Question 1: What is the best first step in management of this patient?
Correct Answer: C. Start plasma exchange.
Although distinguishing among thrombotic thrombocytopenic purpura, typical hemolytic uremic syndrome, and atypical hemolytic uremic syndrome (see Table 1 in the online version of this article at www.ascopost.com) is warranted, it can take several days to obtain appropriate test results. When the diagnosis of thrombotic thrombocytopenic purpura is suspected, emergent therapeutic plasma exchange should be initiated immediately, without waiting for confirmatory test results, due to the substantially high mortality associated with untreated or misdiagnosed thrombotic thrombocytopenic purpura.1,2
This approach is somewhat analogous to immediate initiation of aspirin or ATRA (all-trans retinoic acid) at the first suspicion of ischemic heart disease or acute promyelocytic leukemia, respectively. Timely (“medical emergency’) intervention with daily plasma exchange substantially reduces the mortality associated with thrombotic thrombocytopenic purpura from 90% to less than 25%.3-5
Interestingly, as in our patient, pregnancy can trigger development of both acquired and congenital thrombotic thrombocytopenic purpura. The guidelines developed by the British Committee for Standards in Haematology and the British Transplantation Society endorse that microangiopathic hemolytic anemia and thrombocytopenia due to ADAMTS13 deficiency occurs either due to autoantibodies against ADAMTS13 or ADAMTS13 deficiency secondary to mutations.2
Plasma exchange removes the immunoglobulin G autoantibody against ADAMTS13 and replenishes ADAMTS13 levels.1,2 A recombinant form of ADAMTS13 is currently in the early stages of development and hopefully will make its way into therapeutics.6
Question 2: In the current era, the majority of patients with thrombotic thrombocytopenic purpura will receive therapeutic plasma exchange before the development of “classic pentad”?
Correct Answer: A. True.
Once obvious precipitating causes of microangiopathic hemolytic anemia and thrombocytopenia are excluded, the consensus is to initiate therapeutic plasma exchange.2,3 This approach with “presumptive diagnosis of thrombotic thrombocytopenic purpura” has made the “classic pentad” a rare presentation in an individual patient.
Question 3: What is the next best step in management of this patient?
Correct Answer: A. Emergency blood cultures and initiation of broad-spectrum antibiotics.
In this evolving clinical course, new findings need to be addressed and not assumed to be due to persistent or recurrent thrombotic thrombocytopenic purpura, although it should be considered. The new clinical finding of fever can be associated with recurrent thrombotic thrombocytopenic purpura. The clinical findings of fever, severe hypotension, and bleeding are concerning for sepsis-associated disseminated intravascular coagulation, a known complication of therapeutic plasma exchange.7 The laboratory values, especially the high prothrombin time and the low fibrinogen level, strongly favor acute disseminated intravascular coagulation.
Thus, the most appropriate best first step was to draw blood cultures and start broad-spectrum antibiotics to stabilize the patient. Twenty-four hours later, the blood cultures grew methicillin-resistant Staphylococcus aureus, thought to originate from the plasmapheresis catheter, which was removed. Forty-eight hours later, she had recovered, but the platelet count dropped to 18,000/μL.
Repeat examination of the peripheral blood smear film revealed schistocytes, anemia, and thrombocytopenia. A new pheresis catheter was placed, plasma exchange was restarted (recurrent thrombotic thrombocytopenic purpura), and antibiotics were continued. Repeat blood cultures were negative. The platelet count rapidly increased to 210,000/μL after 3 days of plasma exchange. Following stabilization, she was discharged and sent home in excellent condition, with follow-up in the hematology clinic.
Eculizumab (Soliris) is a monoclonal antibody approved by the U.S Food and Drug Administration for the treatment of pediatric and adult patients diagnosed with atypical hemolytic uremic syndrome.8 Eculizumab binds with high affinity to complement protein C5, blocking the formation of the C5b-9 cell membrane attack complex, leaving proximal functions of opsonization and immune clearance intact. Eculizumab is not indicated for sepsis-associated acute disseminated intravascular coagulation or recurrent thrombotic thrombocytopenic purpura. ■
Disclosure: Drs. Abutalib and Connors reported no potential conflicts of interest.
1. Schwartz J, Winters JL, Padmanabhan A, et al: Guidelines on the use of therapeutic apheresis in clinical practice-evidence-based approach from the Writing Committee of the American Society for Apheresis: The sixth special issue. J Clin Apher 28:145-284, 2013.
2. Scully M, Hunt BJ, Benjamin S, et al: Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies. Br J Haematol 158:323-335, 2012.
3. George JN, Nester CM: Syndromes of thrombotic microangiopathy. N Engl J Med 371:654-666, 2014.
4. Tsai HM: Advances in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura. J Am Soc Nephrol 14:1072-1081, 2003.
5. Sadler JE: Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura. Blood 112:11-18, 2008.
6. Plaimauer B, Kremer Hovinga JA, Juno C, et al: Recombinant ADAMTS13 normalizes von Willebrand factor-cleaving activity in plasma of acquired TTP patients by overriding inhibitory antibodies. J Thromb Haemost 9:936-944, 2011.
7. Basic-Jukic N, Kes P, Glavas-Boras S, et al: Complications of therapeutic plasma exchange: Experience with 4,857 treatments. Ther Apher Dial 9:391-395, 2005.
8. Soliris (eculizumab) prescribing information, Alexion Pharmaceuticals Inc, 2011. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125166s172lbl.pdf. Accessed April 19, 2015.
Syed A. Abutalib, MD, Assistant Director, Hematology & Bone Marrow Transplantation Service, Cancer Treatment Centers of America, Zion, Illinois
Jean M. Connors, MD, Assistant Professor, Harvard Medical School, Hematology Division, Brigham and Women’s Hospital/Dana-Farber Cancer Institute, Boston
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