Hypotensive Transfusion Reactions Research Articles

Hypotensive Transfusion Reaction due to Leukoreduced Platelets

Hypotensive transfusion reaction is a distinct category of adverse sequelae of transfusion characterized by an early and abrupt onset of hypotension, typically resolving promptly upon discontinuation of the transfusion. The primary mechanism behind this reaction seems to be the accumulation of bradykinin in the transfused blood product during processing. The authors wish to highlight a case of isolated hypotensive reaction following administration of leukoreduced platelets in an Indian male patient, which required vasopressors. Awareness of the risk factors and clinical presentation for this type of reaction are vital for proper patient care and the prevention of future incidents.

Incidence and characteristics of hypotensive transfusion reaction: 10-year experience in a single center.

Hypotensive transfusion reaction (HyTR) is rare. It is characterized by a rapid onset of hypotension during transfusion, which usually resolves quickly upon cessation of transfusion. Information on the incidence and clinical characteristics of HyTR has been reported in only a few studies. We retrospectively reviewed HyTR cases from 10-year hemovigilance data in a tertiary care hospital in Seoul, Korea. We identified 37 HyTRs in 35 patients, and the overall incidence of HyTR was 0.50 per 10,000 transfused units. Among the blood components, the incidence of HyTR was highest in filtered random donor platelets (0.75 per 10,000 units). About half of the HyTRs occurred within 15 min after the start of transfusion (19/37). Blood pressure returned to the normal range within an hour in 73.0% of the cases (27/37). All HyTR cases recovered without severe complications. Known risk factors for HyTR were not prominent in our cohort of patients, with no patients taking angiotensin-converting enzyme inhibitors and only five patients transfused with bedside filtered platelets. HyTR can occur in patients with various conditions and types of blood components. Understanding the clinical characteristics of HyTR facilitates proper management, leading to improved transfusion safety.

Subclavian steal syndrome masquerading as a hypotensive transfusion reaction.

Subclavian steal syndrome masquerading as a hypotensive transfusion reaction.

Cleavage of High Molecular Weight Kininogen and Bradykinin Release By Red Blood Cell Microvesicles As a Putative Mechanism for Hypotensive Transfusion Reactions

Background: Hypotensive transfusion reactions are adverse events typified by a sudden decrease in blood pressure that usually occurs within the first minutes after the initiation of a transfusion and resolves shortly after the transfusion is stopped. Due to current passive reporting practices, the incidence is likely underreported, but recent studies estimate an incidence of 1.3 cases per 10000 RBC units. The pathophysiology of these reactions are not fully understood. One hypothesis proposed is that increased bradykinin (BK), a nonapeptide released from cleavage of high molecular weight kininogen (HK), as seen with the use of negatively charged leukoreduction filters and the use of angiotensin-converting enzyme inhibitors, is a major contributor to the pathophysiology. We have recently demonstrated that red blood cell derived microvesicles (RBCMVs) from aging red blood cell (RBC) units are able to trigger thrombin generation via kallikrein activation - a predominant enzyme to cleave high molecular weight kininogen (Noubouossie, Blood, 2020). Thus, we hypothesize that the same RBCMVs would lead to bradykinin generation and might explain these hypotensive events.Objectives: To determine if RBC storage lesion-derived microvesicles are able to facilitate HK cleavage and BK release.Methods: RBCMVs were prepared from 4 recently expired RBC units (42 or 43 day old, AS-3 preserved, prestorage leukoreduced, all A+) via a series of centrifugations and washes. RBCMVs were quantified and characterized using nanoparticle tracking analysis. Obtained RBCMVs were first assessed for the capacity to initiate thrombin generation in microvesicle free human plasma via a substrate cleavage assay. Next, RBCMVs were added to a buffer reaction containing prekallikrein and HK, and kininogen cleavage was assessed via western blot. RBCMVs were also mixed with microvesicle-free human plasma and analyzed for evidence of kallikrein activation, cleavage of high molecular weight kininogen, and bradykinin production by ELISA. Cohn fractionation of plasma was used to enrich for BK.Results: RBCMVs were enumerated and concentrated to 7.5 ± 1.4 x 10 12 per mL (mean±SD size 160 ± 29µm). RBCMVs were able to initiate thrombin generation principally via contact pathway activation, independently of tissue factor. In a buffer system RBCMVs demonstrated activity to generate kallikrein with a sequential high molecular weight kininogen cleavage in a dose-dependent manner. Exclusion of kallikrein from the buffer system or addition of the small molecule inhibitor of kallikrein - ecallantide - halted cleavage of kininogen. A dose-dependent cleavage of high molecular weight kininogen indicated that RBCMVs could cause BK release in plasma; this was confirmed via an independent assay of Cohn -fractionated samples.Conclusions: Results of this current study demonstrate that RBCMVs are leading to high HK cleavage via kallikrein activation in vitro. We suspect that the same mechanisms could lead to BK generation in patients receiving older RBC units, possibly increasing the risk for hypotensive events from transfusion. DisclosuresKarafin: Westat, Inc.: Consultancy. Key: Sanofi: Consultancy; BioMarin: Honoraria, Other: Participation as a clinical trial investigator; Takeda: Research Funding; Grifols: Research Funding; Uniqure: Consultancy, Other: Participation as a clinical trial investigator.

A Study of Frequency and Pattern of Adverse Transfusion Reactions at a Blood Bank in a Tertiary Care Hospital: Towards Hemovigilance

Background: Adequate and safe transfusion facility of blood and its components is necessary as blood transfusions are a part of life saving measures in medical and surgical emergencies. However, transfusion practice could result in non-fatal to fatal adverse transfusion reactions (ATR). Therefore, it is important to identify various adverse reactions so that steps can be taken to minimize such reactions and ensure safer transfusion being carried out.
 Methods: All ATRs reported to the blood bank from January 2013 to December 2016 were reviewed and analysed. The frequency of ATRs and its association with various component types were assessed.
 Result: During the study period, a total of 199106 units of blood were issued from the blood bank out of which there was an incidence of 77 (0.12%) transfusion reactions. Chills/rigors was the most common symptom (27.3%) of the symptomatic cases followed by pruritis (23.4%)
 Majority of the transfusion reaction were non haemolytic, 76 (98.7%) cases. One case was of haemolytic transfusion reaction. Among the non-haemolytic transfusion reactions, febrile non haemolytic transfusion reaction (FNHTR) constituted 28 (36.4%) and allergic reactions constituted 41(53.2%). Other transfusion reactions including hypotensive transfusion reaction (HTR), 1 (1.3%) case and transfusion associated dyspnoea (TAD), 6 (7.8%) cases were also seen. The frequency of ATRs was highest with packed red cells (PC) being 75.3% and least with platelet concentrate (PLTC) being 11.7%.
 Conclusion: The frequency of ATRs in our blood bank was found to be on a lower scale when compared to that of most of the similar studies. Allergic reactions and FNHTR were the most common ATRs seen, introduction of leukoreduction filters would help reduce FNHTRs.

Retrospective evaluation of acute transfusion reactions in a tertiary hospital in Erzurum, Turkey.

OBJECTIVE:Transfusion of blood and blood components is a special type of tissue transplantation, a life-saving treatment. However, besides the benefits of blood product transfusions, there are also some undesirable side effects. In the present study, the frequency and type of transfusion reactions related to blood and blood components were investigated.METHODS:In this retrospective study, types and the time of occurrence of acute transfusion reaction (ATR), the types of blood and blood components used in our hospital between January 2018 and January 2020 were evaluated for hemovigilance using unit blood products application and side effect reporting forms.RESULTS:During the 2-year period, 61,636 blood and/or blood components were used in 9334 patients, and 53 of the transfused patients developed ATR. In two patients, ATR developed 2 times and a total of 55 ATR developed. Of the patients who developed ATR, 18 were female and 35 were male, and their ages ranged from 1 month to 85 years. The frequency of ATR was 0.09%, and 47.3% of ATRs were allergic transfusion reactions, 41.8% were febrile non-hemolytic transfusion reactions (FNHTRs), 7.3% were hypotensive transfusion reactions, and 1.8% were transfusion-related lung injury. Fifty-five ATRs were found to be associated with 61.8% erythrocyte suspension, 30.9% with FFP, 5.5% with platelet suspension, and 1.8% with whole blood.CONCLUSION:There are a limited number of studies evaluating transfusion reaction frequency and reaction types from our country. The most frequent ATR reported in our hospital were mild allergic reactions and FNHTR. The most common side effect of blood product type was erythrocyte suspension. It is important to monitor the transfused patients for undesired reactions during and after the transfusion to determine the frequency, type, risk factors, and safety precautions of the transfusion reactions.

Clinical Pattern in Hypotensive Transfusion Reactions

Hypotensive transfusion reactions (HyTRs) may be underreported and have been associated with patients taking angiotensin-converting enzyme inhibitors (ACEIs) receiving poststorage leukoreduced blood products through negatively charged filters. Although bedside leukoreduction is no longer commonplace, HyTRs still occur and are insufficiently characterized in the prestorage leukoreduction era. We describe recently reported cases at our institution. We reviewed transfusion reaction records at Stanford Healthcare from January 2014 to April 2015. HyTRs were defined by National Health Safety Network Hemovigilance Module classification. Eleven HyTRs occurred in 10 patients. All were adults (mean age 71.7 years; range 45-92 years), 7 were male, and all underwent major surgery 0 to 2 days before the reaction. Nine patients underwent cardiac or vascular surgery, and all 10 were taking ACEIs with the last dose taken within 48 hours of the transfusion reaction in 9 patients. Nine patients were on extracorporeal circuits within 24 hours before the reaction (median duration 180 minutes; range 87-474 minutes). In 5 reactions, the implicated unit was restarted with resultant recurrent hypotension. Implicated units included 9 packed red blood cells, 1 apheresis platelet, and 1 plasma frozen within 24 hours. Contrary to what has been previously reported in the era of prestorage leukoreduction, HyTRs at our institution showed consistent patterns in patients at risk. Patients scheduled to undergo major surgery with cardiopulmonary bypass may benefit from earlier preoperative cessation of ACEIs or temporarily switching to an alternative drug class.

Acute Hypotensive Transfusion Reaction in a Patient Taking Angiotensin Converting Enzyme Inhibitors Therapy: A Case Report and Literature Review

Acute Hypotensive Transfusion Reaction in a Patient Taking Angiotensin Converting Enzyme Inhibitors Therapy: A Case Report and Literature Review

Incidence of hypotension and acute hypotensive transfusion reactions following platelet concentrate transfusions.

Platelet concentrates (PCs) are associated with transfusion reactions involving hypotension, particularly bradykinin-mediated acute hypotensive transfusion reactions. This study aims to determine the incidence of hypotensive events and more specifically acute hypotensive transfusion reaction associated with PC transfusions. We also sought to ascertain whether these reactions are associated with elevated bradykinin levels. This is a prospective descriptive study of PCs administered at Sainte-Justine Hospital over 28 months. All PCs administered during this period were screened for hypotension through review of all transfusion-associated reaction reports (TARRs) sent to the blood bank. All residual PC bags were returned to the blood bank. TARRs associated with hypotension were reviewed by adjudicators that established the imputability of the PC transfusion to the reaction. Bradykinin levels were sampled in the first 168 PC bags returned to the blood bank. Levels were compared between PCs associated with hypotension and control PCs not associated with hypotension. A total of 3672 PC bags were returned to the blood bank; 25 PCs were associated with hypotension. Adjudicators ascertained that five hypotensive events were imputable to PCs of which one was an acute hypotensive transfusion reaction (incidence: 0·03%). Bradykinin level in the latter PC was 10 pg/ml, whereas levels were 226·2 ± 1252 pg/ml in the 143 control PCs. Our results show a low incidence of hypotension after PC transfusion. We identified only one acute hypotensive transfusion reaction. No correlation between bradykinin level and the occurrence of acute hypotensive reactions could be observed given that only one event was identified.

Washed RBCs Prevent Recurrent Acute Hypotensive Transfusion Reactions

To examine whether a liver transplant patient, who was not taking an angiotensin-converting enzyme inhibitor and developed two episodes of hypotension with systolic pressure in the 50s within minutes of starting an RBC transfusion, may have had a disturbance in the production and metabolism of bradykinin and des-Arg(9)-BK. All patient information was obtained by reviewing the electronic medical record, the transfusion service database, and transfusion reaction investigation records. The blood pressure returned to normal once the transfusions were discontinued. In an effort to mitigate the acute hypotension, the blood products were washed. Subsequently, the patient received three additional packed RBC transfusions without further incidents of hypotension. Our experience suggests that washing the products was an acceptable and effective preventative measure to avoid further acute hypotensive transfusion reactions in patients unable to metabolize these vasodilators present in the donor units.

Incidence of acute transfusion reactions to platelets in hospitalized pediatric patients based on the US hemovigilance reporting system

Transfusion reactions in pediatric populations have not been well studied. We investigated the incidence and type of transfusion reactions to platelets (PLTs) in a pediatric inpatient population. Over 1 year, a retrospective review of all PLT transfusions given to pediatric inpatients (≤ 18 years old) was performed at a single institution with application of the US hemovigilance reporting definitions. Intraoperative transfusions were excluded. Any signs or symptoms that could represent an acute transfusion reaction (ATR) within 24 hours after PLT transfusion were reviewed and classified based on the US hemovigilance reporting definitions. Between June 1, 2010, and May 31, 2011, a total of 805 PLT transfusions to 126 patients were identified as appropriate for inclusion. Of these 805 transfusions, 116 (14.4%) met the reporting criteria for ATRs. Some PLT transfusions were associated with multiple types of ATRs leading to 120 ATRs overall, as defined by the US hemovigilance reporting system. Of these 120 reportable ATRs, 54 (45.0%) transfusion-associated dyspnea (TAD) reactions, 38 (31.7%) febrile nonhemolytic transfusion reactions, 15 (12.5%) allergic transfusion reactions, eight (6.7%) hypotensive transfusion reactions, and five (4.2%) transfusion-associated cardiac overload reactions were identified. No resultant deaths associated with ATRs were observed. Of these reportable ATRs, only four (3.34%) were reported to the hospital transfusion service. Our findings indicate that reportable ATRs in the pediatric populations may be more prevalent than previously reported and were underreported to our transfusion service. TAD encompassed the majority of reportable ATRs and is the main contributor to the increased rate of reportable ATRs.

The Development of a Novel Molecular Assay Examining the Role of Aminopeptidase P Polymorphisms in Acute Hypotensive Transfusion Reactions

Acute hypotensive transfusion reactions are potentially harmful adverse effects of transfusion attributable to bradykinin generation. They are most often seen in patients taking angiotensin-converting enzyme (ACE) inhibitors (ACE-Is) because of the role ACE plays in metabolizing bradykinin. However, a number of acute hypotensive transfusion reactions occur in patients not taking ACE-Is. Aminopeptidase P (APP), another important enzyme responsible for bradykinin degradation, is encoded by the polymorphic XPNPEP2 gene. Some polymorphisms in XPNPEP2 have been associated with decreased APP activity. However, the role that APP polymorphisms play in acute hypotensive transfusion reactions has never been investigated. To develop a molecular assay to examine for the C-2399A single-nucleotide polymorphism (SNP) in the APP gene, XPNPEP2, in patients experiencing acute hypotensive transfusion reactions unassociated with ACE-Is. We developed an assay using polymerase chain reaction and DNA sequencing with primers targeted at XPNPEP2 (5'-GAGTATTATGTGGGGACCATCC-3' and 5'-ATGCCTCGCAGAGACAAGAG-3'). Polymorphism zygosity was determined by comparing the sense/antisense sequencing results. This assay was then applied to patients with acute hypotensive transfusion reactions not taking ACE-Is (n = 4). A C-2399A SNP assay was successfully developed and applied to patients with acute hypotensive transfusion reactions. In a pilot study, 2 patients (50%) were found to possess C-2399A polymorphisms. One was found to be homozygous, and the other was heterozygous. Our C-2399A SNP assay can be used to study acute hypotensive transfusion reactions in patients not taking ACE-Is. Initial data indicate that the C-2399A polymorphism may be a contributing factor in such reactions. However, further studies are necessary to better define the role of APP polymorphisms in relation to acute hypotensive transfusion reactions unassociated with ACE-Is.

Acute Hypotensive Transfusion Reaction With Concomitant Use of Angiotensin-Converting Enzyme Inhibitors

Hypotension can be a manifestation of transfusion reactions, including acute hemolysis, bacterial contamination, transfusion-related acute lung injury, and anaphylaxis. In addition to hypotension, these reactions usually present with other characteristic symptoms and signs. In rare cases, hypotension is the only manifestation of a transfusion reaction. This reaction, characterized by early and abrupt onset of hypotension that resolves quickly once the transfusion is stopped, is referred to as acute hypotensive transfusion reaction (AHTR). We report a case of AHTR observed in a patient on angiotensin-converting enzyme inhibitor therapy. The Naranjo adverse drug reaction probability scale score indicated that the association between angiotensin-converting enzyme inhibitor therapy and AHTR was probable. If a patient on angiotensin-converting enzyme inhibitor therapy develops AHTR, it is important to recognize the need to switch to another class of antihypertensive medication, at least while the patient continues to require transfusion.

Effets indésirables receveurs : fiches techniques

Since 1994, adverse effects of transfusion transmitted to the French haemovigilance network are registered on “e-fit”, the database of the French agency for the safety of health products (Afssaps). In order to improve their analysis, guidance supports have been made by Afssaps working groups. Each support deals with a blood transfusion side effect and is composed of five parts including pathophysiological mechanisms, diagnostic criteria, management recommendations, etiologic investigations and rules of filing the notification form on e-fit. The major characteristics of sheets published or soon-to-be published are presented: transfusion-related acute lung injury, transfusion-transmitted bacterial infection, non-haemolytic febrile reaction, allergic reaction, transfusion-associated circulatory overload, hypotensive transfusion reaction, alloimmunization, erythrocyte incompatibility reaction and hemosiderosis. These new supports give relevant guidelines allowing a better analysis and evaluation of recipients’ adverse reactions, particularly their diagnosis, gravity and accountability. They could also initiate studies in European and international haemovigilance and transfusion networks.

Acute Hypotensive Transfusion Reaction With Concomitant Use of ACE Inhibitors

Acute Hypotensive Transfusion Reaction With Concomitant Use of ACE Inhibitors

A Polymorphism in the XPNPEP2 Gene Is Associated with the Development of Hypotensive Transfusion Reactions without ACE Inhibitors.

Abstract 3140Poster Board III-77 IntroductionHypotensive transfusion reactions (HTRs) have been associated with the transfusion of different blood products. They are characterized by the rapid onset and disappearance of hypotension upon starting and finishing the transfusion respectively. The use of ACE inhibitors has been associated with HTRs. However, there are reported HTRs in patients not taking ACE inhibitors. An inability to break down bradykinin (BK) generated during the infusion/transfusion is suggested to be responsible for the hypotensive effect. Angiotensin-converting enzyme (ACE) and aminopeptidase P (APP) are primarily responsible for degradation of BK. We hypothesize that the C-2399A single-nucleotide polymorphism in the membrane-bound APP gene XPNPEP2 (SNP rs3747343) may be linked to HTRs. This polymorphism is present upstream of the coding sequence of the APP gene and has already been associated with severe hypotension in an angioedema patient treated with an ACE inhibitor. This suggests that it may have an important regulatory role. Patients and MethodsWith the approval of our IRB, patients' samples were collected, de-identified, and then used for testing. Specimens from 4 patients who presented with classic HTRs while not taking ACE inhibitors were analyzed through sequencing of DNA acquired from pre-transfusion blood samples. The same primers were used for PCR and sequencing (5'-GAGTATTATGTGGGGACCATCC-3' and 5'-ATGCCTCGCAGAGACAAGAG-3'). Samples were sequenced in both sense and antisense directions. ResultsAmong these patients, two (50%) were found to possess the C-2399A mutation. One was found to have changes in both reference and complementary strands while the other had a C/A mutation only in one strand. ConclusionsThese results indicate that the C-2399A polymorphism may be a contributing factor in the development of HTRs and that it may promote HTRs in the absence of ACE inhibitors. The hypotensive effect may be due to a structural or regulatory change caused by C-2399A though it also seems that other factors may be involved since not all patients assayed possessed the mutation. Further screening of additional contributing factors responsible for HTRs is necessary to fully comprehend the pathogenesis of this type of transfusion reaction.Keywords: XPNPEP2, C-2399A, ACE Inhibitors, Hypotensive Transfusion Reactions, aminopeptidase P.Figure 1: Table of ResultsPatient1Age/SexTransfusion Product1ACE InhibitorsSequencing Result2Clinical Setting170/MSDPNoA,TPost CABG4279/FRBCNoC,TPost CABG370/FRBCNoC,GPost CABG417/FFFPNoC,GEndoscopic procedure1Randomly Assigned ID; 2 SDP = Single donor platelets; RBC = Red Blood Cells; FFP = Fresh Frozen Plasma; 3Normal result is C,G;4CABG = Coronary Artery Bypass Graft Surgery DisclosuresNo relevant conflicts of interest to declare.

L’hypotension artérielle dans les effets indésirables receveurs : du signe clinique associé à la réaction transfusionnelle hypotensive

Objective The first aim of this study was to confirm the presence of hypotension blood transfusion reactions and to assess the part of hypotension as a principal event, as defined by the literature but not characterized in French haemovigilance data. As well, recent series of several cases led us to consider a possible incidence increase. Study design Using a retrospective observation, the haemovigilance data from 2000 to the end of 2007 of two French regions were reviewed. During this period, 1 159 657 blood units were transfused by nearly 100 hospitals and 3727 adverse reactions observed. Results One hundred and sixty-eight adverse reactions with hypotension were noticed and analyzed, representing 4.5% of all transfusion reactions and revealing an incidence of 14.5 for 100 000 blood units transfused. It turned out to be mostly male recipients, severe reactions and appearing rather in the beginning of transfusions. Although platelets having greater incidence, all types of blood products may be involved. The clinical diagnosis was the following: 40 to 47% were classified as febrile reactions, 13 to 17% were allergic reactions, 8 to 9% were due to immunologic and/or haemolytic reactions, 5 to 7% resulted of cardiologic disorders, 5% resulted of hypovolemic contexts and 22% were unexplained hypotensive transfusion reactions. Conclusion In about three cases out of four, transfusion-induced hypotension was associated with other clinical reactions. Indeed, hypotensive transfusion reactions were identified, having an incidence of 3.2 for 100 000 blood units transfused. Furthermore, there was no explanation found for the incidence increase in our region during 2007. A national study was suggested to analyse the national data as well as a prospective study to clear out this type of transfusion reactions.

Acute hypotensive transfusion reaction during liver transplantation in a patient on angiotensin converting enzyme inhibitors from low aminopeptidase P activity

Acute hypotensive transfusion reactions are newly characterized transfusion reactions in which hypotension is the prominent feature. The pathophysiology of acute hypotensive transfusion reactions is related to the bradykinin function and its metabolism. A liver transplant recipient on treatment with an angiotensin converting enzyme inhibitor developed sudden hypotension, that is, systolic pressure of 60 mm Hg, after receiving 200 mL of a blood product mixture without significant surgical blood loss. He responded to the resuscitation measure, although hypotension developed again after a challenge transfusion of 200 mL of the blood mixture. A severe hypotensive reaction to the blood transfusion and diffuse bleeding from the dissection surfaces forced the transplantation to be aborted after the common bile duct had been divided. We hypothesized that the patient had an acute hypotensive transfusion reaction due to disordered bradykinin metabolism. Analysis of his blood showed low levels of both angiotensin converting enzyme and aminopeptidase P enzyme activity, confirming that the patient experienced an acute hypotensive transfusion reaction that was due to the use of the angiotensin converting enzyme inhibitor and was precipitated by an abnormality in the metabolic enzyme pathway. It is recommended to discontinue angiotensin converting enzyme inhibitors and switch to a different class of antihypertensive medications for patients with a high Model for End-Stage Liver Disease score on the waiting list for liver transplantation.

Vasoactive mediators and hypotensive transfusion reactions

Vasoactive mediators and hypotensive transfusion reactions

Acute Hypotensive Transfusion Reactions

Acute hypotensive transfusion reactions (AHTRs) are characterized by early and abrupt onset of hypotension as the predominant clinical manifestation. The drop in blood pressure typically resolves quickly once the transfusion is stopped. Disturbances in the production and metabolism of bradykinin cause the pathophysiology of these reactions. Bradykinin is produced after Factor XII becomes activated due to contact with negatively charged surfaces such as tubing systems, dialysis membranes, and blood filters used for leukoreduction. Bradykinin, a vasoactive peptide that binds to receptors on the endothelium and causes hypotension, is primarily metabolized by the angiotensin converting enzyme (ACE). An increase in the recognition of AHTRs has been due to the growing use of ACE inhibitors, the use of negatively charged leukoreduction filters and both genetic and induced alterations in bradykinin kinetics. This review describes the epidemiology of AHTRs, current understandings about the pathophysiology, and prevention measures.