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2262 Part XII: Hemostasis and Thrombosis Chapter 132: Thrombotic Microangiopathies 2263

age. Patients usually have complicated pneumococcal pneumonia or blood film. Heparin-induced thrombocytopenia (HIT) may sometimes
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meningitis, with normal plasma fibrinogen and normal or minimally resemble TTP (Chap. 118).
prolonged PT and aPTT. The pathophysiology is thought to involve bac- SLE can cause autoimmune hemolysis and thrombocytopenia, and
terial neuraminidase, made by S. pneumoniae and some other organ- lupus vasculitis can cause microangiopathic changes, renal insufficiency,
isms, which removes sialic acid residues from cell surface glycoproteins and neurologic defects consistent with TTP. Vasculitis associated with
and exposes Thomsen-Friedenreich antigen (T antigen). T antigen is other autoimmune disorders can pose a similar diagnostic problem.
recognized by naturally occurring antibodies that fix complement, Although ADAMTS13 deficiency is uncommon among patients with
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causing hemolysis and damaging the renal microvasculature. Because SLE, in rare cases they develop autoimmune ADAMTS13 deficiency
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donor blood usually contains high levels of antibodies against T antigen, and TTP that responds to plasma exchange. Conversely, patients with
red cells and platelets should be washed before transfusion, and plasma TTP and autoantibodies against ADAMTS13 may have other markers
should not be used as a replacement fluid. Exchange transfusion has of autoimmune disease, including ANA or anti-DNA antibodies, pol-
been proposed to stop hemolysis by replacing T-antigen–bearing red yarthritis, discoid lupus, or ulcerative colitis. 101,159
blood cells and removing circulating neuraminidase, but the efficacy of Thrombotic microangiopathy can develop in patients with APS,
this treatment is uncertain. 148 with or without concurrent SLE.
Thrombotic microangiopathy occurs in patients with progressive
systemic sclerosis, particularly in association with acute scleroderma
TISSUE TRANSPLANTS renal crisis and malignant hypertension. Treatment with angiotensin-
Recipients of solid-organ transplants can develop thrombotic microan- converting enzyme inhibitors may be effective. 160
giopathy, often dominated by renal involvement associated with immu-
nosuppression by cyclosporine or tacrolimus. These drugs appear DRUG-INDUCED THROMBOTIC
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to damage renal endothelial cells directly and can cause neurotoxicity,
adding another feature suggestive of TTP. Similarly, hematopoietic stem MICROANGIOPATHY
cell transplant recipients may develop thrombotic microangiopathy Nearly 80 drugs are associated with thrombotic microangiopathy, and evi-
associated with high-dose chemotherapy or radiation, immunosuppres- dence supports a definite or probable causal association for approximately
sive drugs, graft-versus-host disease, or infections. ADAMTS13 levels 44 of them. Three drugs (quinine, cyclosporine, tacrolimus) account for
are normal and plasma therapy is ineffective. 151 60 percent of the patient reports with definite evidence. Some agents
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cause disease by an immune mechanism and others by direct toxicity;
a few drugs reportedly act by either mechanism. With the exception of
CANCER ticlopidine-induced disease, plasma exchange appears to be ineffective or
Thrombotic microangiopathy occurs in a small fraction of patients possibly harmful for drug-induced thrombotic microangiopathy. 162
with cancer, most commonly with adenocarcinoma of the pancreas,
lung, prostate, stomach, colon, ovary, breast, or unknown primary site Immune Mechanisms
that usually is widely metastatic. These cancers also are associated with Quinine is the most common cause of drug-induced thrombotic
Trousseau syndrome or paraneoplastic hypercoagulability and throm- microangiopathy. Most patients are women. Severe thrombotic micro-
bosis. Patients often have variable prolongation of the PT and aPTT angiopathy occurs suddenly within several hours after ingestion of
and increased fibrin degradation products. The thrombosis of Trous- a quinine tablet or a beverage containing it such as tonic water, with
seau syndrome may respond to anticoagulation with heparin but not fever, abdominal and back pain, nausea, vomiting, diarrhea, rash, and
warfarin. 152,153 Abundant schistocytes also have been described in acute oliguric renal failure. Neurologic changes are common. ADAMTS13
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erythroleukemia. Plasma exchange is ineffective. 26,27,153 levels are normal. The mechanism involves a broad range of
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quinine-dependent antibodies against platelets, endothelium, and other
PREGNANCY-ASSOCIATED THROMBOTIC cells. Most patients recover with normal renal function over several
MICROANGIOPATHY weeks, although some develop end stage renal disease.
The antiplatelet drug ticlopidine is unusual because it induces
The differential diagnosis of thrombotic microangiopathy in pregnancy autoantibody inhibitors of ADAMTS13, effectively causing TTP that
includes preeclampsia, eclampsia, HELLP syndrome (hemolysis, ele- responds to plasma exchange. The related thienopyridine drugs clop-
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vated liver enzymes, low platelet count), acute fatty liver of pregnancy, idogrel, prasugrel and ticagrelor do not appear to cause thrombotic
abruptio placenta, amniotic fluid embolism, and retained products of microangiopathy by this mechanism.
conception (Chap. 129). Severe ADAMTS13 deficiency has not been
observed in these conditions. Pregnancy also can trigger disease in Direct Toxicity
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patients with congenital or acquired ADAMTS13 deficiency or defects Cyclosporine and tacrolimus are structurally distinct immunosuppres-
in the alternative complement pathway. sive drugs that indirectly inhibit calcineurin and suppress T-cell activa-
tion. Both agents cause dose-dependent nephrotoxicity, neurotoxicity,
AUTOIMMUNE DISORDERS and thrombotic microangiopathy. 166–168 166 The renal damage is thought to
involve toxic effects on endothelium. Thrombotic microangiopathy
Autoimmune thrombocytopenia may be confused with TTP if other can develop during the first few weeks of treatment, although graft
causes of microangiopathic hemolytic anemia are present. Asymptom- rejection, graft-versus-host disease, or systemic infections can cause
atic thrombocytopenia also may sometimes be the only finding in TTP. similar microangiopathic changes. The thrombotic microangiopathy
Patients have been described in whom TTP and autoimmune throm- often remits with dose reduction or substitution of other immuno-
bocytopenia appeared to occur simultaneously or sequentially. Evan suppressive drugs and may not recur if therapy with cyclosporine or
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syndrome (autoimmune hemolytic anemia with autoimmune thrombo- tacrolimus is reinstituted.
cytopenia) usually can be distinguished from TTP by a positive Coombs Mitomycin C is an alkylating agent that is used for anal carcinoma
test and the prominence of spherocytes relative to schistocytes in the and for some adenocarcinomas. It appears to cause dose-dependent

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