thrombocytopenia, and renal insuf- thienopyridines (ticlopidine and clopidogrel) induce TMA through
ficiency (median creatinine value of 4.2 mg/dL). Approximately 15% either idiosyncratic, immune-mediated mechanisms or by acute
to 20% of such patients develop neurologic dysfunction. A unique endothelial toxicity (see Chapter 131).
feature is noncardiogenic pulmonary edema, which is observed in The first report of quinine-associated TMA described the course
over 50% of patients in some series. Pulmonary function may dete- of three patients with a syndrome resembling idiopathic HUS.
riorate rapidly after red blood cell or platelet transfusion, and patients Patients generally present with severe MAHA, platelet counts below
should be transfused with caution. 50,000/µL, and renal insufficiency, usually requiring dialysis. Neuro-
Chemotherapy-associated TMA is presumed to result from direct logic dysfunction occurs in a minority of patients, but it can be severe;
toxicity to the endothelium. Mitomycin inhibits the production of granulocytopenia and lymphopenia have been reported. In earlier
prostacyclin by umbilical vein endothelium, and infusion of reports, the prognosis was favorable once quinine was withdrawn and
mitomycin-C into the rat kidney induces histologic changes similar plasma exchange instituted. However, in another series, 17 of 225
to those found in chemotherapy-induced TMA. Alternatively, anti- patients with HUS had quinine-associated TMA, 4 of whom died,
VEGF antibodies and other VEGF inhibitors have revealed a critical and 7 survivors were left with chronic renal failure. Although this
dependence of podocytes and glomerular endothelial cells on VEGF. disorder occurs most commonly after the ingestion of quinine tablets,
Toxicity of these agents includes a TMA localized primarily to the cases have been reported after exposure to quinine in beverages such
kidney and manifested mainly by hypertension and proteinuria. as tonic water or herbal health supplements (cinchona). A careful
ADAMTS13 levels are not severely reduced in chemotherapy- history is sometimes necessary to establish the link between quinine
associated TMA. Fewer than 20% of affected patients appear to ingestion and the patient’s clinical disease. The pathogenesis may
respond to plasma exchange and/or corticosteroids, and more than involve idiosyncratic, quinine-dependent antibodies reactive with
50% die within 2 months. platelet GPs IIb/IIIa and Ib/IX and related antigens on endothelial
cells and neutrophils that promote neutrophil aggregation and
binding to endothelial cells in a drug-dependent manner. Patients
Streptococcus pneumoniae with quinine-induced TMA have significant early mortality, though
with appropriate supportive care and treatment of the acute episode,
Infection with S. pneumoniae may lead to desialylation of the glyco- the disorder does not recur without reexposure to quinine.
calyx of cells that express the Thomsen-Freidenreich (T-F) antigen. The thienopyridines are another common cause of drug-induced
The activity of neuraminidase related to influenza virus may present TTP. TTP occurs in a higher percentage of patients exposed to
with the same complication. A naturally occurring, cold reactive IgM ticlopidine, with an incidence ranging from 1 : 600 to 1 : 4814 patient
may recognize the exposed T-F antigen, leading to red cell agglutina- exposures in contrast to an estimated incidence of 4 per 1,000,000
tion in vitro and rarely hemolysis in vivo. Affected individuals have to 1 per 8500–26,000 exposures to clopidogrel. No cases of
a positive antiglobulin test. Postpneumococcal HUS is the second clopidogrel-associated TTP were encountered in the CAPRIE and
most common cause of postinfectious HUS in children, accounting CURE studies, each of which enrolled more than 6200 patients.
for between 5% and 15% of cases, and occurring after approximately Despite the low incidence, the frequency with which clopidogrel is
0.5% of infections with this organism. It generally occurs in children prescribed renders it the most commonly reported drug associated
less than 2 years of age and is associated with significant morbidity with TTP in the Food and Drugs Administration MedWatch data-
and mortality. In two series, 75% of patients required dialysis. base, accounting for more than 30% of all cases. The pathogenesis
Extrarenal manifestations are common. The pathogenesis is not well and natural history of TTP associated with ticlopidine and clopido-
defined but may involve interactions among the IgM, red cells, grel differ. Reductions in ADAMTS13 activity below 15% occur in
platelets, and endothelium. Alternatively, desialylation by neuramini- 85% of patients with ticlopidine-associated TTP but in only 15% of
dase may disrupt factor H binding sites, resulting in unregulated patients with clopidogrel-associated TTP. Reduced ADAMTS13
complement activation and cell injury because factor B can no longer reflects the development of anti-ADAMTS13 antibodies. TTP gener-
regulate C3 convertase. Management is generally supportive, but ally develops within 2–12 weeks of starting ticlopidine and responds