Acquired Autoimmune Thrombotic Thrombocytopenic Purpura

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Acquired autoimmune thrombotic thrombocytopenic purpura

BY VINCENT M. VACCA, JR., MSN, RN

Abstract: Acquired autoimmune thrombotic thrombocytopenic purpura (TTP)—the most common form of TTP—is a life-threatening hematologic disease characterized by hemolytic anemia and thrombocytopenia. Acquired autoimmune TTP can cause signs and symptoms of neurologic and other organ involvement, with mortality approaching 90% if the disease is not promptly recognized and treated. Since the introduction of plasma exchange in 1991, the acquired autoimmune TTP survival rate has increased to 78%.

Keywords: acquired autoimmune TTP, ADAMTS13, hemolytic anemia, plasma exchange, rituximab, thrombocytopenia, thrombotic thrombocytopenic purpura, von Willebrand factor

ALMOST 100 YEARS AGO, Dr. Eli work in this case, the disease was Moschcowitz described a 16-year- named Moschcowitz disease. Ad- old girl who had developed a con- vances over the following decades stellation of signs and symptoms, in understanding the pathologic ap- including pallor, fever, petechiae, pearance of the affected organs led hematuria, and coma. (See Wide- to renaming Moschowitz disease spread petechiae.) Within 2 weeks of to thrombotic thrombocytopenic presentation, she died from her dis- purpura (TTP).1,2 The pathophysiology ease.1,2 At autopsy, her organs were of this disorder was not completely found to be damaged by arteriolar understood, and no reliable diagnos- and capillary thrombi composed tic test for TTP existed until 1966 primarily of platelets. Because of his when researchers defined a classic

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Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved. pentad of clinical findings of TTP, hemolytic anemia, and organ damage TTP typically occurs in the late sec- which include:1-3 associated with TTP. The autoantibod- ond or third trimester, with a me- • microangiopathic hemolytic ane- ies against ADAMTS13 are effectively dian onset at 23 weeks gestation.9 mia (MAHA) removed by PEX.5,6 Many patients • thrombocytopenia with a history of TTP experience a Etiology • severe neurologic findings, such as relapsing-remitting course.1,2 Acquired autoimmune TTP may fluctuating altered mental status Although acquired autoimmune also present in patients with other au- • fever TTP is not the only form of this toimmune disorders such as systemic • acute renal failure. disease, it is the most common.7 lupus erythematosus, Sjögren syn- However, less than 10% of patients This article focuses on the acquired drome, Hashimoto thyroiditis, rheu- with TTP present with the full pentad.3 autoimmune form of TTP. matoid arthritis, psoriasis, and celiac Presentation of four, or even three, disease.2,8 Solid organ or hematopoi- of the classic five clinical findings is Epidemiology etic cell transplant and malignancies sufficient to diagnose TTP and begin Acquired autoimmune TTP has a are also recognized as acquired auto- empirical treatment with plasma ex- known annual incidence of 3 to 11 immune TTP triggers.2,8 Acquired change (PEX).4 PEX is the principal cases per million people, affecting autoimmune TTP is con sidered a treatment for acquired autoimmune up to 10,000 people in the US and hematologic emergency because even TTP and has reportedly reduced mor- Europe annually. In the US, the with appropriate treatment the mortality from approximately 90% to peak incidence of acquired autoim- tality still ranges from 10% to 20%.2,3 between 10% and 20%. The patho- mune TTP occurs in the fifth decade genesis of TTP involves autoantibodies of life. Acquired autoimmune TTP is Pathophysiology that act against von Willebrand factor more common in women as com- TTP is a primary thrombotic micro- (vWF) cleaving metalloproteinase, pared with men at a ratio of 2-3.5:1. angiopathy manifested by thrombo- known as a disintegrin and metallo- It also affects women particularly cytopenia, hemolytic anemia, and protease with a thrombospondin type during and after pregnancy, with thrombosis. In 1982, Moake and 1 motif, member 13 (ADAMTS13). an estimated prevalence of 1 in colleagues reported the presence of Deficiency of ADAMTS13 is respon- 25,000 pregnancies.2,4,8 Pregnancy- an ultra-high-molecular-weight form sible for the microvascular thrombosis, associated acquired autoimmune of von Willebrand factor (UHvWF). A procoagulant molecule, UHvWF is responsible for platelet adhesion in Widespread petechiae patients experiencing an acute episode of TTP. The underlying patho- Patient’s leg showing widespread physiology of acquired autoimmune petechiae with a platelet count of 11,000/µL. Petechiae do not blanch TTP is inhibition and inactivation with pressure because they repre- (deficiency) of a protease identified 4 sent minute hemorrhages; they may as ADAMTS13. ADAMTS13 is re- accumulate preferentially in depen- sponsible for cleaving, or breaking, dent areas such as the lower legs UHvWF into smaller units, which because of hydrostatic pressure. reduces platelet adhesion. In 1998, Petechiae may also present initially ADAMTS13 deficiency was identified on the palate and tongue, so exami- as the defining feature of TTP and nation of the gingiva, oropharynx, became a key criterion for the diag- and retinas is indicated in a patient nosis of acquired autoimmune TTP. with thrombocytopenia because Since then, acquired autoimmune concern for risk of intracranial bleeding is greater if petechiae are present TTP is defined as a thrombotic mi- above the level of the neck. Gener- croangiopathy syndrome resulting ally, the platelet count will be under from a severe ADAMTS13 deficiency 30,000/µL in a patient presenting caused by development of immuno- with petechiae. Platelet counts un- globulin G autoantibodies against der 10,000/µL are associated with spontaneous bleeding and warrant immediate ADAMTS13.1,10-12 intervention. When ADAMTS13 fails due to Source: Weksler BB, Schechter GP, Ely S. Wintrobe’s Atlas of Clinical Hematology. 2nd ed. Philadelphia, PA: insufficient quantity and activity, Wolters Kluwer; 2018. the increase in circulating UHvWF

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Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved. promotes platelet adhesion, particu- An infection may precede an acute larly at sites of vascular injury and at episode of acquired autoimmune A closer look at arteriole-capillary junctions. As red TTP. The more common findings are schistocytes blood cells (RBCs) pass through profound thrombocytopenia, usually narrowed partially obstructed arteriole- less than 30,000/mcL (normal, Schistocytes are red cell fragments capillary junctions, they are sub- 150,000 to 450,000/mcL) and evi- that may be present in microangiopathic hemolysis and other causes of jected to shear stress, leading to cell dence of MAHA, with multiple schis- mechanical hemolysis. Schistocytes rupture within blood vessels. This tocytes visible on peripheral blood are smaller than red blood cells and 14 produces hemolytic anemia, an RBC smear. These findings are associ- lack central pallor. fragmentation with schistocyte for- ated with signs and symptoms such mation, which can be seen on a pe- as cutaneous and mucosal bleeding, ripheral blood smear.12 (See A closer weakness, and dyspnea, and can lead look at schistocytes.) Reduced blood to the diagnosis of acquired autoim- flow due to thrombosis and subse- mune TTP. The brain is affected in quent cellular injury results in the up to 60% of cases with a broad end-organ damage associated with range of signs and symptoms, from a acquired autoimmune TTP.1,11,12 headache and impairment of mental Source: LifeART image ©2018 Lippincott Williams & In acquired autoimmune TTP, status to acute ischemic stroke, Wilkins. All rights reserved. microthrombi are composed of seizures, and coma.2 Chest pain UHvWF and platelets, but very little and elevated troponin I levels may fibrin. Thrombi are present in all be present in 25% of patients.2 • stroke, seizures, transient focal tissues, but the lungs and liver are Dysrhythmias and heart failure may neurologic signs such as motor or less affected than other organs be- occur, but myocardial infarction in sensory abnormalities, diplopia, and cause of lower shear forces in these acquired autoimmune TTP is rare. aphasia low-pressure systems.2 Tissue dam- Mesenteric ischemia is found in • throbbing headache aged by microthrombi can cause approximately 25% of patients diag- • cardiac dysrhythmias thrombocytopenia, MAHA resulting nosed with acquired autoimmune • dyspnea from destruction and loss of RBCs TTP.2 GI tract involvement can • renal impairment in small blood vessels, and subse- include abdominal pain, nausea, • fever quent multiorgan dysfunction and vomiting, and diarrhea. Varying de- • fatigue. failure resulting from ischemia.8 grees of renal dysfunction are often Despite widespread thrombosis, present; however, impairment re- Diagnostic studies tissues typically exhibit minimal quiring renal replacement therapy Testing for ADAMTS13 activity necrosis, suggesting that blood ves- is not typical and, if present, may and autoantibodies directed against sel occlusion and ischemia are not suggest another disorder, such as ADAMTS13 is standard to diagnose persistent or severe enough to cause hemolytic uremic syndrome (HUS).2 acquired autoimmune TTP and necrosis. Recovery from acquired The low platelet count in acquired distinguish it from other disorders autoimmune TTP following appro- autoimmune TTP is a marker of sus- presenting with similar signs and priate and timely treatment with ceptibility to potentially significant symptoms that require and respond PEX is possible.2 damage in the brain and kidneys, so to different treatments.3,8 (See Testing correcting it quickly is critical.15 for TTP.) ADAMTS13 levels are used Signs and symptoms Although patients with known or to determine whether the pathogen- Acquired autoimmune TTP can suspected acquired autoimmune TTP esis of the patient’s TTP is congenital cause widespread signs and symp- may present with various signs and or of an acquired autoimmune ori- toms. The consequences of acquired symptoms resulting from widespread gin, and is also used to distinguish it autoimmune TTP-associated platelet thrombosis, thrombocytopenia, and from other thrombocytopenic disor- thrombi may damage many organ anemia, the most common initial ders such as HUS, idiopathic throm- systems, including the neurologic, sign is nonblanchable, hemorrhagic bocytopenic purpura, and heparin- cardiac, renal, and gastrointestinal skin lesions that result from the leak- induced thrombocytopenia.8 (GI) systems.13 The initial presenta- age of red blood cells into the skin, About two-thirds of patients with tion may be very nonspecific and can known as purpura.16 Other signs and the clinical diagnosis of acquired au- include weakness, headache, confu- symptoms associated with acquired toimmune TTP have ADAMTS13 sion, nausea, vomiting, and diarrhea. autoimmune TTP include:16 activity levels significantly lower than www.Nursing2019.com January l Nursing2019 l 25

Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved. normal (normal, greater than 66%) irreversible renal failure, neurologic Erythropoietin and folic acid ad- and elevated ADAMTS13 autoanti- deterioration, and 90% mortality. ministration can be considered in body level (greater than 140 U/mL, PEX has been the recommended addition to PEX to provide support normal, less than 12 U/mL). These treatment for acquired autoimmune for erythropoiesis.19,21 Glucocorticoids measurements are both highly spe- TTP since the publication of the ran- are often started simultaneously with cific for acquired autoimmune TTP domized clinical trial documenting PEX. Steroids are used initially to and sensitive in differentiating its effectiveness in 1991.4,15 PEX has achieve relatively rapid immunosup- acquired autoimmune TTP from been shown in clinical trials to be pression. The proposed benefits of similar disorders such as HUS, dis- superior to plasma infusion in nor- adding steroids to the treatment seminated intravascular coagulation, malizing platelet counts and reduc- regimen include:15 and other microangiopathies.5,8 (See ing mortality.15 All currently available • they provide coverage for other Microangiopathies associated with TTP.) plasma preparations are equivalent diagnoses and can be discontinued in terms of their effectiveness and if not needed because the results of Treatment outcomes in acquired autoimmune the ADAMTS13 assay are usually For patients who are acutely ill with TTP.9,12,17,19 PEX should be initiated delayed. known or suspected acquired autoim- within 4 to 8 hours of presentation • they are helpful if the patient has a mune TTP, PEX is indicated before test and as soon as possible in life-threat- poor response to initial therapy with results are reported because the treat- ening cases. PEX should continue PEX. ment effectively removes the autoim- daily for a minimum of 2 days after • they are indicated for patients whose mune antibody ADAMTS13 inhibitor the platelet count has been increased platelet counts do not increase with and proinflammatory cytokines and to greater than 150,000/mcL.18,22 In several days of PEX or whose throm- replenishes the deficient active AD- refractory disease, a twice-daily PEX bocytopenia recurs as PEX is decreased. AMTS13. The UHvWF molecules should be considered. Recent data demonstrate the revert to the size found in normal Of note, platelet transfusion is efficacy of glucocorticoid administra- plasma when patients are treated with contraindicated in acquired autoim- tion as an adjunct to PEX therapy to PEX. Clinical improvement typically mune TTP because of the potential efficiently suppress the production of occurs within 3 to 5 days following presence of antibodies causing exten- ADAMTS13 autoantibodies, which initiation of PEX.2,9,20,21 sive thrombus formation. Antiplatelet supports its routine use as an adjunct If left untreated, acquired auto- therapy and splenectomy are ineffec- to PEX in the acute treatment of immune TTP is progressive, with tive and not recommended.2,18 acquired autoimmune TTP.23 Rituximab is currently recommended in the British Society for Haematol- Testing for TTP2,5,6,17-19 ogy guidelines as an alternative to Test Normal range Findings in TTP immunoglobulin for refractory or re- current TTP. Rituximab is a monoclo- Peripheral Hemoglobin, 13.5 to 17.5 g/ Hemolytic anemia with he- smear dL; hematocrit 41% to 53%; moglobin and hematocrit nal antibody with action against CD19 schistocytes and reticulocytes, lower than normal levels; and CD20 B cells that suppresses au- 0.5% to 1.5% multiple schistocytes and toantibody production. Rituximab has reticulocytes present been shown to improve mortality as- Haptoglobin 34 to 200 mg/dL Haptoglobin levels lower sociated with TTP. Anecdotal reports than normal due to loss of and small studies involving a total of RBCs and free hemoglobin 42 patients have been published on molecules the use of rituximab for TTP; com- Direct bilirubin Less than 0.3 mg/dL Elevated from destruction of plete remission occurred in 90% of RBCs cases. Despite the small study size, Total bilirubin 0.1 to 1.2 mg/dL Elevated from destruction of investigators found significantly im- RBCs proved relapse-free survival rates with rituximab treatment. However, there Lactate 140 U/L to 280 U/L Elevated from destruction of is also evidence to support immediate dehydrogenase (LD) RBCs use of rituximab in acute TTP to re- Platelet count 130,000/mcL to Significantly lower than nor- duce exacerbation, refractoriness, 400,000/mcL mal, typically in the 20,000/ number of PEX sessions, and possibly mcL to 30,000/mcL range length of hospital stay.2,12,15,17 When

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Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved. the diagnosis is confirmed to be acquired autoimmune TTP, rituximab Microangiopathies associated with TTP can be used in the treatment of relapsed or refractory TTP. Because A: Coronal section through the brain at autopsy showing multiple small hemor- up to 50% of patients are refractory rhages (arrows). B: Histologic section from the same patient shows diffuse microvascular occlusion of arterioles and capillaries. C: Blood smear from the or unresponsive to first-line PEX same patient displays the microangiopathic picture with RBC fragments and therapy, rituximab may stop the au- profound thrombocytopenia. toantibody production by destroying ADAMTS13-specific B cells.2,12

Outcomes For individuals with acquired autoimmune TTP, there is a significant association between the severity of acute kidney injury (AKI) and the risk of death, with greater risk among patients with more severe AKI. Al- though severe AKI is un common, AKI at the time of an acute episode of TTP may be a significant contributor to long-term risks for hypertension and premature death.20 A major challenge faced by patients with acquired autoimmune TTP is the unpredictable risk of relapse, usually occurring 1 or 2 years after the first episode. In patients with low ADAMTS13 activity, the use of rituximab can reduce the risk of relapse; however, some patients experience a relapse 20 years after the initial occurrence. Long-term administration of rituximab can cause serious sequelae, such as infusion Source: Image courtesy of Dr. J. Bilbao. In: Weksler BB, Schechter GP, Ely S. Wintrobe’s Atlas of Clinical Hematol- reactions, hepatitis B reactivation, ogy. 2nd ed. Philadelphia, PA: Wolters Kluwer; 2018. pulmonary fibrosis, and progressive multifocal leukoencephalopathy, and to obtain blood specimens for nosis and treatment, if necessary, these risks must be considered ADAMTS13 activity, complete consider rapidly transferring the against the benefit.2,5,6,8,11,15,17 blood count (CBC) including plate- patient to a facility prepared to mea- let count, and vWF activity. Serum sure ADAMTS13 and ADAMTS13 Nursing considerations bilirubin, LD, and creatinine, as well antibody levels and administer PEX Nurses need to be aware of the as a urinalysis, are typically per- therapy. If treatment with PEX is urgency to provide appropriate tar- formed to evaluate the function of planned, be prepared to assist with geted treatment, especially because vital organs. If necessary, imaging placement of large-bore dual-lumen they may be the first healthcare pro- studies to determine organ damage apheresis or PEX catheters following fessional to encounter a patient with may also be performed.16,24 facility policy, which typically in- known or suspected acquired auto- Be prepared to assist with immedi- cludes a preprocedure time out or immune TTP. ate PEX therapy because the mortal- safety pause and adherence to a cen- Perform a thorough physical as- ity without treatment is around 80%, tral venous catheter (CVC) place- sessment including a focus on neu- and with treatment, including PEX, ment checklist. Following confirma- rologic, cardiac, pulmonary, and the survival rate is around 90%.16,24 tion of correct placement of the CVC kidney functions, as well as skin Because of the potential high mor- and after PEX is initiated, monitor color and condition. Be prepared tality associated with delay in diag- for signs and symptoms of potential www.Nursing2019.com January l Nursing2019 l 27

Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved. complications associated with renal replacement therapy is rare, patient’s CBC and LD should be per- PEX, including fluid overload from although mild renal impairment may formed. If the platelet count drops or plasma infusion, potential allergic persist for weeks to months.16,24 LD starts to rise, another course of reactions, thrombosis of the CVC, Relapse is possible after effective PEX should be considered. If the pa- and local or systemic catheter- treatment with PEX; to decrease the tient remains stable for a month, the associated infection. incidence of relapse, some investigators recommended frequency of follow- During PEX therapy, hypotension have advocated the use of rituximab up is decreased. The relapse rate is requiring rapid nursing assessment as routine initial treatment together reported as 13% to 36%, and recur- and intervention to stabilize BP may with PEX and corticosteroids.10 rences have been reported after many be necessary. Monitor for signs and Over the past 20 years, the diagno- years in remission. The National symptoms of hypocalcemia such as sis of acquired autoimmune TTP has Heart, Lung, and Blood Institute paresthesias related to the antico- become more accurate and treatment website, www.nhlbi.nih.gov, is a use- agulant sodium citrate used in the has become more effective. Treatment ful resource for more information.16 procedure, because it can bind and of acute episodes of acquired autoim- lower ionized and possibly total cal- mune TTP may become even more Future directions cium requiring intervention to nor- effective with increasing use of cortico- A clinical trial (ClinicalTrials.gov malize serum calcium levels.16,24,25 steroids, rituximab, and the addition Identifier: NCT01554514) is under- Be prepared to administer immu- of new agents, such as caplacizumab way and will study the efficacy of nosuppressants, including corticoste- and recombinant ADAMTS13. With low-dose rituximab administered roids and rituximab, both of which more effective treatments, the need for once per week for 4 weeks, along are standard treatment options in PEX and the risks of death and com- with PEX therapy, to patients with acquired autoimmune TTP, in addi- plications from PEX may decrease.26 severe ADAMTS13 deficiency.17 Re- tion to monitoring for possible ad- Be prepared to educate patients cently, the Study to Assess Efficacy verse reactions such as infection.16,24 and families about long-term man- and Safety of Anti–von Willebrand Although clinical improvement is agement of acquired autoimmune Factor Nanobody in Patients With expected, persistent neurologic ab- TTP. Following successful treatment, Acquired Thrombotic Thrombocyto- normalities may be present after current recommendations are for the penic Purpura (TITAN) demonstrated otherwise successful treatment of patient to be reevaluated every week the efficacy of caplacizumab, an anti- acquired autoimmune TTP. Neuro- for 2 weeks and, if the patient re- vWF antibody.1 Caplacizumab is a logic deficits may result from stroke mains stable, every 2 weeks thereaf- humanized immunoglobulin nano- and may not be reversible. Persistent ter for a month. During this time, body that inhibits the interaction renal dysfunction possibly requiring weekly blood testing to monitor the between UHvWF and platelets. Daily subcutaneous injections of caplacizumab resulted in faster plate- Key points let recovery in acute TTP compared with a placebo when used along with • Symptoms of acquired autoimmune TTP are usually neurologic but can also be renal, cardiac, or GI. Thrombocytopenia and unexplained MAHA are sufficient to PEX. Caplacizumab is not a cure, but suspect TTP. by preventing the interaction between • Acquired autoimmune TTP is diagnosed with the ADAMTS13 assay. In the ap- UHvWF and platelets, it causes rapid propriate clinical setting, an ADAMTS13 activity level lower than 10% is highly reversal of the underlying pathologic indicative of TTP. mechanism, resulting in a potential to • As soon as it is suspected, acquired autoimmune TTP should be treated with reduce early mortality. The fact that daily PEX until a definitive diagnosis is determined, without waiting for ADAMTS13 platelet normalization occurred sig- test results. Any delay in referring the patient for therapeutic PEX is potentially fatal. nificantly faster with caplacizumab, If additional treatment is indicated, as in patients with relapsing or refractory TTP, even in some patients who had not rituximab administration should be considered. An appropriate strategy is to ini- yet had PEX therapy, has potential tially add a glucocorticoid to PEX therapy and withdraw it after several days if it is clinical significance. Caplacizumab determined that it is not needed. has the potential to change TTP • PEX has been shown in clinical trials to be superior to plasma infusion in normal- treatment strategy. The drug is izing platelet counts and reducing mortality. Antiplatelet therapy, platelet transfu- being studied further in a phase III sions, and splenectomy are ineffective and not recommended. Investigators clinical trial.12,15,17,19 found significantly improved relapse-free survival rates associated with rituximab Bortezomib, a proteasome inhibi- and complete remission occurred in 90% of cases.3,8,15 tor, that suppresses production of

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Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved. autoantibodies is another promising 8. Rogers HJ, Allen C, Lichtin AE. Thrombotic purpura without plasma exchange: the Jehovah’s adjunct to PEX in the treatment of thrombocytopenic purpura: the role of ADAMTS13. Witness experience. Blood Adv. 2017;1(24):2161-2165. Cleve Clin J Med. 2016;83(8):597-603. 20. Little DJ, Mathias LM, Page EE, Kremer refractory or relapsed TTP for patients 9. Shen YM. Clinical evaluation of thrombotic Hovinga JA, Vesely SK, George JN. Long-term refractory to rituximab.2,12,15,17,19 microangiopathy: identification of patients with kidney outcomes in patients with acquired suspected atypical hemolytic uremic syndrome. thrombotic thrombocytopenic purpura. Another new TTP drug, which is still Thromb J. 2016;14(suppl 1):19. Kidney Int Rep. 2017;2(6):1088-1095. unnamed and under investigation, is 10. Page EE, Kremer Hovinga JA, Terrell DR, Vesely 21. Abeysundara PK, Athukorala I, Dalpatadu focused on replacing the deficient SK, George JN. Clinical importance of ADAMTS13 KPC, Balendran K, Dilrukshi MDSA, Fernando activity during remission in patients with acquired G. Rare presentation of refractory thrombotic ADAMTS13 with a recombinant thrombotic thrombocytopenic purpura. Blood. thrombocytopenic purpura: jejunal stricture. Int J molecule and blocking antibody 2016;128(17):2175-2178. Hematol Oncol Stem Cell Res. 2017;11(4):293-295. production.8 New and developing 11. King J, de la Cruz J, Lutzky J. Ipilimumab- 22. Blombery P, Scully M. Management of induced thrombotic thrombocytopenic purpura thrombotic thrombocytopenic purpura: current strategies to treat TTP may become (TTP). J Immunother Cancer. 2017;5:19. perspectives. J Blood Med. 2014;5:15-23. 8,15 the future standard of care. ■ 12. Nagalla S, Sarode R. Recent advances in 23. Cataland SR, Kourlas PJ, Yang S, et al. understanding and management of acquired Cyclosporine or steroids as an adjunct to plasma thrombocytopenia. F1000Res. 2018;7:68. exchange in the treatment of immune-mediated REFERENCES 13. Riva S, Oliveri S, Fioretti C, Masiero M, thrombotic thrombocytopenic purpura. Blood Adv. 1. Kaushansky K. Blood’s 70th anniversary: the Pravettoni G. The role of frontal-subcortical 2017;1(23):2075-2082. elusive von Willebrand factor-cleaving protease. circuitry in neuropsychological deficit of attention: 24. Wun T, Nagalla S. Thrombotic thrombo- Blood. 2016;127(18):2163-2164. hypothesis and results in two coagulation cytopenic purpura (TTP) follow-up. Medscape. disorders. Front Hum Neurosci. 2016;10:89. 2. Nuñez Zuno JA, Bhimji SS. Thrombotic 2017. https://emedicine.medscape.com/article/ thrombocytopenic purpura. In: StatPearls [Internet]. 14. Mayo Clinic. Thrombocytopenia (low platelet 206598-followup. Treasure Island, FL: StatPearls Publishing; 2017. count). 2018. www.mayoclinic.org/diseases- 25. Kaplan AA. Therapeutic apheresis (plasma conditions/thrombocytopenia/diagnosistreatment/ 3. Wongrakpanich S, Salahuddin M, Mittar P. An exchange or cytapheresis): complications. UpToDate. drc-20378298. abnormal peripheral blood smear and altered mental 2017. www.uptodate.com. status. Cleve Clin J Med. 2016;83(9):643-644. 15. Appel GB. Thrombotic microangiopathies: 26. Page EE, Kremer Hovinga JA, Terrell DR, Vesely similar presentations, different therapies. Cleve Clin 4. George JN, Cuker A. Acquired TTP: clinical SK, George JN. Thrombotic thrombocytopenic J Med. 2017;84(2):114-130. manifestations and diagnosis. UpToDate. 2018. purpura: diagnostic criteria, clinical features, and www.uptodate.com. 16. DoveMed. Thrombotic thrombocytopenic long-term outcomes from 1995 through 2015. purpura. 2018. www.dovemed.com/diseases Blood Adv. 2017;1(10):590-600. 5. Pandey RK, Dahal S, Fadlalla KFEJ, Bhagat S, conditions/thrombotic-thrombocytopenicpurpura. Bhattarai B. Acquired thrombotic thrombocytopenic purpura in a patient with pernicious anemia. 17. Nakao H, Ishiguro A, Ikoma N, et al. Acquired Vincent M. Vacca, Jr., is an adjunct faculty member Case Rep Hematol. 2017;2017:1923607. idiopathic thrombotic thrombocytopenic at Massachusetts College of Pharmacy and Health purpura successfully treated with intravenous Sciences in Boston, Mass. 6. Sasapu A, Cottler-Fox M, Motwani P. Acquired immunoglobulin and glucocorticoid: a case report. thrombotic thrombocytopenic purpura and Medicine (Baltimore). 2017;96(14):e6547. The author and planners have disclosed no potential atypical hemolytic uremic syndrome successfully conflicts of interest, financial or otherwise. treated with eculizumab. Proc (Bayl Univ Med 18. Birkhoelzer S, Belcher A, Peet H. 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INSTRUCTIONS Acquired autoimmune thrombotic thrombocytopenic purpura

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