No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
The role of blood microfilters in clinical practice
Abstract
Blood filters have been available since the 1930s. In this review we evaluate the role of microaggregate filters (MF) in certain transfusion complications, namely non-haemolytic febrile transfusion reactions (NHFTR), pulmonary injury, thrombocytopenia, fibronectin depletion and histamine release. We review the latest generation of leucocyte depleting filters and discuss their role in preventing alloimmunisation, immunosuppression and CMV transmission. Finally, we provide a rationale for the role of blood microfiltration in the present day practice of intensive care medicine.
... In water and wastewater treatment, filtration through granular media is extensively used to remove micron-sized particles from liquid input streams [Aim et al., 1997], while work in the field of soil pedology attributes the formation of argillic horizons to the translocation of dilute clay suspensions [Hopkins and Franzen, 2003]. In addition, filtration technologies are also used in the filtration of blood to remove infected blood cells in a clinical or diagnostic way Jones et al., 1994;Kapadia et al., 1992;Steneker et al., 1995]. Some of these problems are described in more detail in the following paragraphs. ...
... Filtration through porous media is widely used for water and wastewater treatment [American Water Works Association, 1999] and for medical treatment [Kapadia et al., 1992]. Discrete particles flowing through a porous medium along with interstitial fluid are filtered inside the medium by physical and chemical mechanisms. ...
An understanding of how discrete particles in the micron to submicron range behave in porous media is important to a number of environmental problems. Discrete particle behavior in the interior of a porous medium is complex and influenced by various physical and chemical factors. This work aimed to provide new insight into the physical factors influencing discrete particle movement and attachment in a uniform, saturated porous medium. As part of this aim, a new technique for visualizing discrete particle transport in the interior of a porous medium has been developed. The technique, which includes the construction of a translucent medium and the use of laser induced fluorescence for particle tracking, was used to examine the behavior of a 50 mg/L suspension of negatively charged, micron-size, non-Brownian particles in the interior of a porous medium constructed from water saturated, mono-size 4mm diameter glass beads. Particle behavior as a function of pore fluid velocity and solid surface roughness was imaged at both the macroscopic and microscopic level. Experimental results revealed two interactions between the discrete particles and the solid phase of the medium. One, particle entrapment, resulted in the firm collection of particles at solid-solid contact points and asperities on the solid surfaces. The other, particle hindrance, resulted in non-firm interactions between the particles and the solid's contact points and surfaces. Both entrapment and hindrance were driven by gravity. Hence, the discrete particles were entrapped and hindered at the top surface of the glass beads comprising the medium, and at the upper portion of the contact points.
... As activated platelets release different vasoactive substances, the removal of platelets could reduce thromboxane release with a reduction in vasoconstriction (Bolling et al., 1997). Leukocyte depletion filtration also removes large clots and microaggregates (leukocytes, platelets, and precipitated fibrin "clumps") from blood, which helps decrease the incidence of pulmonary dysfunction and respiratory distress, post-transfusional thrombocytopenia, fibronectin depletion, histamine release, nonhaemolytic febrile transfusion reactions, alloimmunization, and subsequent platelet refractoriness (Kapadia et al., 1992). Blood filters having a pore size around 200 μm do not have capability of leukocyte depletion and can only be used to remove large clots and foreign matter; Filters having a pore size around 50 μm are capable of removing microaggregates from blood and having certain degree of leukocyte depletion (in the order of one log10 reduction in the number of white cells). ...
... 6 The clinical complications associated with transfusion therapy can, to a large extent, be prevented by the use of appropriate bedside blood or blood-product filters. 17 ...
Transfusion therapy remains one of the most commonly used regimens to treat critically ill neonates. Neonatal intensive care professional nurses have a responsibility to ensure that the procedure is as effective, and as safe, as possible. This article aims to provide neonatal intensive care professional nurses with knowledge of the effects of leukodepletion of blood or blood products, the various available bedside blood-product filters, and the role played by the filter pore size in preventing transfusion related reactions in neonates.
... Relevant technological applications include packed bed and membrane reactors Koukou et al., 1998), filtration technologies (Tien, 1989;Bowen and Jenner, 1995), porous bearings (Kwan and Corbett, 1998;Li, 1999) and high efficiency heat exchangers (Lu et al., 1998;Alkam and Al-Nimr, 1999). Examples in the biomedical field include artificial organs (Henderson, 1996), and filtration devices used in blood processing and the clinical setting (Kapadia et al., 1992;Jones et al., 1994). ...
Substantial efforts are currently underway across the community to deploy in silico methods that can aid the development and validation of closure models for applied analysis of fluid transport and related phenomena in porous media and the determination of associated closure parameters. This paper represents a contribution to these efforts. We report, for the first time, a systematic comparison of a lattice-gas automata based explicit numerical simulation (ENS) tool for the flow of single-phase fluids in porous media with experiment. In particular, the study involved comparison of an experimentally determined permeability for a packed bed of spherical particles of mean size with those determined using ENS on representative volumes of the bed taken from: (1) resolution binarized 3D NMR images of the packing; and (2) 3D volumes generated by the reconstruction method of Joshi–Quiblier–Adler (JQA) at resolutions of nα for n=1,2 and 4. Permeabilities were underpredicted in all cases depending on the details of the representative volume. The n=2 and 4 resolution reconstructions on volumes of 125dp3 yielded permeabilities 2.4 and 1.7 smaller than experiment, respectively. The differences between the permeabilities predicted for the n=1 reconstructions and the binarized NMR images and comparison of all the reconstructions with the binarized NMR images allowed these under-predictions to be attributed to the enhancement of surface roughness and fine structure and the loss of underlying collector shape in the JQA reconstructions.
... Membrane-based ÿltration has also been used in more recent years-examples include water clean-up and disinfection (Madaeni, 1999), treatment of industrial waste streams (Awadalla & Kumar, 1994), ÿltration of foods and beverages (Girard & Fukumoto, 2000), and puriÿcation of protein streams in the bioprocess industry (Zeng & Ruckenstein, 1999). Particle-, ÿbre-and membrane-based ÿltration technologies are used in the ÿltration of blood to remove white blood cells and bacteria (Steneker, Pietersz, & Reesink, 1995;Burnouf & Radosevich, 2000), whilst similar technologies are also used in the clinical therapeutic (Kapadia, Valentine, & Smith, 1992) and diagnostic (Jones, Adams, & Evans, 1994) settings. Finally, the ow of liquid-solid suspensions in porous media is highly relevant to the growth and subsequent activity of bioÿlms (Okabe, Kuroda, & Watanabe, 1998). ...
A new explicit numerical simulation (ENS) method based on lattice-gas automata (LGA) is introduced here for the flow of solid/fluid suspensions with deposition in porous media. The ENS method explicitly resolves the dynamics of the individual solid particles and the suspending fluid in the domain defined by the pore walls and solid particle surfaces. After describing the new method, it is applied to the study of solid/fluid suspension flow with deposition in a constriction and in a model random porous solid. This study clearly demonstrates that the deposits strongly influence the local flow fields, which in turn affect the deposition process indicating that this interplay should be modelled if accurate results are desired from trajectory methods.
In this chapter, the performance requirements of various filter fabrics are overviewed, the engineering design of nonwoven air filter fabrics and liquid woven filter fabrics to achieve the required filtration performance are discussed based on the mechanism of depth filtration, surface filtration, and blood filtration theories; the woven and nonwoven filter fabrics used in typical filtration applications such as air, water, oil, and coalescing filters are reviewed.
In this chapter, the characteristics of nonwoven fabric filters and their typical industrial applications are summarized; the mechanisms of filtration including single fibre theory and blood filtration theory were reviewed; the performance and properties of nonwoven filters in air, water, oil and coalescing filtration applications are discussed.
Homologes Blut und seine Derivate sind unverzichtbarer Bestandteil einer adäquaten Hämotherapie. Bei den Blutkonserven und Blutderivaten sind zellhaltige und zellfreie Präparate zu unterscheiden. Folgende Präparate sind gebräuchlich (nach Kretschmer [72]:
Zellhaltig:
Frischblut
Vollblut
Erythrozytenkonzentrate
Thrombozytenpräparate
Leukozytenpräparate.
Zellfrei:
Fresh-frozen-Plasma (FFP);
Gerinnungspräparate:
Kryopräzipitate (F VIII: C, v Willebrand-Faktor, Fibrinogen, AT III, Fibronectin)
Partieller Prothrombinkomplex [F, II, VII, IX, X (Protein C, S)]
Faktorenkonzentrate (F VIII: C, F IX, F XIII)
Inhibitorkonzentrate (AT III)
Factor-VIII-bypassing-activity-Konzentrate (FEIBA)
Phospholipidkonzentrate ( z. B. Fibraccel);
Albumin, Plasmaersatzlösungen, Immunglobuline, Hyperimmunseren.
Die Risiken, die mit der Transfusion von Blut und Blutderivaten verbunden sind, werden häufig unterschätzt. Komplikationen treten etwa bei 2-3% aller Bluttransfusionen auf (Mollison et al. 1987; Walker 1987; Schricker 1988). Diese Komplikationen werden durch immunologische, infektiöse und metabolische Reaktionen verursacht. Ein Risiko in bezug auf metabolische Komplikationen besteht v. a. bei der raschen Infusion großer Mengen an Blutkomponenten.
Labile blood products are obtained from samples of whole blood or aphaeresis. The techniques of preparation evolve with technological advances, which allow both an increasing automation and an intensification of the sanitary safety of the blood products. Over the last ten years, thanks to the availability of new technologies, several measures have been introduced in order to reduce the risk of transmission of pathogens and prevent the onset of transfusion-related acute lung injury (TRALI): leukoreduction, use of platelet storage solutions, inactivation of plasma and presumably of platelets in a very near future. The control of transfusion risk also depends on proper use of labile blood products. To assist the prescriber in his treatment options and to standardize practices, the French Agency for Sanitary Safety of Health Products has issued recommendations in terms of utilization of blood products that are detailed in this review of major labile blood products available.
Labile blood products are obtained from samples of whole blood or aphaeresis. The techniques of preparation evolve with technological advances, which allow both an increasing automation and an intensification of the sanitary safety of the blood products. Over the last ten years, thanks to the availability of new technologies, several measures have been introduced in order to reduce the risk of transmission of pathogens and prevent the onset of transfusion-related acute lung injury (TRALI): leukoreduction, use of platelet storage solutions, inactivation of plasma and presumably of platelets in a very near future. The control of transfusion risk also depends on proper use of labile blood products. To assist the prescriber in his treatment options and to standardize practices, the French Agency for Sanitary Safety of Health Products has issued recommendations in terms of utilization of blood products that are detailed in this review of major labile blood products available.
Evidence suggests that perioperative allogeneic blood transfusion increases the risk of infectious complications after major surgery and of cancer recurrence after curative operation. This has been attributed to immunosuppression. Several authors have suggested that filtered whole blood and/or red cell concentrate, or leucocyte- and buffy coat-reduced red cells in artificial medium or their own plasma, may reduce postoperative immunosuppression. It was also anticipated that the use of autologous blood might minimize the risk of perioperative transfusion, but studies have unexpectedly shown similar postoperative infectious complications and cancer recurrence and/or survival rates in patients receiving autologous blood donated before operation and those receiving allogeneic blood. Future studies should identify common risk factors associated with blood storage.
Blood filters have been available since the 1930s. In this review we evaluate the role of microaggregate filters (MF) in certain transfusion complications, namely non-haemolytic febrile transfusion reactions (NHFTR), pulmonary injury, thrombocytopenia, fibronectin depletion and histamine release. We review the latest generation of leucocyte depleting filters and discuss their role in preventing alloimmunisation, immunosuppression and CMV transmission. Finally, we provide a rationale for the role of blood microfiltration in the present day practice of intensive care medicine.
The use of various types of filters in anaesthesia and intensive care seems ubiquitous, yet authentication of the practice is scarce and controversies abound. This review examines evidence for the practice of using filters with blood and blood product transfusion (standard blood filter, microfilter, leucocyte depletion filter), infusion of fluids, breathing systems, epidural catheters, and at less common sites such as with Entonox inhalation in non-intubated patients, forced air convection warmers, and air-conditioning systems. For most filters, the literature failed to support routine usage, despite this seemingly being popular and innocuous. The controversies, as well as guidelines if available, for each type of filter, are discussed. The review aims to rationalize the place of various filters in the anaesthesia and intensive care environment.
The passage behavior of stored blood through an artificial microchannel system, as a model of capillary vessels, was examined.
Using blood obtained from a total of 17 healthy volunteers, untreated and prestorage leukocyte reduced blood, or untreated and prestorage microfiltered (35 microm-pore size) blood were stored, and then the passage behavior through the microchannels was evaluated. Also, using blood from 16 patients stored for about 2 weeks, the effect of a leukocyte reduction filter, microfilter or mesh filter (175-210 microm-pore size) on the passage through the microchannels was examined.
Untreated blood passed through the microchannels immediately after blood collection, but after 1 week occlusion of the microchannels occurred. Prestorage leukocyte reduced blood, however, passed through the microchannels for up to 6 weeks. Occlusion of the microchannels occurred with both the untreated and prestorage microfiltered blood. Although filtration through a leukocyte reduction filter provided blood that can pass through the microchannels, occlusion occurred with blood filtered in other way.
The present results show that stored blood produces abundant microaggregates, potentially occluding capillary vessels. These microaggregates are not formed after prestorage leukocyte reduction or can be removed by use of a leukocyte reduction filter.
In an effort to determine whether the use of leukocyte (WBC) depleted platelets could modify the development of alloimmunization, 98 adult patients with acute nonlymphocytic leukemia receiving initial induction therapy were randomized to receive standard pooled platelet concentrates (PC) or WBC-depleted PC. WBC depletion was produced by an additional centrifugation of pooled PC, with removal of 81% of WBC and an associated platelet loss of 27%. Lymphocytotoxic antibody (LCTAb) levels were monitored as a serologic marker of alloimmunization. Overall, 5 of 25 evaluable patients receiving WBC-depleted PC developed LCTAb, compared to 13/31 receiving standard PC (p = 0.071). There was no significant difference in alloimmunization rate in the subgroup of patients who had no previous exposure to histocompatibility antigens by pregnancy or prior transfusions (4/15 alloimmunized receiving WBC depleted versus 4/12 receiving standard PC). There was no difference in the number of patients in each group who required HLA-matched platelets during induction therapy. In view of the significant loss of platelets with WBC depletion, the expense and difficulty of providing WBC-poor RBC, the absence of impact on the need for HLA-matched platelets during induction, and the small potential benefit from this approach, WBC- depleted platelets should not be utilized to prevent alloimmunization in patients with leukemia.
Development of permanent platelet refractoriness is a major problem in multitransfused patients with diseases such as leukemia, aplastic anemia, or pediatric solid tumors. We tried to prevent alloimmunization in these patients by systematic use of leukocyte-free blood components with less than one million of contaminating leukocytes per unit of platelets or red cells. Our study group comprised 26 patients with a minimum of 10 platelet transfusions per patient. These patients were compared with a historical reference group of 21 patients who had received standard blood products. In the leukocyte-free group none developed platelet refractoriness, in contrast to the reference group where 11 of the 21 patients became refractory to random platelets. The median corrected platelet increment for random pooled platelets was significantly higher in the leukocyte-free group compared with the reference group. The increasing number of transfusions did not correlate with the development of platelet refractoriness; instead we propose that the lower limit of antigenic exposure is important. We conclude that systematic use of leukocyte-free blood components effectively prevents development of platelet refractoriness and contributes to optimal supportive care of children with cancer.
HLA immunization is a common complication of transfusion therapy in 30% to 60% of oncohematologic patients. Evidence shows that leukocytes present in cellular blood products are the main component involved in the occurrence of HLA immunization, and several studies showed that leukocyte-poor blood products are less able to induce it. However, leukocyte-poor platelet concentrates obtained by conventional techniques, ie, centrifugation, frequently have a high level of remaining leukocytes. Cotton wool filter Imugard IG 500 can be used to obtain leukocyte-poor cellular blood products. The technique is easy to perform, even in an emergency, and can be used with either packed RBCs or platelet concentrates. Means of 97%, 92%, and 76% elimination of leukocytes are obtained for packed RBCs, pooled standard platelet concentrates, and single-donor platelet concentrates, respectively. Patients were randomized to receive either standard (control group) or filtered (leukocyte-poor group) blood products. Of 112 randomized patients, 69 were evaluable, 35 in the control group and 34 in the leukocyte-poor group. Both groups are comparable according to age, diagnosis, sex ratio, previous transfusions, and pregnancies. There is a significant difference in regard to the HLA immunization rate (31.4% in the control v 11.7% in the leukocyte-poor group, P less than .05) and frequency of refractoriness to platelet transfusions (46.6% v 11.7%, P less than .05). We conclude that this filtration technique can be an efficient means to reduce the HLA immunization rate in polytransfused oncohematologic patients.
Development of permanent platelet refractoriness is a major problem in multitransfused patients with diseases such as leukemia, aplastic anemia, or pediatric solid tumors. We tried to prevent alloimmunization in these patients by systematic use of leukocyte-free blood components with less than one million of contaminating leukocytes per unit of platelets or red cells. Our study group comprised 26 patients with a minimum of 10 platelet transfusions per patient. These patients were compared with a historical reference group of 21 patients who had received standard blood products. In the leukocyte-free group none developed platelet refractoriness, in contrast to the reference group where 11 of the 21 patients became refractory to random platelets. The median corrected platelet increment for random pooled platelets was significantly higher in the leukocyte-free group compared with the reference group. The increasing number of transfusions did not correlate with the development of platelet refractoriness; instead we propose that the lower limit of antigenic exposure is important. We conclude that systematic use of leukocyte-free blood components effectively prevents development of platelet refractoriness and contributes to optimal supportive care of children with cancer.
Depletion of leukocytes from all blood products may decrease the incidence of alloimmunization to HLA antigens present on the white cells and thus delay the onset of refractoriness to random donor platelet support. In order to test this hypothesis, 54 patients with hematologic malignancy or marrow aplasia were entered on a prospective randomized trial using cotton-wool filtration as a method of leukocyte depletion of red cell and platelet concentrates. Forty patients were considered evaluable; 20 patients received filtered products and 20 patients in the control group received standard unfiltered products. The filter was 99% efficient in removal of leukocytes (average number of WBC/platelet product, 6 X 10(6)). Platelet loss by this technique was 8%. Alloimmunization was assessed by detection of de novo formed lymphocytotoxic and platelet specific antibodies by microcytotoxicity test, Staph A protein radioimmunoassay, and solid phase red cell adherence test. In the group receiving filtered products, three of 20 (15%) patients developed lymphocytotoxic antibodies while ten of 20 (50%) patients in the control group developed cytotoxic antibodies (P = .01 by actuarial methods). Platelet antibodies were detected in seven of ten alloimmunized patients in the control group and three of three patients in the study group. Clinical evidence of refractoriness was seen in three of 20 patients in the filtered group and ten of 20 in the control group (P = .01 by actuarial methods). The cost of filtration was a fraction of the cost of a plateletpheresis product. Filtration appears to be an effective and economical method for reducing alloimmunization and clinical refractoriness to random donor platelets in patient receiving long-term transfusion support.
Depletion of leukocytes from all blood products may decrease the incidence of alloimmunization to HLA antigens present on the white cells and thus delay the onset of refractoriness to random donor platelet support. In order to test this hypothesis, 54 patients with hematologic malignancy or marrow aplasia were entered on a prospective randomized trial using cotton-wool filtration as a method of leukocyte depletion of red cell and platelet concentrates. Forty patients were considered evaluable; 20 patients received filtered products and 20 patients in the control group received standard unfiltered products. The filter was 99% efficient in removal of leukocytes (average number of WBC/platelet product, 6 X 10(6)). Platelet loss by this technique was 8%. Alloimmunization was assessed by detection of de novo formed lymphocytotoxic and platelet specific antibodies by microcytotoxicity test, Staph A protein radioimmunoassay, and solid phase red cell adherence test. In the group receiving filtered products, three of 20 (15%) patients developed lymphocytotoxic antibodies while ten of 20 (50%) patients in the control group developed cytotoxic antibodies (P = .01 by actuarial methods). Platelet antibodies were detected in seven of ten alloimmunized patients in the control group and three of three patients in the study group. Clinical evidence of refractoriness was seen in three of 20 patients in the filtered group and ten of 20 in the control group (P = .01 by actuarial methods). The cost of filtration was a fraction of the cost of a plateletpheresis product. Filtration appears to be an effective and economical method for reducing alloimmunization and clinical refractoriness to random donor platelets in patient receiving long-term transfusion support.
A simple, effective method for removing granulocytes from stored blood is described. Microaggregate filtration removes approximately 95% of the granulocytes from blood which has been stored for 2 weeks, centrifuged and filtered. The mean number of remaining leukocytes is 8 ± 3.7 x 10^8 / unit. The residual white cell population, which is composed almost entirely of lymphocytes, is substantially less than the average number of cells previously associated with febrile reactions. 45 patients were selected for the study. All had significant febrile transfusion reaction histories, and averaged one reaction for every 3.6 U of conventional red cell product transfused. Administration of 212 units of microaggregate filtered granulocyte poor red cells caused a 95% reduction in the incidence of fibrile reactions. The technique is inexpensive, easily incorporated into the routine of the clinical blood bank, and does not require ‘open-system’ processing. These considerations make microaggregate filtration a logical first choice method for the preparation of granulocyte- poor red blood cells.
11 patients with anaemia and thrombocytopenia due to bone marrow failure each received 2 sets of red-cell transfusions. They were randomised to receive 1 blood transfusion through a standard 170-µm giving set filter and another through a 40 µm micro-aggregate filter. After transfusion, the mean fall in platelet count was 15x10^9/1 (41.7%) and 1.4x10^9/l (4.6%), respectively (p
A 24-hour service was organized to study changes in the hemostatic system in surgical patients undergoing massive transfusion for excessive bleeding during operation or in the early postoperative period. Hemostasis tests gave normal results in only 12 (7%) of the 172 patients, while in the remaining 160 (93%) one or more tests gave abnormal results. The platelet count was the most frequently abnormal, followed by the prothrombin time and plasma fibrinogen. Well-defined hemostatic disorders (such as DIC, heparinization and liver disease) were ascertained in 82 patients (48%). 78 patients (45%) had less specific laboratory abnormalities, with a particularly high incidence of thrombocytopenia and less pronounced alterations in the coagulation tests. Unlike the patients with defined disorders, the strong inverse correlation in this group between platelet count, prothrombin time, plasma fibrinogen, and the number of transfusions suggests that the laboratory abnormalities were induced by massive blood replacement. Standard schemas involving the administration of platelet concentrates and/or fresh-frozen plasma without evaluation of hemostasis did not help to reduce the incidence of abnormalities. These measures also failed to decrease the requirements for whole blood and/or packed red cells. Therefore, indiscriminate administration in the massively transfused postoperative patient of blood components based on preestablished schemes appears to be unjustified. An approach based on hemostasis screening, identification of the underlying disorder, directed therapeutic intervention and laboratory monitoring is likely to be more effective.
Particulate matter accumulates in stored blood and may be directly infused into the pulmonary microvasculature by blood transfusion, causing the respiratory distress syndrome (RDS). The protective effect of fine screen filtration by a 40-μ filter in massive blood transfusion was studied prospectively in 54 patients with trauma. Seventeen patients (control) received from 10 to 40 units (mean 18.8 units) of blood through the standard 170-μ blood filter and were compared to 27 patients (filter) who received from 10 to 63 units (mean 17.9 units) of blood through the 40-μ filter. Seven of the 17 control patients developed the clinical picture of RDS following treatment of their trauma. Despite the similarity in source of injury, anatomic area injured and surgical treatment, only two of the 27 patients with a filter developed the clinical signs of RDS. Three of the seven patients with RDS in the control group and both of the patients with RDS in the group in whom the filter was used had significant chest injury. Three patients in the control group without chest trauma died of intractable hypoxemia. Open lung biopsies and needle biopsies were performed in ten additional patients. Particulate matter in the precapillary arterioles was present in four patients receiving massive blood transfusion without the fine screen filter and in no patients with the fine screen filter. The fine screen filter is recommended to protect the pulmonary microvasculature in transfusions of stored blood.
Two infants who received whole blood filtered through commercially available woven stainless steel micropore filters experienced a sudden onset of hemoglobinuria. The plasma hemoglobin level in one child was 200 mg/dL. To investigate whether filters might lead to RBC destruction, we experimentally quantitated filter-induced hemolysis using standard conditions. Our studies in vitro show that hemolysis decreases with increased speed of transfusion. Hemolysis is particularly extensive with blood stored more than 14 days, but measurable hemolysis occurs with blood stored for as little as one day.
(JAMA 1982;248:1629-1632)
The conditions under which nonhemolytic febrile transfusion reactions developed in eight afebrile patients were investigated. Recipients invariably developed a reaction on transfusion of incompatible white cells if a sufficient quantity of leukocytes was infused. The sensitivity of each patient differed with respect to the number of incompatible white cells which could be tolerated without a reaction. In general, the in vivo reaction to blood from an individual donor could be predicted by the routine leukocyte agglutination test. Mild febrile reactions were inconstantly observed in three patients transfused with presumably compatible leukocytes. Further investigation suggested that the cells inducing reaction were probably incompatible, and that in vivo reactions were a more sensitive index than the in vitro test. Granulocytes, lymphocytes or platelets, separately administered, all induced febrile reactions, provided that the routine leukocyte agglutinin test demonstrated an incompatibility. There was no direct evidence that febrile reactions had occurred in response to plasma infusion. It is concluded that white cell antibodies were the primary cause of nonhemolytic febrile transfusion reactions in this series, and that the detection of white cell antibodies and preparation of leukocyte‐poor blood continue to be procedures of practical importance in modern transfusion therapy.
Résumé
Les conditions sous lesquelles des réactions fébriles transfusionnelles non‐hémolytiques se sont développées chez huit patients afébriles ont été recherchées. Les receveurs ont développé invariablement une réaction transfusionnelle à l'égard de leucocytes incompatibles si la quantité de leucocytes infusés était suffisante. La sensibilité de chaque patient différait selon le nombre de leucocytes incompatibles qui pouvait être toléré sans provoquer de réaction. En général, les réactions in vivo à l'égard du sang de tel ou tel donneur pouvait être prédite en pratiquant le test d'agglutination leucocytaire de routine. Des réactions fébriles moyennes ont été observées d'une manière inconstante chez trois patients transfusés vraisemblablement avec des leucocytes compatibles. D'autres investigations laissent suggérer que les cellules ayant provoqué la réaction étaient probablement incompatibles et que les réactions observées in vivo étaient un index plus sensible que les réactions obtenues in vitro . Les granulocytes, les lymphocytes ou les plaquettes, administrés séparément, peuvent tous provoquer des réactions fébriles lorsque le test d'agglutination leucocytaire de routine démontrait une incompatibilité. Il n'y a pas eu de démonstration évidente directe que les réactions fébriles soient provoquées à la suite d'une infusion de plasma. On conclut que les anticorps anti‐leucocytaires sont la cause primaire des réactions transfusionnelles fébriles nonhémolytiques dans cette recherche et que la mise en évidence des anticorps anti‐leucocytaires et la préparation de sang pauvre en leucocytes constituent un mode de faire d'une importance pratique non négligeable dans la thérapeutique transfusionnelle moderne.
Zusammenfassung
Die Bedingungen, unter welchen bei acht afebrilen Patienten nicht‐hämolytische febrile Transfusionsreaktionen zustande kamen, wurden genau untersucht. Die Empfänger zeigten ausnahmslos eine Reaktion im Anschluß an die Transfusion von inkompatiblen weißen Blutkörperchen, sofern ihnen solche Zellen in genügender Menge infundiert wurden. Die Sensibilität hinsichtlich der Menge weißer Zellen, die eben noch reaktionslos ertragen wurden, wechselte von Patient zu Patient. Im allgemeinen gelang es, die in vivo ‐Reaktion auf Blut eines Einzelspenders an Hand des Leukozytenagglutinationstestes voraus zu sagen. Bei drei Patienten wurden bei Transfusion von augenscheinlich kompatiblen Leukozyten mitunter leichte febrile Reaktionen beobachtet. Bei der weiteren Abklärung zeigte sich, daß es sich höchstwahrscheinlich auch in diesen Fällen um inkompatible Leukozyten gehandelt hat. Die in vivo ‐Reaktionen erwiesen sich als empfindlicher als die in vitro ‐Tests. Falls der Leukoagglutinintest positiv war, traten nach separater Transfusion von Granulozyten, Lymphozyten und Plättchen Fieberreaktionen auf. Direkte Hinweise, daß auch durch Plasma solche Fieberreaktionen erzeugt wurden, konnten nicht beigebracht werden. Nachdem auf Grund dieser Untersuchungsreihe anzunehmen ist, daß Leukozytenantikörper die Hauptursache für nicht‐hämolytische Fieberreaktionen darstellen, erweist sich der Nachweis von Leukozytenantikörpern und die Herstellung von leukozytenarmem Blut als bedeutsame Maßnahme im modernen Transfusionswesen.
Störungen der Mikrozirkulation in der Lunge können durch eine embolische Einschwemmung von Partikeln aus gelagertem Konservenblut verursacht werden. Pathogenetisch spielt die mechanische Verlegung der Lungenendstrombahn eine bedeutsame Rolle bei der Entstehung der progressiven respiratorischen Insuffizienz. Unerwünschte Mikropartikel lassen sich aus Lagerblut durch Filtration zum Teil eliminieren. Trotz des Fehlens einer überzeugenden klinischen Studie über die Wertigkeit der Mikrofiltration von Konservenblut wird der Einsatz kleinporiger Filter empfohlen. Sie sollten bei allen Transfusionen von Standardvollblut und Standarderythrozytenkonzentraten unabhängig von der Zahl der verabreichten Einheiten verwandt werden.
Summary
Disturbances of the pulmonary micro-circulation may be due to embolic obstruction by particles in stored blood. Mechanical blocking of the lung circulation plays an important pathogenetic role in the development of progressive respiratory failure. Extraneous micro-particles can be partly eliminated from stored blood by filtration. Although a detailed clinical study of the value of microfiltration of stored bloods is still missing, the prophylactic use of fine mesh filters is advisable for all transfusions of whole blood or corpuscle concentrates regardless of the quantity to be transfused.
Fresh blood, stored blood and granulocyte concentrates were passed through 170-μm and microaggregate blood filters to determine the degree of complement activation that occurs during transfusion of citrated blood products. Complement activation was assessed by measurement of C3 conversion using crossed immunoelectrophoresis and by assessment of C5a using a leukocyte aggregation functional assay. Prefiltration, fresh or stored blood products showed 0–1% C3 activation. Postfiltration, the degree of C3 conversion did not change for fresh blood or granulocyte concentrates. For stored whole blood, the degree of C3 conversion increased slightly to 2–3%. Prefiltration results for all samples showed a low level of C5a which did not change after passage through any filter. Serum incubated with filter material at 37 °C showed 2–10% C3 conversion. In contrast, results with citrated plasma showed less than 3% conversion of C3. We conclude that although some filter materials may activate complement in serum, filtration of citrated blood products through microaggregate blood filters induces little complement activation.
A simple, effective method for removing granulocytes from stored blood is described. Microaggregate filtration removes approximately 95% of the granulocytes from blood which has been stored for 2 weeks, centrifuged and filtered. The mean number of remaining leukocytes is 8 ± 3.7 × 108/unit. The residual white cell population, which is composed almost entirely of lymphocytes, is substantially less than the average number of cells previously associated with febrile reactions. 45 patients were selected for the study. All had significant febrile transfusion reaction histories, and averaged one reaction for every 3.6 U of conventional red cell product transfused. Administration of 212 units of microaggregate filtered granulocyte poor red cells caused a 95% reduction in the incidence of fibrile reactions. The technique is inexpensive, easily incorporated into the routine of the clinical blood bank, and does not require ‘open-system’ processing. These considerations make microaggregate filtration a logical first choice method for the preparation of granulocyte-poor red blood cells.
In a prospective study we investigated the development and the course of alloimmunization after leukocyte-depleted red cell and multiple random donor platelet transfusions in 335 patients. Of these 335 patients, who had a negative antibody screening on admission and a negative transfusion history, 69 (21%) developed either transien (n = 18) or permanent (n=51) lymphocytotoxic antibodies, but only 31 patients (9%; 95% confidence limits 6–12%) developed multispecific alloantibodies necessitating HLA-matchedplatelet transfusions. There was no difference with regard to the development of antibodies and platelet refractoriness between leukemia patients receiving cytostatic treatment and patients with aplastic anemia receiving prednisone and antithymocyte globulin. Females with previous pregnancies developed platelet refractoriness with an increased incidence(x213.38; p < 0.001) compared to females without previous pregnancies, males, and children.
Pulmonary microembolism of microaggregates associated with massive blood transfusion may be a cause of post-traumatic pulmonary embolism. The purpose of this study was to investigate in the dog the influence on certain physiologic parameters of transfusion of blood containing platelet: white blood cell: fibrin (PWF) aggregates and to evaluate the effects of using blood transfusion filters of varying pore sizes during such transfusions. Exchange transfusions of approximately twice blood volume were performed in three groups of animals. Screen filtration pressure measurements verified the presence of large numbers of PWF aggregates in the transfusions. When no transfusion filters or standard commercially available blood transfusion filters of pore size 170 mu were used, experimental animals developed pulmonary hypertension, a decrease in total body 92 consumption, and metabolic acidosis. Interposition of Dacron wool (Swank) blood transfusion filters prevented these changes.
Blood stored under standard blood band conditions develops microaggregates of platelets and leukocytes. Dog lungs were studied by light and electron microscopy at intervals from 48 hours to six days following exchange transfusions of sublethal volumes of such microaggregate-rich blood through either standard or Dacron wool (Swank) transfusion filters. After transfusion through standard filters, the pulmonary microvasculature was extensively occluded by microemboli. Swelling of capillary endothelial cells, interstitial and alveolar edema, and hypoxic changes in types I and II alveolar epithelial cells were noted. Changes then progressively resolved. These detrimental changes were prevented when microaggregates were removed by Dacron wool (Swank) filters. Mechanical occlusion of the pulmonary vasculature probably plays a minor role in initiating the structural changes observed. Release of lysosomes from disintegrating microaggregates is believed to be the significant factor initiating a chain of events leading to progressive pulmonary damage.
Reactions reported after transfusion of 19,126 units of whole blood and of 42,678 units of red blood cells were analysed. The reaction rate with whole blood was about two and one-half times as great as with red blood cells.
A pronounced depletion of an opsonic protein for hepatic reticuloendothelial (RE) phagocytosis has been demonstrated in critically ill trauma patients. This opsonic alpha(2) surface binding (SB) glycoprotein has immunologic identity and a similar amino acid composition to cold insoluble globulin (CIg). Since CIg can be concentrated in cryoprecipitate, it was utilized as a readily available source of opsonic alpha(2)SB glycoprotein for replacement therapy after injury with documented hypoopsonemia. Six septic patients (2 multiple trauma, 2 thermal burn, and 2 intra-abdominal abscess) were studied to test whether cryoprecipitate infusion would restore this humoral component. Pre- and posttherapy opsonin levels were determined by bioassay and electroimmunoassay. In all patients, severe opsonin depletion was reversed following cryoprecipitate infusion. All patients had a rapid improvement in febrile state, normalization of leukocyte levels, and improvement in pulmonary function as evidenced by decreasing requirements for end expiratory pressure at lowered levels of inspired oxygen. One patient was studied more extensively and demonstrated an increase in cardiac output, limb blood flow, total body and limb oxygen delivery, total body and limb oxygen consumption and a progressive decrease in pulmonary shunt fraction. Thus, opsonic alpha(2)SB glycoprotein deficiency can be reversed by cryoprecipitate infusion in critically ill septic injured patients. Replacement of this humoral factor may be an important therapeutic modality in prevention of multiple organ failure, but it should be administered only after documentation of hypoopsonemia in traumatized patients.
Under laboratory conditions 3 types of filter designed to prevent the passage of microemboli into the circulation during the transfusion of stored blood were compared with the standard Baxter BR10 filter, designed only to hold back macroemboli, in respect of resistance to blood flow and damage to the cellular elements of the blood. In both respects the Pall Ultipor microfilter proved more efficient than the Swank IL200 microfilter and the Bentley Polyfilter (PF-127) and, except with 3-week-old blood, was comparable to the Baxter filter.
Previous work in our department showed that after blood transfusion, the platelet count often falls to levels which are clinically significant. The probable site of platelet sequestration was identified as the spleen, and post-transfusion thrombocytopenia was prevented by blood filters which remove microaggregate debris from the donor blood. Since the duration of the thrombocytopenia has not been investigated, the purpose of the present study was to establish the rate of onset and duration of post-transfusion thrombocytopenia following packed red blood cell transfusions. In addition, the effect of spleen size, patients' diagnosis and post-transfusion history were examined. These observations provide interesting new data on the mechanisms involved in this phenomenon.
The effect of white cell depletion of red cells and platelet concentrates on the transmission of cytomegalovirus (CMV) was studied retrospectively in 150 patients treated intensively for acute leukemia or non-Hodgkin's lymphoma. CMV infection was diagnosed on the basis of IgM and IgG antibody responses to CMV late antigen (CMV-LA). Before cytoreductive therapy for their underlying disease, 59 patients were CMV seronegative and 91 were CMV seropositive. None of the 59 CMV-seronegative patients showed persistent seroconversion 2 months after the cytoreductive treatment. The comparison group, consisting of 312 cardiac surgery patients, showed a significantly higher incidence of primary CMV infections: 10 of 86 (11.6%, p = 0.004). Twenty-five percent of the CMV-seronegative patients and controls had transient IgG antibodies to CMV-LA without IgM antibodies, which is indicative of antibodies passively acquired via blood products. These results indicate that white cell-poor blood products carry a very low risk, if any, of CMV transmission. The policy of transfusing white cell-poor blood products provides a useful alternative to the selection of CMV-seronegative donors.
A multicentre, controlled trial was carried out to determine whether removal of leucocytes from blood by means of 'Imugard IG500' (Terumo) filters would prevent transfusion-acquired cytomegalovirus (CMV) infection in newborn infants. 72 infants whose mothers were seronegative and who received some seropositive blood were followed for 6 months for evidence of CMV infection. There were no significant differences between the groups who received filtered and unfiltered blood in median gestation, birthweight, or amount of seropositive blood received (median volume 32.5 ml and 34.5 ml, respectively). 9 (21%) of the 42 infants who received unfiltered blood and none of the 30 who received filtered blood were infected with CMV. All infected infants weighed less than 1500 g at birth; they represented 31% of very low birthweight (VLBW) infants at risk of CMV infection. None of 24 VLBW infants who received filtered seropositive blood was infected. 1 infected infant died and 5 had clinical features consistent with CMV infection. The results show that transfusion-acquired CMV infection is preventable by filtration of blood through a leucocyte filter. This method has advantages over other methods of removing leucocytes or the use of only seronegative blood for newborn infants.
The effect of a deliberate transfusion policy for prevention of primary cytomegalovirus (CMV) infection, consisting of leukocyte-poor red blood cells from random donors and platelets from CMV-negative donors, was studied in 29 CMV-negative negative recipients of an allogeneic (from CMV-negative donors) or autologous bone marrow transplant. All transplant recipients remained CMV-negative with this approach. Such a policy depends on the availability of CMV-negative platelet donors. Siblings from CMV-negative marrow transplantation candidates appeared to be more often CMV-negative than siblings from CMV-positive transplantation candidates (77% versus 34%, p less than 0.001). Selection of CMV-negative blood bank donors for transfusion of blood products is also easy to perform. As a consequence, CMV-negative marrow transplant recipients have a good chance of receiving CMV-negative marrow transplants and blood products and primary CMV infection can thus be prevented by this transfusion policy.
11 patients with anaemia and thrombocytopenia due to bone marrow failure each received 2 sets of red-cell transfusions. They were randomised to receive 1 blood transfusion through a standard 170-micron giving set filter and another through a 40 micron micro-aggregate filter. After transfusion, the mean fall in platelet count was 15 x 10(9)/l (41.7%) and 1.4 x 10(9)/l (4.6%), respectively (p less than 0.01). The results confirm the findings of a previous study which showed that micro-aggregate filters prevent a post-transfusional decrease in platelet counts. In addition, this new study shows that this is clinically relevant in patients who are thrombocytopenic at the time of their blood transfusion.
Blood transfusion has been linked to clinical phenomena attributable to immune suppression. We prospectively studied the relationship between perioperative blood transfusion and postoperative infectious complications in 343 consecutive patients undergoing surgery for colorectal cancer. Of the 134 patients who received transfusions 33 (24.6 per cent) developed infectious complications compared with 9 (4.3 per cent) of the 209 patients who did not receive blood (P less than 0.0001). The mean number of units of blood received by patients who developed infectious complications significantly exceeded the number for patients without infectious complications (2.31 versus 0.74, P less than 0.0001). The association of transfusion with infections was highly significant (P less than 0.0001) after controlling for age, sex, blood loss, procedure, tumour differentiation, stage, admission haematocrit, duration of surgery, length of the specimen and tumour size. Blood transfusion appears to be an independent risk factor for postoperative infectious complications.
Depletion of leukocytes from all blood products may decrease the incidence of alloimmunization to HLA antigens present on the white cells and thus delay the onset of refractoriness to random donor platelet support. In order to test this hypothesis, 54 patients with hematologic malignancy or marrow aplasia were entered on a prospective randomized trial using cotton-wool filtration as a method of leukocyte depletion of red cell and platelet concentrates. Forty patients were considered evaluable; 20 patients received filtered products and 20 patients in the control group received standard unfiltered products. The filter was 99% efficient in removal of leukocytes (average number of WBC/platelet product, 6 X 10(6)). Platelet loss by this technique was 8%. Alloimmunization was assessed by detection of de novo formed lymphocytotoxic and platelet specific antibodies by microcytotoxicity test, Staph A protein radioimmunoassay, and solid phase red cell adherence test. In the group receiving filtered products, three of 20 (15%) patients developed lymphocytotoxic antibodies while ten of 20 (50%) patients in the control group developed cytotoxic antibodies (P = .01 by actuarial methods). Platelet antibodies were detected in seven of ten alloimmunized patients in the control group and three of three patients in the study group. Clinical evidence of refractoriness was seen in three of 20 patients in the filtered group and ten of 20 in the control group (P = .01 by actuarial methods). The cost of filtration was a fraction of the cost of a plateletpheresis product. Filtration appears to be an effective and economical method for reducing alloimmunization and clinical refractoriness to random donor platelets in patient receiving long-term transfusion support.
In a prospective study we investigated the development and the course of alloimmunization after leukocyte-depleted red cell and multiple random donor platelet transfusions in 335 patients. Of these 335 patients, who had a negative antibody screening on admission and a negative transfusion history, 69 (21%) developed either transient (n = 18) or permanent (n = 51) lymphocytotoxic antibodies, but only 31 patients (9%; 95% confidence limits 6-12%) developed multispecific alloantibodies necessitating HLA-matched platelet transfusions. There was no difference with regard to the development of antibodies and platelet refractoriness between leukemia patients receiving cytostatic treatment and patients with aplastic anemia receiving prednisone and antithymocyte globulin. Females with previous pregnancies developed platelet refractoriness with an increased incidence (Chi 2 13.38; p less than 0.001) compared to females without previous pregnancies, males, and children.
Plasma and whole blood histamine levels and white cell counts have been monitored over a 6-week period of storage in standard citrate-phosphate-dextrose supplemented with adenine (CPDA) blood packs, add-back blood packs, and also CPDA and add-back packs which were subjected to a microfiltration process at the time of collection. Our results indicate that the plasma histamine level rises and the white blood count falls progressively with time, the former being most marked after the 3rd week of blood storage. At 6 weeks, there was no significant difference between the plasma and whole blood histamine level, suggesting that the entire complement of histamine in blood was now in plasma. Microfiltration substantially reduced the white cell count in the packs, and this was reflected in a greatly reduced whole blood and (subsequently) plasma histamine concentration.
The mean fall in the platelet count following 23 routine transfusions of 3-5 units packed cells for anaemia was 32.5%. This was significantly reduced to 12.5% in 15 similar transfusions through a 40 microns microaggregate filter (P less than 0.01) and to 4.6% following five transfusions through a polyester fibre filter (P less than 0.005). In 10 transfusions with frozen or polyester fibre filtered, washed red cells, the decrease in platelet count was 4.2% (P less than 0.001). A study of 111In-oxine labelled autologous platelets in nine patients indicated that the fall in platelet count was due to increased splenic sequestration. Since thrombocytopenia following routine transfusion is reduced by procedures which filter the packed cells, the decrease in platelets is probably caused by their adherence to infused microaggregate debris causing their premature removal from the circulation. Patients with preexisting thrombocytopenia who receive red cell transfusions for anaemia, should therefore receive blood products depleted of microaggregate debris in order to avoid exacerbation of thrombocytopenia and haemorrhagic complications.
The history of the development of blood transfusion and blood filtration is outlined. Clinical and experimental evidence for the efficacy of microfiltration in both small and large volume transfusions is evaluated. Though microfilters do remove the micro-aggregates from stored blood, the results of clinical studies suggest that both the debris from septic processes in the body and the formation of micro-aggregates in the blood stream triggered by processes such as complement activation play a far more important role in the pathogenesis of adult respiratory distress syndrome. If this is so the enhancement of the reticulo-endothelial system by fibronectin therapy may be indicated. It also follows that the use of microfilters is probably an unnecessary expense and, where exsanguination is a risk, may be positively dangerous. Microfilters have been found useful in the preparation of granulocyte-free transfusions after centrifugation of the blood, but their routine use for transfusions, small or large, remains to be justified.
The most commonly used methods for depleting red cells of leukocytes are the inverted spin procedure, which results in excessive red cell loss and poor leukocyte depletion, and washing, which is expensive and yields a product with a 24-hour shelf life. Clinical data now available suggest that nonhemolytic febrile transfusion reactions can be prevented in most clinical situations by microaggregate filtration of red cells during transfusion using the spin-cool-filter procedure with a screen filter. This procedure holds advantages for leukocyte removal, red cell recovery, cost, normal shelf-life, and simplicity over other washing and buffy coat removal procedures currently used. For highly alloimmunized patients requiring virtually total leukocyte removal and where alloimmunization is to be avoided at any cost, adhesion filtration or freezing and deglycerolization should be used.