Good practice statements (GPS) for the clinical care of patients with thrombotic thrombocytopenic purpura
2020; Elsevier BV; Volume: 18; Issue: 10 Linguagem: Inglês
10.1111/jth.15009
ISSN1538-7933
AutoresX. Long Zheng, Sara K. Vesely, Spero R. Cataland, Paul Coppo, Brian Geldziler, Alfonso Iorio, Masanori Matsumoto, Reem A. Mustafa, Menaka Pai, Gail Rock, Lene Russell, Rawan Tarawneh, Julie Valdes, Flora Peyvandi,
Tópico(s)Platelet Disorders and Treatments
ResumoUpon setting the Population, Intervention, Comparison, and Outcome questions for the guidelines, the panel identified a number of topics that might be well suited to non‐Grading of Recommendations Assessment, Development, and Evaluation Good Practice Statements (GPSs). The McMaster team drafted an initial set of statements for distribution to the panelists before our second in‐person meeting. The panelists reviewed the statements for relevance and accuracy. The GPSs were then revised based on feedbacks that were redistributed to the panelists for further revisions and finalization. The Guidelines panel discussed a number of additional considerations to support good clinical care of patients with thrombotic thrombocytopenic purpura (TTP). The "GPSs" are not evidence‐based recommendations. Specifically, they are not based on systematic search or formal review of the evidence. These statements are intended to provide a "snapshot" of the care provided to patients with TTP by expert health care providers. They address scenarios in which there is very limited high‐certainty evidence, yet there is a body of indirect evidence and/or clinical experience that suggests the net benefit of certain actions. GPSs are intended to guide health care providers who have limited experience in treating TTP. They should be used with caution; the provider's own clinical judgment, in combination with the individual patient's clinical situation, values, and preferences, should all be considered. The following statements pertain to initial emergency care and general supportive care of patients with TTP. Clinicians generally consider a diagnosis of TTP in individuals presenting with thrombocytopenia and microangiopathic hemolytic anemia.1.Rock G.A. Shumak K.H. Buskard N.A. et al.Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. Canadian Apheresis Study Group.N Engl J Med. 1991; 325: 393-397Crossref PubMed Scopus (1541) Google Scholar, 2.Bell W.R. Braine H.G. Ness P.M. Kickler T.S. Improved Improved survival in thrombotic thrombocytopenic purpura‐hemolytic uremic syndrome. Clinical experience in 108 patients.N Engl J Med. 1991; 325: 398-403Crossref PubMed Scopus (713) Google Scholar, 3.Zheng X.L. Kaufman R.M. Goodnough L.T. Sadler J.E. Effect of plasma exchange on plasma ADAMTS13 metalloprotease activity, inhibitor level, and clinical outcome in patients with idiopathic and nonidiopathic thrombotic thrombocytopenic purpura.Blood. 2004; 103: 4043-4049Crossref PubMed Scopus (382) Google Scholar, 4.Joly B.S. Coppo P. Veyradier A. Thrombotic thrombocytopenic purpura.Blood. 2017; 129: 2836-2846Crossref PubMed Scopus (314) Google Scholar Patients may be critically ill, or may have relatively minor and nonspecific complaints. Importantly, the classic signs of TTP (eg, hemolytic anemia, thrombocytopenia, fever, neurologic abnormalities, and renal abnormalities) also known as "Raynaud's Pentad" are present in only 40% of patients; therefore, the historical pentad only are only seen in the more severe forms of the disease, or in patients left without appropriate treatment resulting from a delayed diagnosis. The prevalence of this catastrophic presentation has decreased in past few decades as the result of better awareness of the disease among practitioners.4.Joly B.S. Coppo P. Veyradier A. Thrombotic thrombocytopenic purpura.Blood. 2017; 129: 2836-2846Crossref PubMed Scopus (314) Google Scholar, 5.Staley E.M. Cao W. Pham H.P. et al.Clinical factors and biomarkers predict outcome in patients with immune‐mediated thrombotic thrombocytopenic purpura.Haematologica. 2019; 104: 166-175Crossref PubMed Scopus (35) Google Scholar, 6.Moake J.L. Thrombotic microangiopathies.N Engl J Med. 2002; 347: 589-600Crossref PubMed Scopus (1131) Google Scholar, 7.Scully M. Cataland S. Coppo P. et al.Consensus on the standardization of terminology in thrombotic thrombocytopenic purpura and related thrombotic microangiopathies.J Thromb Haemost. 2017; 15: 312-322Crossref PubMed Scopus (268) Google Scholar Therefore, the presence of thrombocytopenia and microangiopathic hemolytic anemia without other explanation should prompt a suspicion of TTP in the differential diagnosis.8.Saha M. McDaniel J.K. Zheng X.L. Thrombotic thrombocytopenic purpura: pathogenesis, diagnosis and potential novel therapeutics.J Thromb Haemost. 2017; 15: 1889-1900Crossref PubMed Scopus (80) Google Scholar We did not systematically search and review the evidence on different clinical or laboratory approaches for diagnostic workup of a patient with suspected TTP. However, an initial laboratory evaluation of presumptive TTP should include a complete blood count with careful review of a peripheral blood film for lack of platelets and presence of fragmented red blood cells (or schistocytes), serum lactate dehydrogenase, and creatinine, testing to demonstrate hemolysis (eg, low haptoglobin, increased indirect bilirubin), coagulation testing (which is expected to be relatively normal in TTP unless it is a severe form of the disease5.Staley E.M. Cao W. Pham H.P. et al.Clinical factors and biomarkers predict outcome in patients with immune‐mediated thrombotic thrombocytopenic purpura.Haematologica. 2019; 104: 166-175Crossref PubMed Scopus (35) Google Scholar and there is a concomitant disseminated intravascular coagulation).9.Wang Z. Yu Z. Su J. Cao L. Zhao X. Ruan C. Sepsis‐induced disseminated intravascular coagulation with features of thrombotic thrombocytopenic purpura: a fatal fulminant syndrome.Clin Appl Thromb Hemost. 2011; 17: 251-253Crossref PubMed Scopus (15) Google Scholar A direct Coombs test is expected to be negative in TTP, but may be positive in autoimmune hemolytic anemia. Troponin I and electrocardiogram should be systematically performed to identify subclinical cardiac involvement.5.Staley E.M. Cao W. Pham H.P. et al.Clinical factors and biomarkers predict outcome in patients with immune‐mediated thrombotic thrombocytopenic purpura.Haematologica. 2019; 104: 166-175Crossref PubMed Scopus (35) Google Scholar, 10.Brazelton J. Oster R.A. McCleskey B. Fuller J. Adamski J. Marques M.B. Increased troponin I is associated with fatal outcome in acquired thrombotic thrombocytopenic purpura.J Clin Apher. 2017; 32: 311-318Crossref PubMed Scopus (14) Google Scholar, 11.Hughes C. McEwan J.R. Longair I. et al.Cardiac involvement in acute thrombotic thrombocytopenic purpura: association with troponin T and IgG antibodies to ADAMTS 13.J Thromb Haemost. 2009; 7: 529-536Crossref PubMed Scopus (77) Google Scholar Computed tomography/magnetic resonance imaging of the brain may also be included in the initial evaluation for TTP if there are symptoms and signs, suggestive of brain injury.12.Rinkel G.J. Wijdicks E.F. Hene R.J. Stroke in relapsing thrombotic thrombocytopenic purpura.Stroke. 1991; 22: 1087-1089Crossref PubMed Google Scholar, 13.Downes K.A. Yomtovian R. Tsai H.M. Silver B. Rutherford C. Sarode R. Relapsed thrombotic thrombocytopenic purpura presenting as an acute cerebrovascular accident.J Clin Apher. 2004; 19: 86-89Crossref PubMed Scopus (43) Google Scholar, 14.Scheid R. Hegenbart U. Ballaschke O. Von Cramon D.Y. Major stroke in thrombotic‐thrombocytopenic purpura (Moschcowitz syndrome).Cerebrovasc Dis. 2004; 18: 83-85Crossref Scopus (15) Google Scholar, 15.Boattini M. Procaccianti G. Stroke due to typical thrombotic thrombocytopenic purpura treated successfully with intravenous thrombolysis and therapeutic plasma exchange.BMJ Case Rep. 2013; 2013Crossref Scopus (11) Google Scholar, 16.Peyvandi F. Scully M. Kremer Hovinga J.A. et al.Caplacizumab reduces the frequency of major thromboembolic events, exacerbations and death in patients with acquired thrombotic thrombocytopenic purpura.J Thromb Haemost. 2017; 15: 1448-1452Crossref PubMed Scopus (81) Google Scholar If the index of suspicion for TTP is high, clinicians should consider the emergency initiation of therapeutic plasma exchange (TPE) and corticosteroids. Because of the severity and instability of their illness, and the foundational role of TPE in the treatment of TTP, patients experiencing an acute event of TTP are usually urgently transferred to a facility that can perform TPE, ideally overseen by a clinician who has expertise in the management of TTP. Most of these patients (>95%) if plasma ADAMTS13 activity is less than 10 IU/dL (or 0.25 μg/L) appears to be associated with increased cardiac and cerebral involvement, ischemic stroke, and mortality in TTP,5.Staley E.M. Cao W. Pham H.P. et al.Clinical factors and biomarkers predict outcome in patients with immune‐mediated thrombotic thrombocytopenic purpura.Haematologica. 2019; 104: 166-175Crossref PubMed Scopus (35) Google Scholar although most patients with an increased level of cardiac troponin remain asymptomatic.5.Staley E.M. Cao W. Pham H.P. et al.Clinical factors and biomarkers predict outcome in patients with immune‐mediated thrombotic thrombocytopenic purpura.Haematologica. 2019; 104: 166-175Crossref PubMed Scopus (35) Google Scholar, 10.Brazelton J. Oster R.A. McCleskey B. Fuller J. Adamski J. Marques M.B. Increased troponin I is associated with fatal outcome in acquired thrombotic thrombocytopenic purpura.J Clin Apher. 2017; 32: 311-318Crossref PubMed Scopus (14) Google Scholar, 23.Benhamou Y. Boelle P.Y. Baudin B. et al.Cardiac troponin‐I on diagnosis predicts early death and refractoriness in acquired thrombotic thrombocytopenic purpura. Experience of the French Thrombotic Microangiopathies Reference.Center. J Thromb Haemost. 2015; 13: 293-302Crossref PubMed Scopus (90) Google Scholar, 24.Gandhi K. Aronow W.S. Desai H. et al.Cardiovascular manifestations in patients with thrombotic thrombocytopenic purpura: a single‐center experience.Clin Cardiol. 2010; 33: 213-216Crossref PubMed Scopus (32) Google Scholar TTP patients often need a central venous access secured urgently. Rapid placement of central venous access allows TPE to be initiated as soon as possible. The type of central venous access depends on the modality of TPE: centrifugal apheresis vs membrane filtration. Centrifugal apheresis involves lower blood flow rates, and enables the use of catheters with smaller diameters, and more flexible walls (such as peripheral catheters or standard triple lumen central venous catheters. Conversely, membrane filtration involves higher blood flow rates, which requires the use of larger diameter, stiffer catheters (such as standard dialysis catheters or single lumen central venous catheters).25.Spindler J.S. Subclavian vein catheterization for apheresis access.J Clin Apher. 1983; 1: 202-205Crossref Scopus (4) Google Scholar, 26.Haller W. Milford D.V. Goodship T.H. Sharif K. Mirza D.F. McKiernan P.J. Successful isolated liver transplantation in a child with atypical hemolytic uremic syndrome and a mutation in complement factor H.Am J Transplant. 2010; 10: 2142-2147Crossref PubMed Scopus (27) Google Scholar, 27.Kalantari K. The choice of vascular access for therapeutic apheresis.J Clin Apher. 2012; 27: 153-159Crossref PubMed Scopus (25) Google Scholar, 28.Golestaneh L. Mokrzycki M.H. Vascular access in therapeutic apheresis: update 2013.J Clin Apher. 2013; 28: 64-72Crossref PubMed Scopus (36) Google Scholar, 29.Tanhehco Y.C. Zantek N.D. Alsammak M. et al.Vascular access practices for therapeutic apheresis: results of a survey.J Clin Apher. 2019; 34: 571-578Crossref PubMed Scopus (10) Google Scholar Clinicians should be aware of, or consult the appropriate service for what modality of TPE is used at their center, so appropriate central venous access can be secured before initiation of TPE. The risk of catheter‐related complications such as bleeding, thrombosis, and sepsis are increased in patients with TTP.30.McClain R.S. Terrell D.R. Vesely S.K. George J.N. Plasma exchange complications in patients treated for thrombotic thrombocytopenia purpura‐hemolytic uremic syndrome: 2011 to 2014.Transfusion. 2014; 54: 3257-3259Crossref PubMed Scopus (14) Google Scholar We did not systematically search and review the evidence on strategies to reduce the risk of bleeding around catheter placement. Depending on local practice and resource availability, procedures to minimize the risk of bleeding may be considered, including placement by an experienced clinician, ultrasound‐guided placement, and internal jugular vein or femoral vein access (rather than subclavian vein access).31.Aouad M.T. Kanazi G.E. Abdallah F.W. et al.Femoral vein cannulation performed by residents: a comparison between ultrasound‐guided and landmark technique in infants and children undergoing cardiac surgery.Anesth Analg. 2010; 111: 724-728Crossref PubMed Scopus (70) Google Scholar, 32.Brass P. Hellmich M. Kolodziej L. Schick G. Smith A.F. Ultrasound guidance versus anatomical landmarks for subclavian or femoral vein catheterization.Cochrane Database Syst Rev. 2015; 1Google Scholar, 33.Benhamou Y. Baudel J.L. Wynckel A. et al.Are platelet transfusions harmful in acquired thrombotic thrombocytopenic purpura at the acute phase? Experience of the French thrombotic microangiopathies reference center.Am J Hematol. 2015; 90: E127-E129Crossref PubMed Scopus (28) Google Scholar Once the platelet count increases and the patient is stable, clinicians usually regularly review whether lines need to be changed and whether venous thromboembolism prophylaxis should be considered. We did not systematically search and review the evidence on the beneficial or harmful effects of platelet transfusions in TTP. Platelet transfusions are usually avoided and considered unnecessary in most cases of TTP. However, platelet transfusion is often carried out before a correct diagnosis of TTP has been made. There are case reports in TTP patients of the association between platelet transfusions and arterial thrombosis, clinical deterioration, and increased relapse rate.33.Benhamou Y. Baudel J.L. Wynckel A. et al.Are platelet transfusions harmful in acquired thrombotic thrombocytopenic purpura at the acute phase? Experience of the French thrombotic microangiopathies reference center.Am J Hematol. 2015; 90: E127-E129Crossref PubMed Scopus (28) Google Scholar, 34.Goel R. King K.E. Takemoto C.M. Ness P.M. Tobian A.A. Prognostic risk‐stratified score for predicting mortality in hospitalized patients with thrombotic thrombocytopenic purpura: nationally representative data from 2007 to 2012.Transfusion. 2016; 56: 1451-1458Crossref PubMed Scopus (30) Google Scholar, 35.Swisher K.K. Terrell D.R. Vesely S.K. Kremer Hovinga J.A. Lammle B. George J.N. Clinical outcomes after platelet transfusions in patients with thrombotic thrombocytopenic purpura.Transfusion. 2009; 49: 873-887Crossref PubMed Scopus (89) Google Scholar However, the causative role of platelet transfusion is not clear. In general, prophylactic platelet transfusions are avoided in nonbleeding TTP patients because their effect is not clear and they carry the potential risk of adverse events, especially when transfusions are repeated. However, platelet transfusions are sometimes used in TTP patients with serious bleedings, or in TTP patients undergoing invasive procedures with a high risk of bleeding.35.Swisher K.K. Terrell D.R. Vesely S.K. Kremer Hovinga J.A. Lammle B. George J.N. Clinical outcomes after platelet transfusions in patients with thrombotic thrombocytopenic purpura.Transfusion. 2009; 49: 873-887Crossref PubMed Scopus (89) Google Scholar However, whether platelet transfusion should be performed before central line placement depends on the experience of the individual placing the line and the patient's overall bleeding risk. Based on indirect evidence in other critically ill patients, patients with TTP usually receive venous thromboembolism (VTE) prophylaxis. Nonpharmacologic VTE prophylaxis (ie, ambulation as tolerated, graduated compression stockings, intermittent pneumatic compression devices) is usually used while the platelet count is 50 × 109/L, pharmacologic VTE prophylaxis such as low molecular weight heparin should be considered. We did not systematically search and review the evidence on long‐term complications of TTP. In patients that have recovered from an acute TTP episode, the panel acknowledged the importance of monitoring for the development of mood disorders, neurocognitive symptoms (including short‐term memory issues), and hypertension, which may develop during remission. Specific recommendations regarding screening for long‐term complications cannot be made at this time, but serial follow‐up and monitoring for these complications should be considered part of routine follow‐up. We did not systematically search and review the evidence on the role of support groups for TTP patients. Health care providers may consider offering patients with TTP professional online resources and/or support groups for this rare disease. A number of established support groups exist for individuals with TTP who are going through or have gone through similar experiences. These are listed in Table 1.Table 1A list of TTP professional online resources and/or support groupGroup nameRegion/CountryWebsiteAnswering TTPCanadahttps://www.answeringttp.org/Association ADAMTS13Francehttps://www.orpha.net/consor/cgi‐bin/OC_Exp.php?lng=FR&Expert=96406Associazione Nazionale Porpora Trombotica Trombocitopenica (ANPTT)Italyhttp://www.anptt.org/Japanese group for cTTP patientsJapanhttps://www.facebook.com/uss.ttp/Oklahoma TTP‐HUS Support Group MeetingsOklahoma, USAhttps://ouhsc.edu/platelets/TTP/pt%20group%20meetings.htmlThe Rhee Wynn FoundationNew Jersey, USAhttps://www.reewynn.org/ Open table in a new tab In this section, the panel provides statements pertaining to the relapse prevention beyond what has provided in Recommendations 3‐5. We did not systematically review the evidence on triggers for relapse. However, a number of potential triggers for relapse have been suggested in patients with TTP who have achieved clinical remission.17.Furlan M. Lammle B. Aetiology and pathogenesis of thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome: the role of von Willebrand factor‐cleaving protease.Best Pract Res Clin Haematol. 2001; 14: 437-454Crossref PubMed Scopus (230) Google Scholar, 36.Cserti C.M. Landaw S. Uhl L. Do infections provoke exacerbations and relapses of thrombotic thrombocytopenic purpura?.J Clin Apher. 2007; 22: 21-25Crossref PubMed Scopus (33) Google Scholar, 37.Kremer Hovinga J.A. Vesely S.K. Terrell D.R. Lammle B. George J.N. Survival and relapse in patients with thrombotic thrombocytopenic purpura.Blood. 2010; 115: 1500-1511Crossref PubMed Scopus (417) Google Scholar Any illness or a special health condition can trigger a relapse; however, the most commonly discussed triggers include:•Infections, including influenza, community‐acquired pneumonia, periodontal and dental infections, and gastroenteritis•Pregnancy•Major trauma or surgery•Intake of oral contraceptives•Cocaine and other recreational drugs•Intake of other drugs including quinine, ticlopidine, clopidogrel, check point inhibitors, cyclosporine, and tacrolimus, etc.•Pancreatitis Clinicians usually counsel patients on triggers for relapse and encourage them to seek medical attention for concerning signs and symptoms of any illness. We did not systematically search and review the evidence on the role of ADAMTS13 monitoring in TTP patients in remission. Patients in remission are usually assessed regularly during follow‐up (typically every month for the first 3 months, then every 3 months for the first year, then every 6‐12 months if stable). If available, ADAMTS13 activity is usually measured serially during each follow‐up assessment, and more frequently if levels begin to drop. Durably stable ADAMTS13 activity close to the lower limit of normal is usually a reassuring finding. Conversely, patients with persistently low ADAMTS13 activity (<10 IU/dL or 10% of normal) may be at risk for relapse, which may be prevented by administration of rituximab.38.Westwood J.P. Thomas M. Alwan F. et al.Rituximab prophylaxis to prevent thrombotic thrombocytopenic purpura relapse: outcome and evaluation of dosing regimens.Blood Adv. 2017; 1: 1159-1166Crossref PubMed Scopus (63) Google Scholar, 39.Jayabose S. Dunbar J. Nowicki T.S. Tugal O. Ozkaynak M.F. Sandoval C. Rituximab therapy to prevent relapse in chronic relapsing thrombotic thrombocytopenic purpura (TTP) in a child.Pediatr Hematol Oncol. 2011; 28: 167-172Crossref Scopus (17) Google Scholar The following nine statements pertain to the use of TTP treatment strategies that fall outside of the panel's prespecified Population, Intervention, Comparison, Outcome questions. We did not systematically search and review the evidence on vincristine for TTP patients. Patients with refractory TTP unresponsive to standard treatments may be considered for other immunosuppressive treatments (with scant supporting evidence), such as vincristine.40.Ferrara F. Annunziata M. Pollio F. et al.Vincristine as treatment for recurrent episodes of thrombotic thrombocytopenic purpura.Ann Hematol. 2002; 81: 7-10Crossref Scopus (28) Google Scholar, 41.Ferrara F. Copia C. Annunziata M. et al.Vincristine as salvage treatment for refractory thrombotic thrombocytopenic purpura.Ann Hematol. 1999; 78: 521-523Crossref PubMed Scopus (34) Google Scholar, 42.Bobbio‐Pallavicini E. Porta C. Centurioni R. et al.Vincristine sulfate for the treatment of thrombotic thrombocytopenic purpura refractory to plasma‐exchange. The Italian Cooperative Group for TTP.Eur J Haematol. 1994; 52: 222-226Crossref PubMed Scopus (62) Google Scholar, 43.Durand J.M. Lefevre P. Kaplanski G. Telle H. Soubeyrand J. Vincristine for thrombotic thrombocytopenic purpura.Lancet. 1992; 340: 977-978Abstract PubMed Scopus (19) Google Scholar In these cases, vincristine (2 mg) is usually administered intravenously, at a slow rate of infusion. Typically, a single dose is used because additional doses can cause neurotoxicity and bone marrow suppression.44.Matsumoto M. Fujimura Y. Wada H. et al.Diagnostic and treatment guidelines for thrombotic thrombocytopenic purpura (TTP) 2017 in Japan.Int J Hematol. 2017; 106: 3-15Crossref PubMed Scopus (57) Google Scholar We did not systematically search and review the evidence on cyclosporine A for TTP patients. Patients with refractory TTP unresponsive to standard treatments may be considered for other immunosuppressive treatments (with scant supporting evidence), such as cyclosporine A. In these cases, cyclosporine A is usually administered orally (300 mg/day) or intravenously (2‐3 mg/kg/day, divided twice daily). The appropriate duration of therapy is unknown, although administration of this drug for several months, followed by tapering, has been reported.45.Cataland S.R. Kourlas P.J. Yang S. et al.Cyclosporine or steroids as an adjunct to plasma exchange in the treatment of immune‐mediated thrombotic thrombocytopenic purpura.Blood Adv. 2017; 1: 2075-2082Crossref PubMed Scopus (42) Google Scholar, 46.Yilmaz M. Eskazan A.E. Unsal A. et al.Cyclosporin A therapy on idiopathic thrombotic thrombocytopenic purpura in the relapse setting: two case reports and a review of the literature.Transfusion. 2013; 53: 1586-1593Crossref Scopus (14) Google Scholar, 47.Nosari A. Redaelli R. Caimi T.M. Mostarda G. Morra E. Cyclosporine therapy in refractory/relapsed patients with thrombotic thrombocytopenic purpura.Am J Hematol. 2009; 84: 313-314Crossref Scopus (22) Google Scholar, 48.Cataland S.R. Jin M. Lin S. et al.Cyclosporin and plasma exchange in thrombotic thrombocytopenic purpura: long‐term follow‐up with serial analysis of ADAMTS13 activity.Br J Haematol. 2007; 139: 486-493Crossref PubMed Scopus (54) Google Scholar, 49.Enami T. Suzuki T. Ito S. et al.Successful treatment of refractory thrombotic thrombocytopenic purpura with cyclosporine and corticosteroids in a patient with systemic lupus erythematosus and antibodies to ADAMTS13.Intern Med. 2007; 46: 1033-1037Crossref Scopus (12) Google Scholar, 50.Cataland S.R. Jin M. Ferketich A.K. et al.An evaluation of cyclosporin and corticosteroids individually as adjuncts to plasma exchange in the treatment of thrombotic thrombocytopenic purpura.Br J Haematol. 2007; 136: 146-149Crossref PubMed Scopus (66) Google Scholar, 51.Zheng X. Pallera A.M. Goodnough L.T. Sadler J.E. Blinder M.A. Remission of chronic thrombotic thrombocytopenic purpura after treatment with cyclophosphamide and rituximab.Ann Intern Med. 2003; 138: 105-108Crossref PubMed Scopus (128) Google Scholar We did not systematically search and review the evidence on cyclophosphamide for TTP patients. Patients with refractory TTP unresponsive to standard treatments may be considered for other immunosuppressive treatments (with scant supporting evidence), such as cyclophosphamide. In these cases, cyclophosphamide (500 mg/day) is usually administered intravenously over a 2‐hour period. Typically, a single dose is used because additional doses may cause severe bone marrow suppression.8.Saha M. McDaniel J.K. Zheng X.L. Thrombotic thrombocytopenic purpura: pathogenesis, diagnosis and potential novel therapeutics.J Thromb Haemost. 2017; 15: 1889-1900Crossref PubMed Scopus (80) Google Scholar, 44.Matsumoto M. Fujimura Y. Wada H. et al.Diagnostic and treatment guidelines for thrombotic thrombocytopenic purpura (TTP) 2017 in Japan.Int J Hematol. 2017; 106: 3-15Crossref PubMed Scopus (57) Google Scholar, 51.Zheng X. Pallera A.M. Goodnough L.T. Sadler J.E. Blinder M.A. Remission of chronic thrombotic thrombocytopenic purpura after treatment with cyclophosphamide and rituximab.Ann Intern Med. 2003; 138: 105-108Crossref PubMed Scopus (128) Google Scholar, 52.Beloncle F. Buffet M. Coindre J.P. et al.Splenectomy and/or cyclophosphamide as salvage therapies in thrombotic thrombocytopenic purpura: the French TMA Reference Center experience.Transfusion. 2012; 52: 2436-2444Crossref PubMed Scopus (69) Google Scholar, 53.Lin T.Y. Chang C.C. Chang C.C. Yuan J.Y. Chen H.H. Cyclophosphamide‐rescued plasmapheresis‐unresponsive secondary thrombotic thrombocytopenic purpura caused by Sjogren's syndrome.Arch Med Sci. 2012; 8: 934-938Crossref Scopus (7) Google Scholar We did not systematically search and review the evide
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