Page 2281 - Williams Hematology ( PDFDrive )

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

prosthetic heart valves. Severe hemolysis and marked schistocyto- Common practice is to give prednisone or equivalent at a total daily dose
42
sis occur in patients with defective mechanical heart valves. Patients of 1 mg/kg, in one or two doses, for the duration of plasma exchange,
receiving marrow allografts or autografts for a variety of indications had followed by tapering. An alternative regimen is methylprednisolone 1 g
a mean of 0.7 percent schistocytes 6 weeks after transplantation, with a intravenously daily for 3 days. 55
range of 0 to approximately 4 percent schistocytes. 48,49 Approximately
10 percent of patients had at least 1.3 percent schistocytes, placing them Antiplatelet Agents
at risk for a diagnosis of thrombotic microangiopathy. 49 The use of antiplatelet agents in TTP is controversial. Aspirin and
ADAMTS13 levels are normal to moderately decreased in new- dipyridamole often are combined with plasma exchange but have not
8,64
borns, during pregnancy, after surgery, and in chronic liver cirrhosis, been shown conclusively to modify the course of TTP. Low-dose
chronic renal insufficiency, acute inflammatory states, and a variety aspirin (e.g., 80 mg/day) has been suggested for thromboprophylaxis,
9
of thrombocytopenic disorders other than TTP. 44,50 Severe sepsis may once the platelet count exceeds 50 × 10 /L. 55
sometimes cause acquired severe ADAMTS13 deficiency, although the
51
incidence and clinical significance of the finding remain uncertain. Platelet Transfusion
Some patients with acute viral hepatitis, severe liver cirrhosis or Transfusion of platelets may correlate with acute deterioration and
52
53
venoocclusive disease after stem cell transplantation have had severe death in TTP. 7,29,65,66 Therefore, platelet transfusions are relatively con-
ADAMTS13 deficiency (<10 percent) at least transiently, which is con- traindicated and should be reserved for the treatment of life-threaten-
sistent with the synthesis of ADAMTS13 in liver. 17–19 ing hemorrhage, preferably after plasma exchange treatment has been
initiated. Platelets generally need not be given prophylactically before
establishing venous access for plasma exchange. 67,68 Platelets have been
THERAPY transfused before emergency surgery, immediately after preparation by
Plasma Exchange intensive plasma exchange. 65
The mainstay of therapy for TTP is plasma exchange, which removes
antibody inhibitors of ADAMTS13 and replenishes the enzyme. After Rituximab
diagnosing TTP, or determining that the diagnosis is sufficiently likely TTP that is refractory to plasma exchange usually responds to rituximab
to justify treatment, plasma exchange therapy should be started as (e.g., 375 mg/m weekly for 4 doses). At least 80 percent of patients have
2
soon as feasible. Studies establishing the value of plasma therapy have complete responses within 1 to 3 weeks of starting treatment, includ-
69
excluded secondary thrombotic microangiopathy, so the efficacy of ing a normal ADAMTS13 level and disappearance of anti-ADAMTS13
7,8
plasma exchange has been demonstrated directly only for TTP. The antibodies (if present). Relapses occur in a minority of patients after
optimal dose of plasma is not known, but a common practice is to per- successful treatment, usually after intervals of 6 months to 4 years, and
form plasma exchange once daily at a volume of 40 or 60 mL/kg, equiv- most such patients respond to retreatment.
alent to 1.0 or 1.5 plasma volumes. For refractory disease, the intensity Acute reactions to rituximab are controlled by premedication with
of plasma exchange can be increased to 1 plasma volume twice daily. glucocorticoids, antihistamines, and analgesics. Because rituximab is
54
Prompt treatment is important and if plasma exchange must be delayed removed by plasma exchange, it should be administered immediately after
more than a few hours, plasma should be given by simple infusion at 20 plasma exchange to maximize the interval until the next plasma exchange.
to 40 mL/kg total dose per day, consistent with the patient’s ability to Rituximab has been given together with plasma exchange at the
tolerate the fluid load. 55 time of initial diagnosis, which may shorten the time to treatment
The replacement fluid should contain ADAMTS13. Satisfactory response and reduce the incidence of relapse. 55,69,70 Rituximab also has
results have been obtained with fresh-frozen plasma, plasma cryosu- been administered preemptively to patients with persistent or recurrent
7,8
pernatant, 56–58 and various pathogen-inactivated plasma products. The severe ADAMTS13 deficiency after achieving remission of TTP, and
59
incidence of allergic reactions and transfusion-associated lung injury this approach may prevent subsequent relapses. 70,71
may be lower with solvent/detergent-treated plasma than with fresh- In some settings, rare but serious complications associated with
frozen plasma, but the incidence of thrombosis may be increased with rituximab have included bronchospasm, hypotension, serum sickness,
60
some preparations. 59,61 Cryosupernatant is depleted in the largest VWF susceptibility to infections, and progressive multifocal leukoencephal-
multimers but has normal ADAMTS13 levels, which could make cryo- opathy. Such events have been very rare for patients with autoimmune
62
72
supernatant particularly suitable for the treatment of TTP. Nevertheless, diseases like TTP. 73,74
small randomized trials suggest that cryosupernatant is not superior Patients who have not been vaccinated for hepatitis B should be
to fresh-frozen plasma for the initial treatment of TTP. 56,57 Methylene screened for hepatitis B infection before receiving rituximab. Those
blue-treated plasma may be less effective than fresh-frozen plasma, 59,63 with evidence of past infection should be considered for antiviral pro-
despite having a similar concentration of ADAMTS13. 59 phylaxis as well as monitoring for hepatic injury and viral reactivation
Plasma exchange should be continued daily until the patient has for 6 to 12 months after treatment. 74
a treatment response as shown by a platelet count greater than 150 ×
10 /L for at least 2 days. Whether plasma exchange then should be Splenectomy
9
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simply stopped or tapered is not known. A typical strategy is to reduce Splenectomy can result in lasting remissions or reduce the frequency
the frequency of plasma exchange to every other day (or twice per week) of relapses for some patients with TTP that is refractory to plasma
for several days. If the disease remains quiescent, then treatment can be exchange or immunosuppressive therapy, presumably by removing a
stopped and the patient monitored closely for recurrence. Alternatively, major site of anti-ADAMTS13 antibody production. 75,76 Laparoscopic
plasma exchange can be stopped abruptly with monitoring for recurrent splenectomy can be performed safely in most patients regardless of
thrombocytopenia over several days. platelet count. 77

Glucocorticoids Other Treatments
TTP is an autoimmune disease and the use of glucocorticoids is logi- Anecdotal experience suggests that vincristine may be beneficial
cal, although a beneficial effect has not been demonstrated conclusively. for refractory TTP, although its efficacy is difficult to assess. Dosing

Kaushansky_chapter 132_p2253-2266.indd 2256 17/09/15 3:47 pm