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2254 Part XII: Hemostasis and Thrombosis Chapter 132: Thrombotic Microangiopathies 2255

the ADAMTS13 locus was identified by linkage analysis in families consistently. The demographics of TTP are similar to those of systemic
affected by congenital TTP and causative ADAMTS13 mutations were lupus erythematosus (SLE). TTP is relatively uncommon before age 20
characterized. 19 years, with a peak incidence between ages 30 and 50 years. 24,25 Across
many reports the female-to-male ratio averages approximately 2:1, but
female preponderance is more pronounced below age 50 years and the
ETIOLOGY AND PATHOGENESIS ratio approaches equality above age 60 years. 24,25 Other risk factors for TTP
TTP is caused by unregulated VWF-dependent platelet thrombosis. include African ancestry 26,27 and obesity. 27,28 Women have a tendency to
Large VWF multimers mediate platelet adhesion at sites of vascular present during late pregnancy or peripartum (reviewed in Refs. 29 and 30).
injury by binding to connective tissue and to glycoprotein Ib (GPIb) HLA-DRB1*11 is overrepresented severalfold in whites with TTP. 31,32
on the platelet surface (Chap. 120). The VWF subunit from which mul-
timers are constructed has a modular structure consisting of five types
of conserved structural motifs (Fig. 132–1). VWF multimers bind to CLINICAL FEATURES
collagen through domain A3, and to platelet GPIb through domain The onset of TTP can be dramatically acute or insidious, developing
A1. When platelets bind to VWF under conditions of high fluid shear over weeks. Approximately one-third of patients have symptoms of
stress, the VWF multimer is stretched and the Tyr 1605 -Met 1606 bond hemolytic anemia. Thrombocytopenia typically causes petechiae or
3,29
within domain A2 becomes accessible to ADAMTS13, which cleaves it purpura; oral, gastrointestinal or genitourinary bleeding is less common
and thereby can release any adherent platelets. ADAMTS13 deficiency but can be severe. Many patients describe an antecedent upper respira-
prevents this feedback inhibition of platelet adhesion and leads to tory tract infection or flu-like illness. Abdominal pain and tenderness
widespread microvascular thrombosis. ADAMTS13 levels greater than are common. Nausea, vomiting, and diarrhea may occur, but bloody
10 percent appear sufficient to prevent thrombotic microangiopathy. diarrhea is uncommon.
ADAMTS13 deficiency in TTP is caused by polyclonal auto- Systemic microvascular thrombosis typically affect the kid-
antibodies against ADAMTS13, usually immunoglobulin (Ig) G but ney, heart, brain, pancreas, adrenals, skin, spleen, marrow, and most
occasionally IgA or IgM. 13,14 These antibodies almost always bind the other tissues except the lungs, which are spared. Renal involvement
ADAMTS13 spacer domain, and often bind to the CUB domains is common, but acute renal failure occurs in fewer than 10 percent of
and first thrombospondin-1 repeat; they bind less frequently to other cases. 26,27,29 Neurologic findings can be transient or persistent and may
thrombospondin-1 repeats, the metalloprotease domain, or the pro- include headache, visual disturbances, vertigo, personality change, con-
peptide. 20–22 Most patients have autoantibodies that inhibit ADAMTS13 fusion, lethargy, syncope, coma, seizures, aphasia, hemiparesis, and
activity. The rest have noninhibitory antibodies that are likely to medi- other focal sensory or motor deficits. The frequency of neurologic
3,29
ate clearance of ADAMTS13 from the circulation. 23 findings or fever has decreased from more than 90 percent to approxi-
mately 50 percent over the past 40 years, 3,8,26,27,29 probably because these
features no longer are recognized as necessary to diagnose TTP.
EPIDEMIOLOGY The symptoms of TTP sometimes can be quite atypical, either
The annual incidence of TTP reportedly is two to six per million popula- at first presentation or upon relapse. Thrombocytopenia without
tion in the United States and approximately 2.2 per million in the United hemolytic anemia may herald the onset of disease. In rare instances,
Kingdom. 24,25 Seasonal or geographical trends have not been observed visual disturbances, pancreatitis, stroke, or other thrombosis may

Figure 132–1. Structure of von Willebrand factor
(VWF). Multimeric VWF (top) is composed of identical
subunits with four kinds of structural motifs, including
three A domains, six C domains and a homologous D4N
domain, two complete and one partial D domains, and
a cystine knot (CK) domain. Subunits (middle) are linked
′ into multimers by disulfide bonds between C-terminal
CK domains and N-terminal D3 domains. Domain A1
(bottom) binds platelet glycoprotein Ibα (GPIbα), domain
A3 binds collagen in extracellular matrix, and domain A2
contains a Tyr-Met bond that is susceptible to cleavage
by ADAMTS13 (a disintegrin and metalloprotease with a
thrombospondin type 1 motif member 13).

Kaushansky_chapter 132_p2253-2266.indd 2254 17/09/15 3:47 pm