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Chapter 134 Thrombotic Thrombocytopenic Purpura and the Hemolytic Uremic Syndromes 1989

Management of Thrombotic Thrombocytopenic Purpura and Management of Atypical Hemolytic Uremic Syndrome)
Management of TTP Management of aHUS
• A high index of suspicion is necessary to make a diagnosis of TTP. • A high index of suspicion is necessary for diagnosis of aHUS.
○ ADAMTS13 activity should be determined before initiation of ○ aHUS is a systemic disorder
plasma therapy. ■ Advanced renal failure, hypertension and increased vascular
• Prompt initiation of therapy is required to prevent organ dysfunction permeability suggest a diagnosis of aHUS rather than TTP
or death. ■ Neurologic and gastrointestinal symptoms are common.
• Prophylaxis is recommended during pregnancy. • aHUS is a diagnosis of exclusion
• For suspected or confirmed acquired (autoimmune) TTP: ○ TTP should be excluded with ADAMTS13 assay
○ Plasma exchange is recommended (exchange 1–1.5 plasma ○ STEC-HUS should be excluded with stool culture and/or tests
volumes [40–60 mL/kg]) daily. Plasma infusion may be used for Shiga toxin
until exchange is initiated. ○ Other causes of microangiopathic hemolytic anemia should be
○ Continue plasma exchange until the neurologic symptoms have excluded with history, coagulation studies, infectious disease
resolved and the serum LDH and platelet count is normal; studies, serologies, etc.
many experts recommend continuing plasma exchange for an ○ Plasma studies of C3, C4, and complement control proteins
additional 2–3 days thereafter. (CFH, CFI, CFB) and autoantibody to CFH may be normal,
○ Corticosteroids are often used as part of initial therapy as may be genetic studies (CFH, CFI, CFB, C3, MCP, THBD,
○ Administration of rituximab together with plasma exchange DGKE). Initiation of therapy should not be delayed while
early in the course of disease appears to induce a more rapid awaiting test results.
response and may delay relapse. • Treatment of suspected or confirmed aHUS:
○ Use of rituximab is controversial for treatment of asymptomatic ○ Plasma exchange is recommended until a diagnosis of TTP is
patients (in clinical remission) with ADAMTS 13 deficiency. excluded.
○ Splenectomy is generally reserved for patients who are refractory ○ Eculizumab is currently the therapy of choice for aHUS
to plasma exchange and rituximab. ■ Vaccination to prevent meningococcal infection is required;
○ Immunosuppressive agents are only recommended for patients antibiotic prophylaxis should also be considered.
with critical illness that is unresponsive to plasma exchange, ■ Early treatment reduces the risk of long-term renal
corticosteroids, and rituximab. impairment.
○ Platelet transfusion should be reserved for life-threatening ■ Thrombocytopenia and hemolysis tend to respond early, but
bleeds. Packed red blood cells can safely be transfused in TTP. renal recovery may take months.
• For hereditary TTP (Upshaw-Schülman syndrome) ■ Long-term therapy is currently recommended. If eculizumab
○ Plasma infusion is often sufficient to treat acute symptoms. is discontinued, close follow up to detect early relapse is
○ Prophylactic plasma infusion may prevent symptomatic suggested.
recurrence.
ADAMTS13, A disintegrin and metalloproteinase with Thrombospondin type 1 motifs, member 13; aHUS, atypical hemolytic uremic syndrome; CFB, complement factor
B; CFH, complement factor H; CFI, complement factor I; DGKE, diacyl glycerol kinase ε; LDH, lactate dehydrogenase; MCP, membrane cofactor protein; STEC, Shiga
toxin-producing E. coli; THBD, thrombomodulin; TTP, thrombotic thrombocytopenic purpura.

only infusion of plasma. At 6 months, complete remissions were seen has not been determined. The volume of exchange can be increased
in 78% of patients treated with exchange versus 31% of those treated to 1.5–2 plasma volumes daily if the initial response is poor. Neuro-
with plasma infusion. This study did not resolve the question as to logic improvement occurs most rapidly, often within hours to days.
whether removal of a disease-inciting agent or replacement of a The serum LDH level typically falls by 50% within 3 days in
missing factor accounted for the superior response, particularly responders, and the platelet count begins to rise at a mean of 5 days,
because patients in the exchange arm received a threefold larger though normalization may take up to several weeks. Impaired renal
volume of plasma. Indeed, a retrospective study demonstrated no function and disappearance of schistocytes are generally the last to
significant difference in outcome in patients with acquired TTP who improve.
received equal volumes of plasma by exchange or infusion. However, Daily plasma exchange should be continued until neurologic
the current model for the pathogenesis of acquired idiopathic TTP symptoms have resolved and both a normal serum LDH and platelet
suggests that plasma exchange is superior because it both removes an count have been achieved; many experts recommend an additional
IgG inhibitor of ADAMTS13 and replaces the deficient protein. In 2–3 days of plasma exchange thereafter. Approximately 85% to 90%
contrast, plasma infusion (or potentially infusion of a factor concen- of patients show a clinical and laboratory response to plasma exchange
trate containing ADAMTS13) suffices for patients with genetic within 3 weeks, most often within 10 days (mean 15.8; range 3–36
ADAMTS13 deficiency. Large volumes of plasma are more easily days). However, 20% to 40% of patients will experience an exacerba-
administered by exchange, and unless a genetic deficiency of tion of disease within 30 days after stopping plasma exchange,
ADAMTS13 has been documented, plasma infusion should be whereas approximately 30% will relapse at later dates, usually within
reserved for situations in which exchange is not immediately avail- the first year. The decision to switch to CPP or to introduce another
able. The recovery of ADAMTS13 levels may lag behind other form of therapy is empiric but is generally not considered until the
indicators of clinical response, and the utility of monitoring patient has received a minimum of 10–14 days of daily exchange with
ADAMTS13 levels during treatment has not been established. FFP. One prospective nonrandomized study suggested that adminis-
Plasma (either fresh frozen plasma [FFP] or thawed plasma) tration of rituximab early in the course of disease in conjunction with
remains the most commonly used replacement product for plasma plasma exchange induced more rapid responses and reduced relapses.
exchange. There is no clear advantage to the use of cryo-poor plasma Little or no data are available to support either abrupt discontinua-
(CPP), which is depleted of vWF. These findings are consistent with tion or “tapering” of plasma exchange after remission.
a recent study showing similar concentrations and stability of Complication rates associated with plasma exchange therapy have
ADAMTS13 during storage at 1–5°C in CPP and FFP. Pilot studies been reported to be as high as 30%, but recent reports suggest a lower
suggest that solvent-detergent treated plasma (which contains rate. The majority of adverse events are related to central venous
ADAMTS13 at concentrations approximately 20% lower than those catheter insertion, infection, allergic reactions to plasma and occa-
in FFP) is as efficacious as FFP and is associated with fewer allergic/ sionally thrombosis.
urticarial reactions. Plasma exchange is effective for patients with or without inhibi-
Treatment is generally initiated with the goal of exchanging 1–1.5 tors, and clinical responses frequently occur despite persistence of
plasma volumes (40–60 mL/kg) daily, although the optimal regimen both the inhibitor and severe ADAMTS13 deficiency, although