Progress of quality-associated costing: extension to platelet transfusion practice and the manufacturing scope for plasma proteins.

Realistic estimates about the potential misallocation of health service resources, in relation to the cost-beneficial use of blood products, is enabled by tracing manufacturing costs, through product specification elements to corresponding post-transfusion outcomes. This quality-associated costing (QAC) philosophy is completed in this article by understanding the issues that surround the manufacture of platelets, and by its comparison with the generally used but arbitrary methods for blood product costing. Without QAC, cost-beneficial platelet therapy will not be realized, due to an estimated Western underfunding of approximately one quarter of a billion pounds per annum by arbitrary methods. A reciprocal consequence of such platelet QAC is a significant reduction in the currently perceived cost of source plasma. Western estimates, based upon this, demonstrate that the not-for-profit fractionation of source plasma into purified proteins is probably underfunded by approximately one fifth of a billion pounds per annum through the use of arbitrary costing methods.

The principles of quality-associated costing: derivation from clinical transfusion practice.

As clinical transfusion practice works towards achieving cost-effectiveness, prescribers of blood and its derivatives must be certain that the prices of such products are based on real manufacturing costs and not market forces. Using clinical cost-benefit analysis as the context for the costing and pricing of blood products, this article identifies the following two principles: (1) the product price must equal the product cost (the "price = cost" rule) and (2) the product cost must equal the real cost of product manufacture. In addition, the article describes a new method of blood product costing, quality-associated costing (QAC), that will enable valid cost-benefit analysis of blood products.

The practice of quality-associated costing: application to transfusion manufacturing processes.

This article applies the new method of quality-associated costing (QAC) to the mixture of processes that create red cell and plasma products from whole blood donations. The article compares QAC with two commonly encountered but arbitrary models and illustrates the invalidity of clinical cost-benefit analysis based on these models. The first, an "isolated" cost model, seeks to allocate each whole process cost to only one product class. The other is a "shared" cost model, and it seeks to allocate an approximately equal share of all process costs to all associated products.

A theoretical evaluation of the role of precision and quality in clinical costings.

This study examines the nature of the problems caused by costing activities which focus on isolated treatments. The possible misallocation of resources is identified and a solution which accounts for full treatment until cure is postulated.

Blood product costing: relationship to price and clinical efficacy.

Detailed information is provided about primary product costing and price issues as they affect transfusion manufacturing practice and clinical transfusion practice. Product price is shown to have a crucial influence upon clinical practice and associated research. By focusing particularly upon cost-benefit analysis of blood product transfusion therapy a substantive conclusion is drawn that price should equal the associated manufacturing cost. Clinical outcome studies relate clinical efficacy to the manufacturing specification of the product, which should therefore determine the product cost. Thus, the true manufacturing cost is the sum of all the process activity costs that create the final product specification, e.g. red cell number+volume reduction+leucocyte reduction+microbiological safety, for processed red cells. Sometimes different product specifications may compete for a single activity cost, e.g. one-spin processing achieves volume reduction and leucocyte reduction for processed red cells but also plasma removal for protein fractionation. A method for understanding the relative clinical importance of different products is described, which guides the cost allocation process. Furthermore, for some products there is uncertainty about the clinical benefits of some components of the specification, e.g. leucocyte load and immunomodulation, and a method is described for ranking this quality-uncertainty level objectively. The optimal costing model must ensure that the product with the highest uncertainty ranking is assured a high degree of cost stability. These concepts prepare the way for a Quality Associated Costing model for blood products that correlates with clinical efficacy.

Costing complexities in mixed apheresis.

For mixed apheresis procedures {plasma (PMA) and platelets (PLTs) as products}, six cost-accounting methods are described for apportioning the unit procedure cost ($156.02; representative example) to the two products. The methods are derived from clinical/scientific apheresis principles, but provide a wide range of unit PLT costs ($14.10, 19.71, 34.37, 42.06, 43.82 and 52.00) which relate inversely to the corresponding unit PMA costs ($73.84, 63.01, 34.36, 19.37, 15.94 and 0.00). Two of the methods appear particularly appropriate, depending upon whether the procedure is driven by PLTs predominantly or by PMA+PLTs equally. The paper encourages apheresis physicians and scientists to debate the relative attributes of the methods, develop refinements of the same, and determine through dialogue that mixed apheresis costing models properly account for the clinical science of the service provided.

Microwave thawing of biological materials using a cylindrical rotational mixing system: a calibration model.

A cylindrical device is described for placement within a domestic microwave oven, in order to achieve rapid thawing of biological materials, including plasma, located within the cylinder. The device is economical to fabricate within standard workshop facilities. It secures uniform microwave exposure and continuous mixing of material by rotation of the cylinder in two planes, entraining the motion of the oven drive spindle by a very simple system of frictional gears. Data are presented on the accuracy of this system, and on some important points relating to its use both as a calibration model and a research tool. Such research may eventually enable this system to provide a cheap and reliable option for thawing therapeutic materials for clinical use.

Preparation of platelet concentrates after overnight hold at 20 degrees C.

The clinical demand for platelet concentrates has increased dramatically in the last decade, and poses logistical problems for regional transfusion centres. Pietersz et al. (Vox Sang 1989; 56: 145-150) have shown that it is possible to prepare clinically effective platelet concentrates with substantially reduced white cell contamination, whilst maintaining satisfactory levels of factor VIII:C after holding whole blood at 20 degrees C overnight. This approach offers a method of production that will allow platelet concentrates to be prepared from potentially all donations collected, without resorting to extensive out-of-hours working. Following laboratory evaluation of the procedure we were able to reproduce Pietersz's findings, although hypotonic shock response results were less favourable than observed in our routine platelet concentrates.

Platelet thermophysiology: a new field of investigation dependent upon an improved sub-ambient platelet aggregometer.

Studies of platelet aggregation are normally performed at 37 degrees C. However, in hypothermia during certain surgical procedures (for example, cardiopulmonary bypass) efficient aggregation may be needed at temperatures below 37 degrees C: therefore, assessment of platelet aggregation at temperatures below 37 degrees C may be relevant. This paper describes a sub-ambient aggregometry system developed for this purpose. The effect of temperature (range of 4.5 degrees-37.0 degrees C) upon ADP-induced and spontaneous aggregation of platelets from normal subjects was studied. Platelet aggregation was found to be maximal at room temperature, and may represent 'pure' aggregation. At higher temperatures platelet disaggregation becomes measurable, and at lower temperatures, cold-induced platelet shape-change predominates. These parameters are briefly discussed in terms of their relevance to future research into the physiology of platelet storage and clinical haemostasis.

In-vitro platelet sensitivity to collagen-induced aggregation and in-vitro platelet deterioration rate during storage, are both inversely proportional to the in-vivo blood platelet concentration in normal individuals: preliminary documentation of these theoretically predictable relationships.

This preliminary study documents two new functional relationships for platelets obtained from normal subjects, whose individual blood platelet concentrations (IBPCs) are in the normal range. Firstly, platelets from subjects (or donors) with high-normal IBPCs are the least sensitive to collagen-induced aggregation (a significant inverse correlation). This may be of importance in determining the likely efficacy of fresh platelet transfusions obtained from donors with different IBPCs within the normal range. Secondly, platelets from subjects/donors with high-normal IBPCs deteriorate less rapidly during storage (a significant inverse correlation), perhaps due to differences in platelet biochemical activity between individuals. Such measurements of platelet deterioration rate were based upon the development of a new experimental technique, in which sterile test-PRP was incubated at 37 degrees C with continuous (quarter-hourly) indirect measurements of changes in platelet morphology. This tube-based method is described in detail. The functional relationships observed do have a theoretical basis within the work of others, which is appopriately outlined. Particular discussion pivots around the possibility of using the deterioration rate relationship to predict how therapeutic platelet concentrates prepared from a given donor of know IBPC, may retain their morphological integrity during routine blood bank storage.

Sub-ambient measurement of platelet function: the requirements for modification of a standard platelet aggregometer.

This methodological report documents the electro-mechanical modifications that were applied to a commercially available aggregometer, in order to achieve direct platelet aggregation measurement at sub-ambient temperatures. This development provides a facility, not previously available, for examining certain aspects of platelet physiology at any desired temperature. This innovation was primarily developed for investigating optimum storage parameters for platelets, as they apply to clinical blood transfusion practice. However, a wider scope of application is envisaged, including its use as both a general research tool, and eventually as an additional component of clinical measurement in the routine coagulation laboratory. Some illustrative data is briefly provided.

Ultrasound-induced orientation of discoid platelets and simultaneous changes in light transmission: preliminary characterisation of the phenomenon.

Discoid platelet suspensions were subjected to ultrasonic fields, in the 1-10 MHz frequency range and at estimated acoustic pressures in the range of 0.05-7.6 X 10(4) Pa. Absolute definition of the acoustic field/pressures was precluded by the small dimensions, and internal reflective surfaces, of the experimental configurations employed. Direct microscopy revealed platelet flow, in patterns consistent with theory for ultrasonically induced streaming. This ultrasonic effect was presumed to be accompanied by platelet orientation since it could be quantitated by simultaneous light transmission measurements. The preliminary characterisation of this phenomenon, defined as ultrasound induced light transmission change (USILTC) is reported, and indicates that it may be readily quantitated in a reproducible manner, but which shows a complex relationship both to pressure and frequency. In addition, qualitative characteristics of the response traces are apparent under certain conditions, particularly 5 MHz above 1 X 10(4) Pa, and may relate to platelet viability. Preliminary evidence is provided and discussed, which suggests that USILTC may be a useful model for studying certain ultrasound bioeffects, and may be a useful tool for indirectly assessing platelet morphology and viability for quality assurance purposes.

Ultrasound-induced light transmission change within platelet suspensions as an indirect measure of platelet morphology: preliminary correlation with stirring-induced light transmission change.

Discoid platelets were directionally orientated using stirring or ultrasound, and the change from random orientation was measured by light transmission. Stirring-induced light transmission change (SILTC), already well established as a good indirect indicator of platelet morphology, was compared with ultrasound-induced light transmission change (USILTC) in order to determine whether USILTC may be a similarly good indicator of platelet morphology. Numerous direct comparisons were made between SILTC and USILTC at various static temperatures, and during the dynamic thermal transitions of warming and cooling. Good correlation exists between quantitated SILTC and USILTC values, but the relationship is not exact. Furthermore, single stirring events may considerably distort the relationship under certain conditions. At the ultrasound frequency of 5 MHz and at an estimated peak positive pressure of 2.03 X 10(4) Pa, the USILTC response patterns exhibit a qualitative "spike" pattern for unfixed platelets, which disappears following glutaraldehyde fixation. These preliminary findings are described and discussed in detail, since they suggest that USILTC is a better index of platelet viability than SILTC, although much research is still required in this area.

Continuous monitoring of platelet morphology during small-scale in vitro storage.

A commercially available aggregometer was mechanically and electronically modified to enable automatic repeated measurements of platelet morphology for platelet suspensions undergoing prolonged storage within a sealed perspex cuvette, at any temperature. The modifications are described in sufficient detail to enable others to readily produce the same or similar apparatus. Representative experiments with such apparatus are described, and indicate its potential usefulness in defining the rate of change of platelet morphology occurring during storage at any given temperature, e.g. progressive alteration of shear-induced light transmission change values.

Sub-ambient aggregometry: a tool for examining platelet storage at any temperature between 4-22 degrees C.

A specifically modified commercially available aggregometer, referred to as a sub-ambient aggregometer, was used to measure certain parameters of platelet function throughout the temperature range of 4-37 degrees C. Platelet aggregation responses to ADP and stirring (spontaneous aggregation) were found to be maximal at room temperature. The possible relevance of this to routine platelet storage is discussed. Shear-induced light transmission change (SILTC) as a quick, repeatable, non-invasive index of platelet morphology was used to monitor small-sample platelet storage at 4 degrees C and during its subsequent resuscitation at 37 degrees C. This confirmed the combined usefulness of the sub-ambient aggregometer and SILTC measurements for monitoring platelets during storage. Further application of this approach should enable the optimum temperature for the liquid storage of platelets to be defined, which may not necessarily be 22 degrees C as usually employed.

Microwave-thawed plasma for cryoprecipitate production.

A microwave oven has been used to obtain rapid and controlled thawing of frozen plasma packs for cryoprecipitate production. The resulting factor VIII yields were higher than the average of 77.8 IU (in a volume of 17.2 ml) obtained by the slow overnight thaw procedures in routine use. Assays on 10 individual packs showed mean results of 142 +/- 24.5 IU factor VIII procoagulant activity, 188.6 +/- 51.68 IU factor VIII-related antigen, 0.152 +/- 0.05 g fibrinogen and 218.9 +/- 66.5 IU fibronectin in a volume of 23.2 +/- 6.6 ml. The results of this preliminary study indicate that microwave thawing of plasma is worthy of further investigation and should be reconsidered for routine production of cryoprecipitate and high yield fibronectin.

Rapidly fatal respiratory failure and angioimmunoblastic lymphadenopathy: possible contributions of immunoblastic leukaemia, chemotherapy, and multiple antibodies directed against mature blood cells.

A patient with angioimmunoblastic lymphadenopathy, immunoblastic leukaemia, pulmonary immunoblastic infiltration, and multiple antihaemocytic antibodies in his serum deteriorated rapidly after chemotherapy due to severe progressive respiratory of dysfunction. The haematological and immunological changes that accompanied this are described and discussed in the light of the pulmonary changes observed at necropsy of pulmonary oedema, fibrinous thrombi within venules, and immunoblastic infiltration of these thrombi and the venule walls. A pathophysiological mechanism is postulated in an attempt to rationalise these findings, and to act as a guide for the future assessment and management of similar cases.

Systemic lupus erythematosus, repeated abortions, and thrombocytopenia.

A case is described of severe thrombocytopenia in a pregnant patient with mild SLE. Three previous pregnancies had ended in abortion. Attempts to reverse the thrombocytopenia with steroids, plasmapheresis, and splenectomy failed, the platelet count returning to normal immediately after the death of the fetus at 20 weeks gestation.