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CHAPTER 132 Tissue injury can affect almost any organ but often results in neuro-
logic damage. TTP is associated with autoantibodies against the plasma
THROMBOTIC metalloprotease ADAMTS13 (a member of the “a disintegrin and
metalloprotease with thrombospondin repeats” family) that reduce
MICROANGIOPATHIES plasma ADAMTS13 activity to less than 10 percent of normal.
Eli Moschcowitz reported the first detailed description of TTP
1
in 1924. The patient was a 16-year-old girl with fever, severe anemia,
leukocytosis, petechiae, and hemiparesis. Her renal function was not
J. Evan Sadler impaired, but the urine contained albumin, hyaline casts, and granular
casts. She became comatose and died 2 weeks after her first symptoms.
At autopsy, hyaline thrombi were found diffusely in terminal arterioles
and capillaries, particularly of the heart and kidney. For many years,
SUMMARY patients with similar findings were said to have Moschcowitz disease.
The name TTP was proposed in 1947 and widely adopted thereafter.
2
Thrombotic microangiopathy is a general term for the combination of microan- In 1966, a review of 272 published cases defined the major clinical
3
giopathic hemolytic anemia and thrombocytopenia, often accompanied by features of TTP. Most patients were females between the ages of 10 and
signs and symptoms consistent with disseminated microvascular thrombosis. 39 years. The symptoms and physical findings included thrombocytope-
Thrombotic thrombocytopenic purpura (TTP) refers to thrombotic microan- nia, hemolytic anemia with numerous fragmented red cells or schisto-
giopathy, without an obvious predisposing condition, and without oliguric cytes, neurologic findings, renal damage, and fever. Mortality exceeded
renal failure. TTP is caused by autoantibodies to ADAMTS13 (a disintegrin and 90 percent; the average hospital stay was only 14 days before death, and
metalloprotease with a thrombospondin type 1 motif member 13), a plasma 80 percent of patients lived fewer than 90 days after the onset of symp-
toms. However, dramatic recoveries occurred in some cases following
metalloprotease that normally cleaves von Willebrand factor (VWF) and regu- splenectomy.
lates VWF-dependent platelet aggregation. Inherited deficiency of ADAMTS13 This grim prognosis was recorded before a report in 1976 that
causes congenital TTP, which typically responds to plasma infusion. Most whole blood exchange transfusions induced prompt remissions in eight
patients with acquired TTP respond to plasma exchange, although many have of 14 patients. Similar responses were described after plasmapher-
4
relapsing disease. Hemolytic uremic syndrome (HUS) refers to thrombotic esis with plasma replacement. One remarkable case report showed
5
microangiopathy that usually causes oliguric or anuric renal failure. Ingestion of that plasmapheresis was effective if the replacement fluid was plasma
Shiga toxin-producing Escherichia coli can cause the most common or “typical” or cryoprecipitate-depleted plasma, but ineffective if the replacement
6
form of HUS that is usually preceded by bloody diarrhea. Inherited or acquired fluid contained just albumin. Furthermore, simple plasma infusions
defects in the regulation of the alternative complement pathway cause HUS without plasmapheresis could induce sustained remissions, suggesting
referred to as “atypical” because it occurs without a prodrome of bloody diar- that replacement of a missing plasma factor sometimes was sufficient to
6
rhea. Secondary thrombotic microangiopathy can occur in association with ameliorate TTP.
These reports led to the widespread adoption of plasma therapy for
metastatic cancer, infections, organ transplantation, and certain drugs. These TTP, and two studies published in 1991 provided compelling evidence
variants of thrombotic microangiopathy differ in pathogenesis and prognosis, for its efficacy. Plasma infusion was associated with 91 percent survival
but can be difficult to distinguish because their clinical features often overlap. in 108 patients, an impressive improvement over historical experi-
ence. The same year, a prospective randomized comparison of plasma
7
8
exchange and plasma infusion in 102 patients with TTP was reported.
THROMBOTIC THROMBOCYTOPENIC Long-term survival was 78 percent for the plasma exchange group and
PURPURA 63 percent for the plasma infusion group, a significant difference in
favor of plasma exchange.
A link between TTP and von Willebrand factor (VWF) was pro-
DEFINITION AND HISTORY posed in 1982, based on studies of four patients with chronic relapsing
Thrombotic thrombocytopenic purpura (TTP) refers to thrombotic TTP. Their plasma VWF multimers were much larger than those of
9
microangiopathy without another apparent cause and without acute healthy controls and similar in size to the VWF multimers secreted by
renal failure, although mild or modest renal insufficiency may be seen. endothelial cells. Patients with TTP were proposed to lack a depoly-
merase activity, perhaps a protease or a reductase, that shortens newly
secreted VWF multimers in vivo and produces the multimer distribu-
Acronyms and Abbreviations: ADAMTS, a disintegrin and metalloprotease tion of normal plasma. The absence of this depolymerase would cause
with thrombospondin repeats; aHUS, atypical hemolytic uremic syndrome; ANA, the persistence of “unusually large” VWF, which promotes intravascular
anti-nuclear antibody; APS, antiphospholipid syndrome; aPTT, activated partial platelet aggregation, thrombocytopenia, and microvascular thrombo-
thromboplastin time; CFH, complement factor H; CFHR, complement factor H-related sis. Plasma exchange therapy could provide the missing depolymerase
protein; DDAVP, desmopressin; DGKE, diacylglycerol kinase ε; Gb3, globotriaos- activity, or remove other factors that provoke clinical relapses.
ylceramide 3; HELLP, hemolysis, elevated liver enzymes, low platelet count; HIT, A candidate depolymerase was identified in 1996, when a metal-
heparin-induced thrombocytopenia; HUS, hemolytic uremic syndrome; LDH, lactate loprotease in plasma was shown to cleave VWF multimers subjected to
dehydrogenase; MCP, membrane cofactor protein; MMACHC, methylmalonic aciduria high fluid shear stress or to mild protein denaturants. 10,11 Soon thereafter,
and homocystinuria type C protein; PT, prothrombin time; SLE, systemic lupus eryth- children with congenital TTP were shown to have inherited deficiency
ematosus; STEC, Shiga toxin-producing Escherichia coli; Stx, Shiga toxin; TM, throm- of this metalloprotease, and adults with acquired TTP were shown
12
bomodulin (gene name THBD); TTP, thrombotic thrombocytopenic purpura; VEGF, to have autoantibody inhibitors of the enzyme. 13,14 The VWF cleaving
vascular endothelial growth factor; VWF, von Willebrand factor. protease was purified, 15,16 cloned, 17,18 and named ADAMTS13, a new
member of the ADAMTS family of metalloproteases. Simultaneously,

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