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1、输血过滤器的临床应用 陈育新,Military Aircraft Engine Intake Air,Royal Navy Sea King Helicopter filtered by PALL Filtration,1-2-30,Leo YangPall TWN Sciences,Welcome to Pall Corporation,Pall is All Around You,Ensuring the purity and clarity of the wine,beer and water you drink,Pall is All Around You,Helping to mak
2、e vaccines pure and safe,A Culture of Innovation,1946Dr Pall invents porous stainless steel and founds the company that will become Pall Corporation.,1958Palls Filters provide protection for hydraulic systems on Jupiter C booster.,1959Rigimesh filter media is developed by Pall for the protection of
3、Boeing 707 hydraulic systems.,1969Pall develops a spacesuit heat exchanger and lunar module filtration for the Apollo 11 mission.,1971Blood filters based on the Pall Ultipor filter media are introduced to protect cardiac patients from microemboli,improving post operative outcomes.,A Culture of Innov
4、ation,1979PMM filter media is developed as a clean-up solution for Three Mile Island site.,1988Pall introduces its leukoreduction filters to combat post-transfusion fever and allergic reactions.,1989Palls Scientific and Laboratory Services develops filtration and maintenance standards for hydraulics
5、 systems on the Eurotunnel boring machines,ensuring reliable operation under challenging environmental conditions.,1990Dr.Pall is awarded the National Medal of Technology by President George Bush Sr.,A Culture of Innovation,1991The Pall CentriSep System provides innovative protection for the militar
6、ys intake systems in harsh conditions during operation“Desert Storm”.,1993The BB25 breathing circuit filter,developed by Pall to prevent contamination of ventilating equipment.It becomes critically important in fighting the spread of SARS and Avian Flu.,1995Pall Corporation introduces the DV50,the f
7、irst validated virus-retention cartridge filter for the pharmaceutical industry.,2006Palls Acrodose PL System is introduced to increase the safety and availability of life-saving platelets.,Tomorrow Pall products will continue to protect mission critical systems in even the harshest environments.,Fi
8、lters Used for Blood Components Administration,Type of Filter Removal CharacteristicClot Screen Pore size of 170 umMicroaggregate Pore size of 20 40 umLeukocyte removal Rate on the efficiency of leukocyte remove-not by pore size,BLOOD FILTRATION TECHNOLOGYMicroaggregateLeucocyte reductionred cellspl
9、ateletssalvaged bloodBlood bank filtersBedside(hospital)filters,Transfusion-AssociatedLeukocyte-Mediated Morbidity,Walker JH.Amer J Clin Path 88:374-8,1987,Frequency of Occurrence,Dose-Response for Transfusion and Infection,Patients transfused with 1 to 4 units have infectious complications rates ap
10、proaching 20%.,Dose-Response Relationship Allogeneic Transfusion and Infection,A single transfused unit has been correlated with significantly increased infectious complications approximating 15%.,CLINICAL EFFECTS OF CONTAMINATING LEUCOCYTES,HLA AlloimmunisationReactionsPlateletGraftRefractorinessRe
11、jection Viral Transmission Cytomegalovirus(CMV)EBV,HTLV I&II,Varicella zosterImmune SuppressionPost Cancer LatentOperativeRecurrenceViralInfectionReactivation,Contaminating Leucocytes,Known effects of Leucocytes,Alloimmunization-leading on to RefractorinessInfection transmission-viruses and bacteria
12、Immuno-modulation-higher incidence of post op.InfectionImmuno-suppression-higher AND increased incidence of solid tumour reformation,ALLOIMMUNISATIONANDREFRACTORINESS,Antigen Presenting Cell,B-Lymphocyte,Plasma Cell,Memory Cell,T-Lymphocyte,Donor,Recipient,Transfusion,Y Y Y Y,Y Y Y,Y Y Y,Y Y,Y Y Y Y
13、,Y Y Y Y,Antibody Production,*The production of HLA antibodies is a 2 signal process requiring the presence of both Class I and Class II antigensLocation of HLA*HLA Class IPresent on ALL nucleated cells(white cells)and platelets*HLA Class II Present ONLY on Monocytes,Macrophages,B-Lymphocytes,activa
14、ted T-Lymphocytes,dendritic cellsNB:red cells do not express HLA,Alloimmunisation,ALLOIMMUNISATION%,Control Groups Filter Groups,ANALYSIS OF UTILIZATION AND COST OF PLATELET TRANSFUSION IN REFRACTORY HEMATOLOGY/ONCOLOGY PATIENTS,Number of Average Platelets Average Admissions Transfused Platelet Cost
15、s($),Lill et al.,A.S.H.1997,82%,*Authors found additional cost savings in terms of length of hospital stay(23-41%reduction)and total charges(10-41%reduction)in the leucocyte depleted arm,造成血小板减少的病人出血之原因，除了血小板数目外，很多其它的临床症状也要考虑，例如败血症，尿毒症，凝血功能异常，以及药物的影响等。不之疾病造成血小板之减少症，对输血小板之反应不尽相同，如败血症，脾肿大，免疫性血小板减少症，则对
16、输血小板之反应不佳。因此，除了血小板的数目外，引起血小板减少之原因及疾病亦应注意，才能掌握血小板输注的正确时效。,治疗性血小板输注呢？一般而言，是只对正在出血的血小板减少之病人之治疗方法。这时在输血小板之前及之后，对血中血小板数量的监测与比较是很重要的，因为这样可以评估血小板的存活数量，以及预测未来对输血小板的需求。如果血小板的数量没有爬升，即使是反覆的输血，可能对病人并没有什么好处。通常此时医师必须积极去追查造成顽固性血小板减少的原因。有一些疾病所导致的血小板减少症对输血小板的反应良好，特别是针对骨髓抑制所造成的顽固性血小版减少症。如化学治疗后，放射线治疗后，维持生活素缺乏，或是再生性不良性
17、贫血等。,另外有一些疾病所导致的血小板减少症则对输血小板反应不好，如：败血症(sepsis)，脾脏肿大(splenectomy)，以及免疫性血小板减少症，包括自体免疫性血小板减少症(immunethrombocytopenia)，药物引起之血小板减少症，或是淋巴增生性疾病等。相对的，有一些疾病所导致的血小板减少症，输血小板则为其禁忌症。如血栓性血小板减少性紫斑症(thromboticthrombocytopenic purpura，可能会因输血小板而导致血栓更加恶化。,顽固性(refractory)的血小板减少症：顽固性(refractory)的血小板减少症包含了：1.非免疫性(non-imm
18、une)的顽固性的血小板减少症2.异体免疫性(alloimmunization)的顽固性的血小板减少症 非免疫性的顽固性血小板减少症的原因包含：败血症(sepsis)，弥漫性血管内凝血症(DIC)，以及脾脏肿大(splenomegaly)等。,对于非免疫性的顽固性的血小板减少症的处理方法有：1.使用ABO血型相符之血品2.使用新鲜血小板3.在脾脏肿大(splenectomy)的病人则应增加血小板的剂量4.治疗败血症(sepsis)及弥漫性血管内凝血症(DIC)的原因5.考虑使用单一捐赠者HLA相符之血小板等,异体免疫性的顽固性血小板减少症根据统计，约有20%至70%反覆输血小板患者会产生异体抗
19、体(allo-antibody)，一般发生在输血小板两个月内。有少数的病人于输血小板前即有异体抗体(allo-antibody)，多半是因为从前曾输血小板或怀孕的缘故。90%的异体抗体(allo-antibody)与HLA-typing有关。血小板只有携带第一型(classI)HLA抗原，血小板本身并不足以对这些抗原引发原发性免疫性免疫反应。但是白血球同时携带第一型(classI)及第二型(class II)HLA抗原，足以引发异体免疫(alloimmunization)反应。一但白血球引发原发性异体免疫反应(primary alloimmunization)，血小板亦引发次发性异体免疫反应(
20、secondary alloimmunization)。,使用类固醇(steroid)或脾藏切除(splenectomy)对处理具异体免疫抗体患者的效果不好，而使用IVIG亦只有对少数患者有效。减少捐赠者的人数并没有减少异体免疫抗体产生的机会。即便是仅使用单一捐赠者输血小板，亦只有少数研究报告显示有统计上的差异。脾切除：脾切除对自体免疫性血小板减少症及脾功能过盛之病人亦为一很好之治疗方法。根据我们最进之统计资料约有70%脾切除后之自体免疫性血小板减少之病人，不必服药而其小血小板有明显之升高至正常护接近正常之现象。,临床上红血球抗体的发生，与红血球抗原的致免疫性(immunogenecity，或
21、称抗原性)有关。当然，致免疫性之高低，虽然主要是因抗原不同而异，但免疫途径、免疫方法及频率也有所影响，宿主本身的免疫力和身体状况更是影响抗体发生的重大因素。红血球抗原的致免疫性以Rh(D)抗原最强，K抗原其次。其大致的致免疫性如下(以一次输血后会发生抗体的频率表示),Non-hemolytic febrile transfusion reactions.AlloimmunizationPost-transfusion thrombocytopeniaCytomegalovirus transmissionTransfusion induced immunosuppression(infecti
22、on,cancer recurrence)Reduction of the risk of nvCJD transmission,Leukocyte Depletion of Homologous Blood Products(Red cells,platelets,plasma),Barrier Retention and Pore Size,SCREEN FILTRATIONScreens 20-40um(40um most common)Absolute filters.Large surface area if membrane is pleated Normally made of
23、polyester,DEPTH FILTRATIONVariable pore size removal efficiency of particles/airdependant on density Low surface area.Modified polyesters-adsorb leukocytes.,WHEN TO FILTER:THE LOGISTICS,Filter,Donation Hold Processing Storage Transfusion,Warm Blood,VariableTemperature,ControlledTemperature,Non-Hemol
24、ytic Febrile Transfusion Reactions,Residual leukocyte count(109),1.0 0.5,0.2,-0.1,0.05,Patient reaction rate(%),Sirchi:Transfusion 30:30-33,1990,Prevention of NHFTR of thalassemia patient treated with multiple blood transfusion,Factors of Platelet Refractoriness,Major Factors Influencing the Correct
25、ed Count Increment Non-Immune:1.Splenomegaly 2.Disseminate Intravascular Coagulation(DIC)3.Drugs(Number of Antibacterials and Amphotercin B)4.Sepsis/Infection 5.Fever Immune:1.Platelet-Specific Antibody 2.HLA-Antibody,Alloimmunization,Trial to Reduce Alloimmuization to PlateletsTRAP Study New Engl J
26、 Med:337:1861-1869,T.R.A.P.Study ResultsRate of Alloimmune Refractoriness(%),Very low incidence of refractoriness.All arms are equally effective in reducing the incidence of alloimmune refractoriness.There is no additional benefit of using filtered SD platelets compared to pooled PC(platelet concent
27、rates)preventing alloimmune refractoriness.,T.R.A.P.Study ResultsConclusions,Platelet Transfusion,SDP,RDP,A.Thomas,M.D.,Economic Roadmaps to Universal Leukocyte Reduction 99;Pall Program/AABB.,ROLE OF BLOOD TRANSFUSION IN CMV TRANSMISSION AND REACTIVATION:,CMV,PRIMARY INFECTION eg Blood Transfusion,
28、REINFECTION2nd Strain Introduced in Blood Transfusion,REACTIVATION eg Immunosuppression,Leukocyte Reduction Comparable to CMV Seronegative Blood,Bowden RA et al.Transfusion(1995)35:719-722,A prospective,randomized trial 520 CMV seronegative marrow recipients:Screened Blood:N=252 Filtered Blood:N=250
29、 Between days 21 and 100 after transplant,patients were monitored for the development of CMV infection and tissue-documented CMV disease.,Leukocyte Reduction Comparable to CMV Seronegative Blood,Transfusion Treatment,%,P 0.05Seronegative vsUnscreened Filtered,Bowden RA et al.Transfusion(1995)35:719-
30、722,Transfusion induced immunosuppression(infection),Adapted from Jensen et al.Lancet 1996;348:841-845.,Infection Rate(%)or Reoperation,Reduces Wound Infection,Pneumonia and Reoperation,Transfusion Regimen,141185,Days in Hospital,Dollars(thousands),Cost-Effectiveness of Leukoreduction,Transfusion Re
31、gimen,Adapted from Jensen et al.Transfusion 1995;35:719-722.,The Road to Universal Leukocyte Reduction,American Red Cross BPAC Public Statements,The American Red Cross will present the following views at the Food and Drug Administration Blood Products Advisory Committee(BPAC)meeting today and Friday
32、.The BPAC advises the FDA on a variety of issues that pertain to blood products,from recommending approval of new products to recommending changes of regulations.It is strictly an advisory committee.This information may appear somewhat technical,however,it involves Red Corss policy onf improved test
33、ing for infectious agents to improve the safety of Americas blood supply.,AABBs Association Bulletin#97-2,Limitations in the Interpretation of the Above Data:Many of the early studies could not have been an accurate assessment of residual leukocyte counts in the components administered.The focus at
34、that time was on percent leukocyte reduction.In addition,many of the studies did not have appropriate control groups,nor were they randomized.In addition to the problem of primary vs secondary analyses,the final paper noted above lacks an intent-to-trea analysis,and contains protocol and typographic
35、al errors.Nevertheless,this large randomized trial appears to document that when a particular manufacturers filters were used at the bedside under the conditions determined by the study protocol,results were equivalent to the use of seronegative donor blood.From the available data it cannot be deter
36、mined whether such results would be obtained outside the setting of a controlled clinical trial,with the use of other manufacturers components or with the use of other leukocyte reduction technologies.Recent studies,in fact,have suggested that the performance of bedside filtration of red cell concen
37、trates may be suboptimal compared to filtration under laboratory conditions.Studies by Ledent and Sirchia have provided in-vitro evidence that slow filtration a room temperature(as occurs in a bedside setting)allows warming of red cell concentrates and subsequent suboptimal removal of donor leukocyt
38、es.Hospital transfusion services should continue to reevaluate the most appropriate application of leukocyte reduction technology in light of ongoing research.by Karen Shoos Lipton,JD.Chief Executive Officer,AABBs Association Bulletin#97-2(Continuous),Expectation of a Low Incidence of TT-CMV Followi
39、ng Transfusion of Leukocyte-Reduced Components:It is possible that normal blood donors can have a transient and episodic viremia.Possibly due to a decrease in the regulatory control over the latent infection.This concept is unproven,and the incidence and kinetics of the viremia have not been studied
40、.Unpublished data(Hillyer,CD)on the use of PCR have confirmed that free plasma will transmit CMV despite the use of current leukocyte reduction filters.Additionally,the degree of leukocyte reduction necessary to decrease the risk of TT-CMV had not been determined.Thus,it is possible that some leukoc
41、yte-reduced components may transmit CMV.In addition,clinicians who rely exclusively on the use of antibody resting to make the diagnosis of CMV must recognize that the use of CMV-untested leukocyte-reduced blood may result in the passive transfer of donor antibodies to CMV,which could complicate the
42、 diagnosis of CMV infections in patients.by Karen Shoos Lipton,JD.Chief Executive Officer,CONCLUSION:The data confirm that distinct phenotypic differences exist among PCs prepared with different devices and/or procedures.It is suggested that as for non-generic pharmaceuticals,the clinical benefits o
43、f these various PCs should be individually proved.TRANSFUSION Volume 38,July1998,White cell subsets in apheresis and filtered platelet concentratesS.O.Sowemimo-Coker,A.Kim,E.Tribble,H.J.Brandwein,and B.Wenz,TRANSFUSION Volume 38,July1998,White cell subsets in apheresis and filtered platelet concentr
44、ates(Continuous),TRANSFUSION Volume 38,July1998,White cell subsets in apheresis and filtered platelet concentrates(Continuous),Functions of Leukocyte Subsets,Monocytes:Major Antigen Presenting Cells(which are able to initiate immune reactions leading to alloimmunization).Granulocytes:Phagocytic cell
45、s which engulf and destroy foreign matter.Mainly responsible for febrile transfusion reactions.Evidence suggests that cytomegalovirus(CMV)may be specific to granulocytes,although monocytes may also harbor CMV.Lymphocytes:Carry out a variety of immune functions.Main reservoir for cell associated retr
46、oviruses.B Lymphocytes:Committed B lymphocytes produce and secrete antibodies(IgG,IgM).Major antigen presenting cells responsible for alloimmunization.,Functions of Leukocyte Subsets(Continuous),T4-Lymphocytes:T cells having CD4 phenotype play key“helper role in regulating the immune response by vir
47、tue of their ability to direct“B cells to differentiate and produce antibodies,direct activation of CD8 positive cytotoxic effector cells,activate macrophages and Natural Killer Cells(NK),and also direct the generation of CD8-positive suppressor cells.T8-Lymphocytes:T cells having CD8 phenotypes can
48、 develop into T-suppressor cells(that also play an important role in modulating the production of antibodies by B lymphocytes)and also T-Cytotoxic cells which are important in the defense against viruses.Natural Killer Cells:Lymphoid cells that are distinct from T and B lymphocytes and are important
49、 in transplantation rejection and elimination of malignant tumors.,主旨 NH(F)TR发生的概率并无法因Prestorage之白血球过滤处理而具有任何统计上意义之降低，目前一系列新的证据显示，使用乏白血球处理后之血小板，能使NH(F)TR发生比率再降低之关键并非以Prestorage方式去白血球可以降低之Cytokine，而在血小板本身产生之Chemokine RANTES系列。说明 请参考后附之Transfusion 1999;39:1179-1184期刊所发表之论文。在该篇论文中详细记录、统计、分析了19921996年间，
50、德国血液及肿瘤科因化疗或脊髓功能不健全而造成血小板缺乏症而需输血小板患者之所有输血反应之记录，其二组对照比较之情况（均用PALL Filter），如表一：,Febrile and allergic transfusion reactions after the transfusion of white cell-poor platelet preparationsH.Kluter,S.Bubel,H.Kirchner,and D.Wilhelm,CONCLUSION:Prestorage WBC filtration did not reduce the incidence of these
