Tools
Thrombotic Thrombocytopenic Purpura
Introduction
Thrombotic thrombocytopenic purpura (TTP) is a type of microangiopathic hemolytic anemia that classically has been characterized by the pentad of fever, thrombocytopenia, hemolytic anemia, renal dysfunction, and neurologic dysfunction. TTP results from either a congenital or acquired decrease/absence of the von Willebrand factor-cleaving protease ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif member 13). Low levels of ADAMTS13 result in microthrombi formation, which leads to end-organ ischemia and damage.[1][2][3] This is due to the inability of the ADAMTS13 to inactivate the large multimer von Willebrand factor (VWF) that is necessary to prevent spontaneous coagulation. Unchecked, the large multimers have a tremendous avidity to bind platelets and initiate thrombi formation. The central nervous system (CNS) and kidneys are the two most common organ systems affected by TTP. Timely diagnosis is very important because TTP is a medical emergency which, without treatment, has a mortality of about 90%.[4] About 80% of patients respond to initial treatment, and the post-treatment mortality is 10 to 15%.[5]
Etiology
Register For Free And Read The Full Article
Search engine and full access to all medical articles- 10 free questions in your specialty
- Free CME/CE Activities
- Free daily question in your email
- Save favorite articles to your dashboard
- Emails offering discounts
Learn more about a Subscription to StatPearls Point-of-Care
Etiology
TTP results from a decrease or absence of the enzyme ADAMTS13 activity. TTP can be either congenital or acquired. Acquired TTP is more common than the congenital type and is caused by autoantibodies targeting ADAMTS13. Antiplatelet drugs, immunosuppressive agents, HIV, estrogen-containing birth control, and pregnancy are the most commonly listed triggers for ADAMTS13 autoantibody formation causing acquired TTP. The less common congenital form of TTP results from mutations to ADAMTS13.[6][7] The deficiency of ADAMTS13 activity alone does not cause clinically apparent TTP. Individuals with hereditary ADAMTS13 deficiency remain asymptomatic until a triggering event such as an infection or pregnancy occurs.[8] Risk factors for the development of inhibitory autoantibodies to ADAMTS13 are not clearly defined.
Epidemiology
TTP is a rare disease; the exact prevalence is not clear. Studies cite incidences between 1 and 13 cases per million people depending on geographic location. TTP most often occurs after 40 years of age, but congenital forms can occur in children. TTP is more common in women with a 2:1 female to male predominance.[9]The mortality in TTP without treatment is 90%,[4] but this drops to a mortality of 10% to 15%[5] with proper treatment. TTP is very rare in children. Other factors associated with a higher risk of TTP include female sex, African American descent, and pregnancy.[10]
Pathophysiology
A deficiency of ADAMTS13 that is caused by gene mutations or acquired autoantibodies is central to the pathophysiology of TTP. TTP is defined by severely deficient activity of the ADAMTS13 protease to less than 10%.[10] ADAMTS13 is a plasma von Willebrand factor (VWF)-cleaving protease. It cleaves the ultra-large VWF multimer to a smaller-sized multimer. When ADAMTS13 activity is reduced, VWF multimers accumulate on the endothelial surface, causing platelet aggregation and eventual thrombi formation.[11] ADAMTS13 is synthesized in hepatic stellate cells and by endothelial cells and megakaryocytes.[11][12] The microthrombi cause ischemia, leading to end-organ damage, with the most commonly involved systems being the central nervous system (CNS) and kidneys. Thrombocytopenia results from platelet consumption during thrombus formation. Anemia results from hemolytic destruction of red blood cells as they pass through small vessels partially occluded by thrombi. The destruction of the erythrocytes causes a disruption of their morphology, best described as a structural shattering leading to the term "schistocytes."[13][14]
Histopathology
The histopathology of TTP and other thrombotic microangiopathies (TMAs) is characterized by small vessel changes with swelling of endothelial cells and the subendothelial space. There is vessel wall thickening, and platelet microthrombi are noted in small arterioles and capillaries obliterating the vessel lumen. Large-vessel thrombosis is not seen in TTP.[15] A 2006 study looking at autopsies of patients who had died secondary to an acute episode of TTP reported the presence of microvascular thrombi characteristic of TTP in almost all organs.[16] Bone marrow evaluation, if performed, typically reveals normal trilineage maturation. Increased thrombopoiesis and erythropoiesis may be noted secondary to increased consumption of platelets and red blood cells (RBCs) in the peripheral circulation.[17] The white blood cell (WBC) count is typically normal in TTP, and coagulation abnormalities are also uncommon.
History and Physical
In TTP, renal involvement is relatively rare when compared with other primary TMAs. Neurologic symptoms dominate the clinical picture of TTP[18] and include headache, focal neurologic deficits, seizures, confusion, and vertigo. The initial presentation includes fatigue, dyspnea, petechiae, or bleeding.[19] In patients with idiopathic TTP, neurologic complaints were noted to be the most common (44%), and the most common symptom was reported to be abdominal pain (23.5%). Less than 10% of patients reported bleeding secondary to thrombocytopenia as a presenting symptom.[19] As stated above, kidney involvement is uncommon and usually only seen on biopsy. Pulmonary involvement is also rare.[20] Patients with TTP can also have cardiac involvement, and an elevation of serum troponin in patients presenting with TTP is considered a bad prognostic sign. It was shown to be an independent factor associated with a three-fold increase in the risk of death or refractoriness to treatment in patients presenting with TTP.[21] Patients with TTP present with a myriad of signs and symptoms of varying severity, and there appears to be little uniformity in patients presenting with the disease. High clinical suspicion is required to adequately diagnose the patients. Multiple epidemiologic studies are used to define presenting signs and symptoms for TTP, with the Oklahoma Registry being the most frequently cited study.
Clinical Presentation According to the Oklahoma Registry[22]
- Gastrointestinal symptoms 69%
- Weakness 63%
- Bleeding or purpura 54%
- Major neurologic findings (coma, stroke, seizure, transient focal abnormalities) 41%
- Minor neurologic findings (headache, confusion) 26%
- Fever and chills 10%
- Classical pentad comprising of hemolytic anemia, thrombocytopenia, fever, acute kidney injury, and severe neurologic findings less than 5%
Evaluation
Laboratory evaluation plays a critically important role in diagnosing TTP because signs and symptoms are variable, and end-organ damage can be delayed. For diagnosis, the laboratory data must show anemia and thrombocytopenia along with an indication of active hemolysis, such as the presence of schistocytes, increased unconjugated bilirubin, increased reticulocyte count and increased lactate dehydrogenase.[23][24][25] As with any hemolysis in general, the serum haptoglobin decreases as it combines with the free hemoglobin released from the destroyed erythrocytes.
PLASMIC Score
The PLASMIC score is calculated using findings on presentation and predicts the likelihood of ADAMTS13 activity being less than or equal to 10% to help make a presumptive diagnosis of TTP in the appropriate clinical setting.[26] The presence of peripheral schistocytes is required to apply this score. One point is given for each of the following features:
- Platelet count less than 30,000/microL
- Presence of hemolysis (reticulocyte count greater than 2.5%, undetectable haptoglobin, or indirect bilirubin greater than 2 mg/dL)
- Mean corpuscular volume (MCV) less than 90 fL
- International normalized ratio (INR) of less than 1.5
- Creatinine less than 2.0 mg/dL
- Absence of cancer
- Absence of solid organ or stem cell transplant
The higher the score, the greater the likelihood of TTP, with a score of greater than 5 suggesting a high probability of TTP and a score lower than 5 suggesting a low probability of TTP. This score has been validated with a reported sensitivity of 99% and a specificity of 57%. Due to its high negative predictive value, it is recommended as a screening tool for patients who are unlikely to have TTP.[27]
ADAMTS13 activity assays report the activity of the protease as a percentage of normal. An activity level of less than 10% confirms the diagnosis of TTP in patients with evidence of hemolysis and thrombocytopenia. However, this assay is not specific for TTP, and levels less than 10% have been reported in cases of severe sepsis and systemic cancer.[28] A decrease of the ADAMTS13 activity to less than 20% after initial recovery from an acute episode is considered a relapse, even if thrombocytopenia and hemolysis are absent.
Evaluation of end-organ damage is completed by measuring serum troponin levels and obtaining a brain magnetic resonance imaging study.
Treatment / Management
The mainstay of treatment in TTP is plasma exchange (PEX) with high-dose corticosteroid therapy.[29] Corticosteroids operate by decreasing the activity of the reticuloendothelial system as well as decreasing autoantibody production. This should be initiated as soon as possible in all patients with unexplained hemolytic anemia and thrombocytopenia with a normal coagulation profile. Both the ultra-large VWF multimers and the ADAMTS13 autoantibodies are effectively removed from circulation by plasma exchange therapy. The recommended volume of exchange is one estimated plasma volume (usually 40 mL/kg of body weight) with each treatment. Plasma is used as the preferred fluid replacement during the treatment because it repletes ADAMTS13. The treatment should be provided once daily.[30] When remission is achieved, PEX can be stopped abruptly without any need for tapering. The generally recommended dose for corticosteroids is 1 mg/kg per day of prednisone in neurologically intact patients. In severely ill patients, intravenous methylprednisolone 1000 mg as a single daily dose for three days or 125 mg two to four times daily may be more appropriate.[29] Corticosteroids are continued as long as PEX is continued and subsequently tapered off based on clinical response. (B3)
Other treatments used include splenectomy, cyclosporine, cyclophosphamide, vincristine, and rituximab.[31][32][33] These are typically adjunctive agents given when first-line therapy (PEX and corticosteroids) fail. The addition of glucocorticoids and rituximab to PEX has been shown to decrease the required duration of therapeutic plasma exchange.[34] Splenectomy removes a major site of antibody production and complex assimilation. It is a major intervention with results that have been quoted as "variable" in terms of efficacy. Rituximab is an anti-CD20 monoclonal antibody found to help treat TTP refractory to PEX. It targets B-lymphocytes and has a good response rate in refractory and relapsed TTP. It has gained more favor than other nonspecific immunosuppressive agents. Vincristine, cyclophosphamide, and cyclosporine are immunosuppressive agents with less than exemplary efficacy. For this reason, they are usually given concurrently with other secondary therapies in refractory cases or when first-line therapy has failed.(B3)
A newer agent, caplacizumab, has a high potential for the treatment of TTP. It is a humanized monoclonal antibody fragment (a bivalent, variable-domain-only fragment) that attacks the A1 section of VWF and prevents platelet adhesion.[35] In recent clinical studies, caplacizumab has been shown to have a more rapid onset of action compared to most agents. With the use of this agent, deaths have been significantly decreased, and some experts do advocate its use as a frontline modality. It rapidly halts the formation of microthrombi in TTP. However, it does not reduce the production of the autoantibody against ADAMTS13. Caplacizumab is given as an initial intravenous dose followed by subcutaneous injections for 30 days after PEX has been stopped. This should coincide with an increase in ADAMTS13 activity to above 20%. Caplacizumab can increase the risk of bleeding, and clinically significant bleeding attributable to caplacizumab should warrant discontinuation of therapy and/or VWF concentrate infusion.[36]
Plasma infusion without exchange is not an adequate treatment for TTP. It can be used as a temporizing measure in patients who are unable to receive PEX immediately. This is supported by the data that plasma infusion has similar efficacy to PEX if equivalent volumes of plasma are administered.[37] However, this is not feasible in most cases, given the high volume of infusion required.(B2)
A packed red blood cell (PRBC) transfusion can be given if there is a clinical indication. Platelet transfusion is controversial but is considered to be contraindicated unless major bleeding is present.[38] Monitoring for response is essential to determine the duration of plasma exchange. Typically, hemolysis markers are checked daily. Plasma exchange usually is stopped once the platelet levels stabilize at above 150,000/microL for more than 48 hours.[39](B3)
2020 Treatment Guidelines by the International Society on Thrombosis and Hemostasis[29]
- For initial treatment of TTP, they gave a strong recommendation for the addition of corticosteroids to therapeutic plasma exchange (PEX) over PEX alone; however, they did not make any specific recommendation regarding a preferred dosage or type of corticosteroids.
- For patients with the first acute event, the panel suggested the addition of rituximab to corticosteroids and PEX. The primary documented effect of rituximab in patients with TTP is to prevent relapses, although they noted that the true benefit of rituximab might be masked by the fact that it has only been used in severe cases. They make a conditional recommendation for the use of this therapy based on practitioner judgment, especially if comorbid autoimmune disorders exist.
- For patients with relapsing TTP, the panel recommended PEX, corticosteroids, and rituximab as recommended for initial treatment, with the addition of caplacizumab.
- For patients with TTP who are in remission but still have low plasma ADAMTS13 activity without any evidence of clinical signs/symptoms, they recommended using rituximab for prophylaxis.
- For patients who are pregnant and have decreased plasma ADAMTS13 activity but have no clinical signs/symptoms of TTP, the panel recommended prophylactic treatment with plasma infusion products.
Differential Diagnosis
- Cancer-associated TMA; the majority are due to adenocarcinomas, particularly gastric, breast and prostate.[40]
- Disseminated intravascular coagulation; schistocytes are relatively uncommon, there are abnormal coagulation studies, and fibrinolysis is more common in DIC than TTP.[41][42]
- Haemopoietic transplant-associated TMA; can be due to the transplant regimen (e.g., TBI, tacrolimus), graft versus host disease, and infections.[43]
- Common ailments have also been known rarely to cause TTP.[44] Hypertension (malignant), pregnancy (HEELP), autoimmune disease (e.g., SLE), and vasculitis (e.g., scleroderma).
- Immune thrombocytopenia
- Infections; CMV, Streptococcus pneumonia, and HIV.[45]
- Drug-induced TMA.[46] This covers a wide field of drugs, including chemotherapy (e.g., mitomycin C, interferon, gemcitabine), antibiotics (e.g., trimethoprim, penicillin, rifampin), and cardiovascular medications, particularly clopidogrel.[47][48][49] The exact mechanism of clopidogrel-acquired TTP is unknown. Clinical data has shown that as many as 75% of patients with clopidogrel-TTP have normal ADAMTS13 levels. This finding lends some credence to the belief that there is a direct endothelial injury, followed by TMA, as the possible etiology. It is relatively uncommon, with 1 case per 20,000 patients treated with this medication. Clopidogrel is utilized for its antiplatelet effect in dealing with myocardial infarction with post-catheterization. It acts by disrupting the ADP binding sites (P2Y12 components) on platelets, thereby interfering with the binding of the large multimers with the platelet IIb/IIIa receptors. TTP occurs within the first two weeks of therapy, and skin reactions may be the only harbinger of this reaction. Discontinuation of the medication alone is insufficient to stop the process, and patients must be given plasma exchange (PEX) with concurrent steroids as the primary treatment with rituximab as second-line. The survival rate is upwards of 100% with PEX; however, the rate falls to 27% with a delay of diagnosis.
Prognosis
Without treatment, the mortality of thrombotic thrombocytopenic purpura is 90%.[4] Early treatment (with plasma exchange and corticosteroids) decreases the mortality to 15%.[5] The longer the patient waits for treatment, the more likely they are to have adverse outcomes. Early suspicion of the disease followed by administrations of plasma exchange/corticosteroids significantly reduces mortality. The primary cause of demise can occur with coronary thrombosis leading to an acute myocardial infarction, congestive heart failure, and sudden death.[50]
Complications
Plasma infusion should be used if plasma exchange is not readily available. Rigorous infusion of plasma can lead to congestive heart failure but, once plasma exchange is established, this issue can be addressed and reversed.[50]
Complications of PEX may be related to the central venous catheter placements and exposure to donor plasma. Transfusion-related acute lung injury (TRALI) can occur.[51] According to one study, mortality in patients with TTP due to complications of PEX was reported at 4.4%. These complications included pulmonary hemorrhage and central venous catheter-associated bloodstream infections.[22] Other nonlethal complications of PEX reported in the study included bacteremia, catheter-related venous thrombosis requiring systemic anticoagulation, and anaphylaxis. However, a significant decline in complications associated with PEX has been observed over a 15-year period of observation.[34] This is thought to be due to the use of multimodal adjunctive therapies that decrease the required frequency and duration of PEX.
Consultations
Thrombotic thrombocytopenic purpura (TTP) is a medical/hematologic emergency, and all TTP patients should be placed in an intensive care unit (ICU) setting. An internist can act as the operational hub, but if an intensivist is available, they should be used for tactical level management. Organ ischemia may develop into failure, and other specialties (e.g., renal) may need to be involved.[50]
Deterrence and Patient Education
An extended rehabilitation is likely dependent on the severity of the patient's organ ischemia and residual deficits. Patients should remain alert to the return of their thrombotic thrombocytopenic purpura signs and symptoms. Laboratory data should be monitored closely once the plasma exchange and corticosteroids have been tapered. Relapse, if it occurs, may resume quickly. Rituximab is available for secondary prevention in a select group of patients (as outlined above), and caplacizumab is also available as a prophylactic agent.[50]
Pearls and Other Issues
HUS and TTP are subsets within the general category of microangiopathic hemolytic anemia (MHA).[52] TTP and HUS do overlap in terms of their clinical manifestations. This 'overlap' extends to their manifestation of schistocytosis. Their primary difference is causation. Both diseases can manifest fever, thrombocytopenia, hemolysis, renal injury, and neurologic symptoms. Acute kidney injury in TTP is less frequent as compared to HUS. Whereas TTP is due to the paucity of ADAMTS13, HUS is a complement-mediated illness. The hereditary form requires complement mutation studies to diagnose, while the acquired form requires stool culture and PCR analysis for the Shiga toxin. This toxin is produced by Shigella bacteria and entero-toxin producing E. Coli 0157H7. The patient, usually a child, presents with colitis manifesting bloody diarrhea. The toxin binds to the endothelial walls of blood vessels leading to uncontrolled complement activation, vessel damage, and thrombosis with fibrosis. Blood cells are fractionated as they travel through these vessels leading to their formation as schistocytes. Treatment is supportive, with volume expansion as the mainstay of successful intervention. Antibiotics are of little help.
A difficult situation occurs where the patient presentation may initially overlap between TTP and HUS to such an extent that the clinician may be unclear as to the true problem. In this circumstance, since TTP carries the more immediate and higher mortality, it is better to place the patient initially on plasma exchange (PEX). If the patient has TTP, this would be most beneficial. PEX has been known to provide at least a modicum of relief in HUS, but if a response is not forthcoming, then the administration of eculizumab is recommended. This drug is a monoclonal antibody against the C5 of the C5-9 complement complex. It thereby obstructs complement-mediated MHA, and it can improve renal function.
Enhancing Healthcare Team Outcomes
TTP is a serious life-threatening disorder that is best managed by an interprofessional team that includes a nurse, hematologist, emergency department physician, nephrologist, neurologist, and internist. Recall that the results of diagnostic testing, like ADAMTS13, may be delayed, and therefore it is the clinical acumen of the healthcare team that can determine a patient's survival or demise. Failure to suspect TTP makes for delayed treatment and a moribund patient. It is recommended that TTP patients be admitted initially to the intensive care setting where close monitoring by critical care nursing and management by an intensivist and co-management by a hematologist would be ideal. Besides corticosteroids, these patients benefit primarily from plasmapheresis (PEX).
If PEX cannot be initiated in a timely manner, then plasma infusion should be performed. Hence, the role of the nurse as well as the apheresis team cannot be understated. Monitoring for response is essential to determine the duration of plasma exchange. Typically, hemolysis markers are checked daily. Plasma exchange usually is stopped once the platelet levels stabilize at above 150,000/microL for more than 48 hours. The prognosis of patients with TTP depends on age, neurological deficits, renal dysfunction, response to treatment, and other co-morbidities. Most patients will require a prolonged stay in the hospital as recovery is gradual.[53][54]
The apheresis team and clinical nurse are essential in monitoring the patient during treatment to ensure fluid overload and cardiac arrhythmias do not occur. Clinical pharmacists play the crucial role of monitoring patients for treatment side-effects and reconciling medications to prevent adverse outcomes. A well-coordinated interprofessional team can significantly improve outcomes for patients affected with this potentially lethal disease.[Level 5] For those patients with residual organ damage from the thrombogenesis, a stay at a rehabilitation center is in order.
References
Tanner L, Müller MM. [Blood Transfusion: a Guide to Clinical Decision Making]. Anasthesiologie, Intensivmedizin, Notfallmedizin, Schmerztherapie : AINS. 2019 Mar:54(3):194-205. doi: 10.1055/a-0593-4390. Epub 2019 Mar 13 [PubMed PMID: 30866023]
Coppo P, Cuker A, George JN. Thrombotic thrombocytopenic purpura: Toward targeted therapy and precision medicine. Research and practice in thrombosis and haemostasis. 2019 Jan:3(1):26-37. doi: 10.1002/rth2.12160. Epub 2018 Nov 16 [PubMed PMID: 30656273]
Wiernek SL, Jiang B, Gustafson GM, Dai X. Cardiac implications of thrombotic thrombocytopenic purpura. World journal of cardiology. 2018 Dec 26:10(12):254-266. doi: 10.4330/wjc.v10.i12.254. Epub [PubMed PMID: 30622684]
Cox EC. Thrombotic thrombocytopenic purpura: report of three additional cases and a short review of the literature. Journal of the South Carolina Medical Association (1975). 1966 Dec:62(12):465-70 [PubMed PMID: 5232420]
Level 3 (low-level) evidenceBell WR, Braine HG, Ness PM, Kickler TS. Improved survival in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Clinical experience in 108 patients. The New England journal of medicine. 1991 Aug 8:325(6):398-403 [PubMed PMID: 2062331]
Gavriilaki E, Anagnostopoulos A, Mastellos DC. Complement in Thrombotic Microangiopathies: Unraveling Ariadne's Thread Into the Labyrinth of Complement Therapeutics. Frontiers in immunology. 2019:10():337. doi: 10.3389/fimmu.2019.00337. Epub 2019 Feb 27 [PubMed PMID: 30891033]
Amin Asnafi A, Jalali MT, Pezeshki SMS, Jaseb K, Saki N. The Association Between Human Leukocyte Antigens and ITP, TTP, and HIT. Journal of pediatric hematology/oncology. 2019 Mar:41(2):81-86. doi: 10.1097/MPH.0000000000001381. Epub [PubMed PMID: 30543580]
van Dorland HA, Taleghani MM, Sakai K, Friedman KD, George JN, Hrachovinova I, Knöbl PN, von Krogh AS, Schneppenheim R, Aebi-Huber I, Bütikofer L, Largiadèr CR, Cermakova Z, Kokame K, Miyata T, Yagi H, Terrell DR, Vesely SK, Matsumoto M, Lämmle B, Fujimura Y, Kremer Hovinga JA, Hereditary TTP Registry. The International Hereditary Thrombotic Thrombocytopenic Purpura Registry: key findings at enrollment until 2017. Haematologica. 2019 Oct:104(10):2107-2115. doi: 10.3324/haematol.2019.216796. Epub 2019 Feb 21 [PubMed PMID: 30792199]
Swart L, Schapkaitz E, Mahlangu JN. Thrombotic thrombocytopenic purpura: A 5-year tertiary care centre experience. Journal of clinical apheresis. 2019 Feb:34(1):44-50. doi: 10.1002/jca.21673. Epub 2018 Dec 8 [PubMed PMID: 30536422]
Terrell DR, Vesely SK, Kremer Hovinga JA, Lämmle B, George JN. Different disparities of gender and race among the thrombotic thrombocytopenic purpura and hemolytic-uremic syndromes. American journal of hematology. 2010 Nov:85(11):844-7. doi: 10.1002/ajh.21833. Epub [PubMed PMID: 20799358]
Level 2 (mid-level) evidenceShelat SG, Ai J, Zheng XL. Molecular biology of ADAMTS13 and diagnostic utility of ADAMTS13 proteolytic activity and inhibitor assays. Seminars in thrombosis and hemostasis. 2005 Dec:31(6):659-72 [PubMed PMID: 16388417]
Zander CB, Cao W, Zheng XL. ADAMTS13 and von Willebrand factor interactions. Current opinion in hematology. 2015 Sep:22(5):452-9. doi: 10.1097/MOH.0000000000000169. Epub [PubMed PMID: 26186678]
Level 3 (low-level) evidenceChiasakul T, Cuker A. Clinical and laboratory diagnosis of TTP: an integrated approach. Hematology. American Society of Hematology. Education Program. 2018 Nov 30:2018(1):530-538. doi: 10.1182/asheducation-2018.1.530. Epub [PubMed PMID: 30504354]
Dane K, Chaturvedi S. Beyond plasma exchange: novel therapies for thrombotic thrombocytopenic purpura. Hematology. American Society of Hematology. Education Program. 2018 Nov 30:2018(1):539-547. doi: 10.1182/asheducation-2018.1.539. Epub [PubMed PMID: 30504355]
George JN, Nester CM. Syndromes of thrombotic microangiopathy. The New England journal of medicine. 2014 Aug 14:371(7):654-66. doi: 10.1056/NEJMra1312353. Epub [PubMed PMID: 25119611]
George JN. Clinical practice. Thrombotic thrombocytopenic purpura. The New England journal of medicine. 2006 May 4:354(18):1927-35 [PubMed PMID: 16672704]
George JN. Systemic malignancies as a cause of unexpected microangiopathic hemolytic anemia and thrombocytopenia. Oncology (Williston Park, N.Y.). 2011 Sep:25(10):908-14 [PubMed PMID: 22010388]
Ruggenenti P, Remuzzi G. Pathophysiology and management of thrombotic microangiopathies. Journal of nephrology. 1998 Nov-Dec:11(6):300-10 [PubMed PMID: 10048496]
Griffin D, Al-Nouri ZL, Muthurajah D, Ross JR, Ballard RB, Terrell DR, Vesely SK, George JN, Marques MB. First symptoms in patients with thrombotic thrombocytopenic purpura: what are they and when do they occur? Transfusion. 2013 Jan:53(1):235-7. doi: 10.1111/j.1537-2995.2012.03934.x. Epub [PubMed PMID: 23294213]
Level 3 (low-level) evidenceNokes T, George JN, Vesely SK, Awab A. Pulmonary involvement in patients with thrombotic thrombocytopenic purpura. European journal of haematology. 2014 Feb:92(2):156-63. doi: 10.1111/ejh.12222. Epub 2013 Nov 26 [PubMed PMID: 24164539]
Level 3 (low-level) evidenceBenhamou Y, Boelle PY, Baudin B, Ederhy S, Gras J, Galicier L, Azoulay E, Provôt F, Maury E, Pène F, Mira JP, Wynckel A, Presne C, Poullin P, Halimi JM, Delmas Y, Kanouni T, Seguin A, Mousson C, Servais A, Bordessoule D, Perez P, Hamidou M, Cohen A, Veyradier A, Coppo P, Reference Center for Thrombotic Microangiopathies. Cardiac troponin-I on diagnosis predicts early death and refractoriness in acquired thrombotic thrombocytopenic purpura. Experience of the French Thrombotic Microangiopathies Reference Center. Journal of thrombosis and haemostasis : JTH. 2015 Feb:13(2):293-302. doi: 10.1111/jth.12790. Epub 2014 Dec 18 [PubMed PMID: 25403270]
Page EE, Kremer Hovinga JA, Terrell DR, Vesely SK, George JN. Thrombotic thrombocytopenic purpura: diagnostic criteria, clinical features, and long-term outcomes from 1995 through 2015. Blood advances. 2017 Apr 11:1(10):590-600. doi: 10.1182/bloodadvances.2017005124. Epub 2017 Apr 6 [PubMed PMID: 29296701]
Level 3 (low-level) evidencePlautz WE, Raval JS, Dyer MR, Rollins-Raval MA, Zuckerbraun BS, Neal MD. ADAMTS13: origins, applications, and prospects. Transfusion. 2018 Oct:58(10):2453-2462. doi: 10.1111/trf.14804. Epub 2018 Sep 12 [PubMed PMID: 30208220]
Chang JC. TTP-like syndrome: novel concept and molecular pathogenesis of endotheliopathy-associated vascular microthrombotic disease. Thrombosis journal. 2018:16():20. doi: 10.1186/s12959-018-0174-4. Epub 2018 Aug 11 [PubMed PMID: 30127669]
Jia X, He Y, Ruan CG. [Research Advances of Acquired Thrombotic Thrombocytopenic Purpura--Review]. Zhongguo shi yan xue ye xue za zhi. 2018 Aug:26(4):1230-1234. doi: 10.7534/j.issn.1009-2137.2018.04.048. Epub [PubMed PMID: 30111436]
Level 3 (low-level) evidenceJamme M, Rondeau E. The PLASMIC score for thrombotic thrombocytopenic purpura. The Lancet. Haematology. 2017 Apr:4(4):e148-e149. doi: 10.1016/S2352-3026(17)30024-8. Epub 2017 Mar 2 [PubMed PMID: 28259521]
Paydary K, Banwell E, Tong J, Chen Y, Cuker A. Diagnostic accuracy of the PLASMIC score in patients with suspected thrombotic thrombocytopenic purpura: A systematic review and meta-analysis. Transfusion. 2020 Sep:60(9):2047-2057. doi: 10.1111/trf.15954. Epub 2020 Aug 5 [PubMed PMID: 32757237]
Level 1 (high-level) evidenceRieger M, Mannucci PM, Kremer Hovinga JA, Herzog A, Gerstenbauer G, Konetschny C, Zimmermann K, Scharrer I, Peyvandi F, Galbusera M, Remuzzi G, Böhm M, Plaimauer B, Lämmle B, Scheiflinger F. ADAMTS13 autoantibodies in patients with thrombotic microangiopathies and other immunomediated diseases. Blood. 2005 Aug 15:106(4):1262-7 [PubMed PMID: 15890682]
Level 2 (mid-level) evidenceZheng XL, Vesely SK, Cataland SR, Coppo P, Geldziler B, Iorio A, Matsumoto M, Mustafa RA, Pai M, Rock G, Russell L, Tarawneh R, Valdes J, Peyvandi F. ISTH guidelines for treatment of thrombotic thrombocytopenic purpura. Journal of thrombosis and haemostasis : JTH. 2020 Oct:18(10):2496-2502. doi: 10.1111/jth.15010. Epub 2020 Sep 11 [PubMed PMID: 32914526]
Byrnes JJ, Moake JL, Klug P, Periman P. Effectiveness of the cryosupernatant fraction of plasma in the treatment of refractory thrombotic thrombocytopenic purpura. American journal of hematology. 1990 Jul:34(3):169-74 [PubMed PMID: 2363411]
Level 3 (low-level) evidenceFox LC, Cohney SJ, Kausman JY, Shortt J, Hughes PD, Wood EM, Isbel NM, de Malmanche T, Durkan A, Hissaria P, Blombery P, Barbour TD. Consensus opinion on diagnosis and management of thrombotic microangiopathy in Australia and New Zealand. Nephrology (Carlton, Vic.). 2018 Jun:23(6):507-517. doi: 10.1111/nep.13234. Epub [PubMed PMID: 29419916]
Level 3 (low-level) evidenceMatsumoto M. [New developments in treatment modalities of thrombotic thrombocytopenic purpura]. [Rinsho ketsueki] The Japanese journal of clinical hematology. 2017:58(10):2081-2086. doi: 10.11406/rinketsu.58.2081. Epub [PubMed PMID: 28978852]
Miyakawa Y. [TTP and aHUS: new insights]. [Rinsho ketsueki] The Japanese journal of clinical hematology. 2017:58(5):530-536. doi: 10.11406/rinketsu.58.530. Epub [PubMed PMID: 28592771]
Som S, Deford CC, Kaiser ML, Terrell DR, Kremer Hovinga JA, Lämmle B, George JN, Vesely SK. Decreasing frequency of plasma exchange complications in patients treated for thrombotic thrombocytopenic purpura-hemolytic uremic syndrome, 1996 to 2011. Transfusion. 2012 Dec:52(12):2525-32; quiz 2524. doi: 10.1111/j.1537-2995.2012.03646.x. Epub 2012 Apr 15 [PubMed PMID: 22501034]
Cilla N, Dallemagne J, Vanhove M, Stordeur P, Motte S, De Wilde V. Delayed Thrombotic Complications in a Thrombotic Thrombocytopenic Purpura Patient Treated With Caplacizumab. Journal of hematology. 2020 Sep:9(3):84-88. doi: 10.14740/jh614. Epub 2020 Aug 14 [PubMed PMID: 32855757]
Siddiqui A, Journeycake JM, Borogovac A, George JN. Recognizing and managing hereditary and acquired thrombotic thrombocytopenic purpura in infants and children. Pediatric blood & cancer. 2021 May:68(5):e28949. doi: 10.1002/pbc.28949. Epub 2021 Mar 4 [PubMed PMID: 33660913]
Novitzky N, Jacobs P, Rosenstrauch W. The treatment of thrombotic thrombocytopenic purpura: plasma infusion or exchange? British journal of haematology. 1994 Jun:87(2):317-20 [PubMed PMID: 7947273]
Level 2 (mid-level) evidenceMatsumoto M. [Consensus report on the diagnosis and management of thrombotic thrombocytopenic purpura 2017]. [Rinsho ketsueki] The Japanese journal of clinical hematology. 2017:58(4):271-281. doi: 10.11406/rinketsu.58.271. Epub [PubMed PMID: 28484152]
Level 3 (low-level) evidenceAdamski J. Thrombotic microangiopathy and indications for therapeutic plasma exchange. Hematology. American Society of Hematology. Education Program. 2014 Dec 5:2014(1):444-9. doi: 10.1182/asheducation-2014.1.444. Epub 2014 Nov 18 [PubMed PMID: 25696892]
Govind Babu K, Bhat GR. Cancer-associated thrombotic microangiopathy. Ecancermedicalscience. 2016:10():649. doi: 10.3332/ecancer.2016.649. Epub 2016 Jun 28 [PubMed PMID: 27433282]
Pannu AK, Saroch A. Thrombotic Thrombocytopenic Purpura or Disseminated Intravascular Coagulation? Indian journal of critical care medicine : peer-reviewed, official publication of Indian Society of Critical Care Medicine. 2017 Aug:21(8):539. doi: 10.4103/ijccm.IJCCM_174_17. Epub [PubMed PMID: 28904488]
Vincent JL, Castro P, Hunt BJ, Jörres A, Praga M, Rojas-Suarez J, Watanabe E. Thrombocytopenia in the ICU: disseminated intravascular coagulation and thrombotic microangiopathies-what intensivists need to know. Critical care (London, England). 2018 Jun 13:22(1):158. doi: 10.1186/s13054-018-2073-2. Epub 2018 Jun 13 [PubMed PMID: 29895296]
Rosenthal J. Hematopoietic cell transplantation-associated thrombotic microangiopathy: a review of pathophysiology, diagnosis, and treatment. Journal of blood medicine. 2016:7():181-6. doi: 10.2147/JBM.S102235. Epub 2016 Sep 2 [PubMed PMID: 27621680]
Bommer M, Wölfle-Guter M, Bohl S, Kuchenbauer F. The Differential Diagnosis and Treatment of Thrombotic Microangiopathies. Deutsches Arzteblatt international. 2018 May 11:115(19):327-334. doi: 10.3238/arztebl.2018.0327. Epub [PubMed PMID: 29875054]
Booth KK, Terrell DR, Vesely SK, George JN. Systemic infections mimicking thrombotic thrombocytopenic purpura. American journal of hematology. 2011 Sep:86(9):743-51. doi: 10.1002/ajh.22091. Epub [PubMed PMID: 21850657]
Level 2 (mid-level) evidenceMedina PJ, Sipols JM, George JN. Drug-associated thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Current opinion in hematology. 2001 Sep:8(5):286-93 [PubMed PMID: 11604563]
Level 3 (low-level) evidenceManor SM, Guillory GS, Jain SP. Clopidogrel-induced thrombotic thrombocytopenic purpura-hemolytic uremic syndrome after coronary artery stenting. Pharmacotherapy. 2004 May:24(5):664-7 [PubMed PMID: 15162901]
Level 3 (low-level) evidenceAzarm T, Sohrabi A, Mohajer H, Azarm A. Thrombotic Thrombocytopenic Purpura associated with Clopidogrel: a case report and review of the literature. Journal of research in medical sciences : the official journal of Isfahan University of Medical Sciences. 2011 Mar:16(3):353-7 [PubMed PMID: 22091257]
Level 3 (low-level) evidenceKhodor S, Castro M, McNamara C, Chaulagain CP. Clopidogrel-induced refractory thrombotic thrombocytopenic purpura successfully treated with rituximab. Hematology/oncology and stem cell therapy. 2016 Jun:9(2):76-9. doi: 10.1016/j.hemonc.2015.11.003. Epub 2015 Dec 2 [PubMed PMID: 26684918]
Azoulay E, Bauer PR, Mariotte E, Russell L, Knoebl P, Martin-Loeches I, Pène F, Puxty K, Povoa P, Barratt-Due A, Garnacho-Montero J, Wendon J, Munshi L, Benoit D, von Bergwelt-Baildon M, Maggiorini M, Coppo P, Cataland S, Veyradier A, Van de Louw A, Nine-i Investigators. Expert statement on the ICU management of patients with thrombotic thrombocytopenic purpura. Intensive care medicine. 2019 Nov:45(11):1518-1539. doi: 10.1007/s00134-019-05736-5. Epub 2019 Oct 7 [PubMed PMID: 31588978]
Mintz PD, Neff A, MacKenzie M, Goodnough LT, Hillyer C, Kessler C, McCrae K, Menitove JE, Skikne BS, Damon L, Lopez-Plaza I, Rouault C, Crookston KP, Benjamin RJ, George J, Lin JS, Corash L, Conlan MG. A randomized, controlled Phase III trial of therapeutic plasma exchange with fresh-frozen plasma (FFP) prepared with amotosalen and ultraviolet A light compared to untreated FFP in thrombotic thrombocytopenic purpura. Transfusion. 2006 Oct:46(10):1693-704 [PubMed PMID: 17002625]
Level 1 (high-level) evidenceTrachtman H. HUS and TTP in Children. Pediatric clinics of North America. 2013 Dec:60(6):1513-26. doi: 10.1016/j.pcl.2013.08.007. Epub [PubMed PMID: 24237985]
Bayer G, von Tokarski F, Thoreau B, Bauvois A, Barbet C, Cloarec S, Mérieau E, Lachot S, Garot D, Bernard L, Gyan E, Perrotin F, Pouplard C, Maillot F, Gatault P, Sautenet B, Rusch E, Buchler M, Vigneau C, Fakhouri F, Halimi JM. Etiology and Outcomes of Thrombotic Microangiopathies. Clinical journal of the American Society of Nephrology : CJASN. 2019 Apr 5:14(4):557-566. doi: 10.2215/CJN.11470918. Epub 2019 Mar 12 [PubMed PMID: 30862697]
George JN. TTP: long-term outcomes following recovery. Hematology. American Society of Hematology. Education Program. 2018 Nov 30:2018(1):548-552. doi: 10.1182/asheducation-2018.1.548. Epub [PubMed PMID: 30504356]