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2256 Part XII: Hemostasis and Thrombosis Chapter 132: Thrombotic Microangiopathies 2257

schedules have included 2 mg intravenously on day 1 followed by 1 alkalosis and hypocalcemia, and may cause unintentional platelet
79
mg on days 4 and 7, or 2 mg intravenously per week for 2 to 14 weeks. removal. Serious complications attributable to plasma are less common,
78
Prostacyclin analogues 80,81 or high-dose intravenous immunoglobulins 82,83 occurring in approximately 4 percent of patients, and include broncho-
have been used without convincing evidence of efficacy. spasm, anaphylaxis, hypotension, hypoxia, and serum sickness. 97
Although cyclosporine can cause secondary thrombotic microan- The mortality rate for TTP treated with plasma exchange ranges
giopathy, apparent responses, with normalization of ADAMTS13 activity, from 10 to 20 percent. Most deaths occur within a few days after presen-
have been observed with cyclosporine 2 to 3 mg/kg daily in two divided tation, and almost all occur within the first month. 7,8,26,94
doses as an adjunct to plasma exchange. 84 Late sequelae of TTP may include long-term deficits in quality
Other treatments have included oral or intravenous cyclo- of life and cognition in many patients, 98,99 severe persistent neuro-
85
55
phosphamide, oral azathioprine, bortezomib, mycophenolate, logic deficits in 5 to 13 percent, chronic renal insufficiency in up to
100
86
87
100
N-acetylcysteine, combination chemotherapy with cyclophos- 25 percent, and dialysis dependent renal failure in 3 to 8 percent of
phamide, doxorubicin, vincristine, and prednisone, and autologous patients. 100,101
88
89
stem cell transplantation. Agents that prevent the binding of VWF
to platelets are under development and may prove useful for the treat-
ment of TTP. 90,91 CONGENITAL THROMBOTIC
THROMBOCYTOPENIC PURPURA
Supportive Therapy
Daily laboratory monitoring should include complete blood count with DEFINITION AND HISTORY
platelet count, LDH, electrolytes, blood urea nitrogen and creatinine.
29
Because of the high incidence of cardiac damage, continuous electro- Congenital TTP, or Upshaw-Schulman syndrome, refers to TTP that is
cardiographic monitoring and periodic assessment of cardiac enzymes caused by inherited deficiency of ADAMTS13.
102
103
should be considered. Patients should receive supplemental folic acid Schulman and colleagues and Upshaw first described a con-
55
and vaccination for hepatitis B. Allergic reactions, metabolic alkalo- genital disorder resembling TTP characterized by autosomal recessive
sis, and hypocalcemia associated with plasma exchange should be pre- inheritance and chronic relapsing thrombotic microangiopathy from
vented or treated by appropriate adjustments in therapy. infancy. Congenital TTP, or Upshaw-Schulman syndrome, shared many
9
After the platelet count increases to above 50 × 10 /L, prophylaxis features with acquired TTP in adults, including the consistent response
for venous thromboembolism may be instituted with low-molecular- to plasma. 103
61
weight heparin and low-dose aspirin. 55
ETIOLOGY AND PATHOGENESIS
COURSE AND PROGNOSIS Congenital TTP is caused by homozygosity or compound heterozygos-
19
The platelet count normalizes after a median of 11 plasma exchanges, ity for inactivating mutations in the ADAMTS13 gene on chromosome
9q34 (reviewed in Ref. 104). The mutations usually impair the synthesis
with a wide range of four to 55 sessions. Normalization of serum LDH or secretion of ADAMTS13. As yet no evidence convincingly indicates
92
lags behind the platelet count by approximately 9 days and persistent locus heterogeneity in congenital TTP.
elevation of LDH does not correlate with the risk of exacerbation or
relapse. 93
Exacerbations are defined as TTP recurring within 30 days after a EPIDEMIOLOGY
treatment response and 25 to 50 percent of patients have an acute exac- Congenital TTP is autosomal recessive and affects the genders almost
erbation within 2 weeks that requires further treatment with plasma equally. The prevalence of congenital TTP is approximately one per
105
exchange. Some have repeated exacerbations over several months. million population in Japan and appears to be similar elsewhere. Con-
94
106
A durable treatment response, lasting more than 30 days, is achieved genital TTP accounts for a few percent of patients presenting with TTP.
eventually in approximately 80 percent of patients. 92
Relapses, defined as recurrences more than 30 days after a complete
response, occur in up to one-third of patients within 2 years after treat- CLINICAL FEATURES
ment with plasma exchange and glucocorticoids alone. Most relapses The clinical features of congenital TTP are similar to those of acquired
occur during the first year, but have occurred 13 years or more after TTP, except for age of onset. Most children with congenital ADAMTS13
diagnosis. 26,94 Evaluation for relapsing TTP should be considered for deficiency have neonatal jaundice and hemolysis but no evidence of
any symptom compatible with thrombotic microangiopathy, especially ABO blood group or Rh incompatibility. Approximately half of the
in association with a common trigger of relapse such as infection, sur- children continue to have a chronic relapsing course from infancy. The
gery, or pregnancy. 34,95 Relapsing patients typically respond to plasma remaining children usually develop symptoms in their late teens or early
exchange. Relapses in TTP are associated with severe ADAMTS13 defi- twenties. In either case, acute exacerbations often are triggered by infec-
ciency and detectable ADAMTS13 autoantibody inhibitors. Conversely, tions, otitis media, surgery, or other inflammatory stress. 105,107 Patients
patients without severe ADAMTS13 deficiency at diagnosis rarely may suffer an acute attack after receiving desmopressin (DDAVP),
relapse (approximately 9 percent across several studies) (reviewed in which stimulates the release of VWF from endothelial cell stores; one
Ref. 96). such patient was receiving a low dose of intranasal DDAVP for enure-
Serious catheter-related complications of plasma exchange therapy sis. As in acquired TTP, most patients with congenital TTP have some
108
occur in approximately 26 percent of patients with TTP and include renal involvement with proteinuria, hematuria, or a mildly elevated
pneumothorax and hemorrhage, cardiac perforation, venous thrombo- serum creatinine during acute attacks. Chronic renal failure can occur,
sis, catheter thrombosis, and bacterial or fungal infections. 97 usually after a prolonged course of relapsing disease. 107
Hives or pruritic reactions to fresh-frozen plasma occur in one- Females often present during their first pregnancy, possibly because
to two-thirds of patients but usually can be managed by premedication VWF levels are increased late in pregnancy. If untreated, pregnancies
with antihistamines. High-volume plasma exchange causes metabolic usually end in spontaneous abortion, stillbirth or premature delivery.

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