Critical Considerations in the
Development of Blood Bags and
Platelet Storage Bags

Medical Plastics Data Service 14apr02

Medical Plastics Data Service is an industry journal produced in India.

Technology
Dr CSB Nair, Director (R&D), Terumo Penpol Ltd, Trivandrum, Kerala State

The Development of Blood Bags

Blood transfusion became safe, dependable and convenient and a result of three important developments – the landmark discovery of blood groups by Prof. Carl Landsteiner (1900), the safety and effectiveness of citrate for intra venous administration by Hustin (1914) and the development of the anticoagulant solution ACD. Modern blood banking, however, was initiated with the pioneering work of development of PVC bags for blood collection and storage started by Prof. Carl W Walter of Harvard Medical School in 1947. He had to face several problems in developing his design to a commercial product. After extensive clinical trials conducted in the USA, he finally got permission to manufacture this item in 1962.

Plasticised PVC containers possess a number of advantages which makes it the material of choice for medical and more particularly for blood contact applications. Its more important features are: ability to be welded together by high frequency – which enables the production of leak-free products and offers infinite design possibilities, steam sterilisability even at 121oC, its favourable cost/performance ratio and its low bulk density offering low storage and distribution costs. The plasticisers used in the compounding of PVC is mainly responsible for building in the desirable characteristics for medical applications such as low toxicity, transparency, flexibility, strengths, elongation, stability at low and high temperatures, permeability to water, oxygen and carbon dioxide in the desired range. While a wide range of plasticisers are available, for food contact and medical applications, the choice for blood contact applications is very limited. The principal plasticiser used is di, (2-ethyl hexyl) phthalate (DEHP) which offers the benefits of overall performance, ready availability at high purity and cost effectiveness.

The Migration of the Plasticiser DEHP into Blood and Blood Products and its Effects

DEHP is not covalently bonded to PVC and so could migrate out of the plastic. This is particularly so in the presence of solubilising lipids, lipoproteins and albumin. Jaegar and Rubin (1970) reported the leaching of DEHP into stored human blood. Several studies conducted subsequently demonstrated the extractability of DEHP from PVC blood bag into whole blood, platelet concentrates and plasma during storage. Concern have been expressed about the adverse effects of DEHP leached into blood and blood products and extensive studies have been made to assess every facet of the problems reported including excellent reviews. PVC materials plasticised with DEHP have been used in patient health care for over 50 years and there are over 3000 published papers discussing its potential toxicological hazards. A recent report by Dr Everett Koop (June 1999) former Surgeon General and Chairman of an expert panel convened by the American Council on Science and Health, sums up the present position succinctly "DEHP in medical devices is not harmful to even highly exposed people, those who undergo certain medical procedures such as regular haemodialysis, or extra corporeal membrane oxygenation. The panel concluded that "DEHP imparts a variety of important physical characteristics that are critical to the function of medical devices and eliminating DEHP in these products could cause harm.

The Collection and Storage of Platelet Concentrates

DEHP Plasticised PVC

It is now well established that platelets could be stored with reasonable post transfusion recovery and survival for up to 72 hours in DEHP plasticised blood bags. In an earlier study, it was demonstrated that thin walled DEHP plasticised PVC containers behaved better indicating thereby that higher oxygen and carbon dioxide permeabilities were desirable.

The effect of DEHP plasticiser on stored platelets was studied by Zoltan Racz and Clara Baroti (1995). They found that :

Platelet aggregation was the only parameter that was slightly inhibited in DEHP plasticised bags indicating that the presence of DEHP had no harmful effect during storage.

Platelets from 400 ml donor blood could be stored in DEHP plasticised bags meant for storage of platlets from 450 ml of blood without deterioration. Such platelets were not inferior to platelet concentrates stored for 5 days in PL 732 (Polyolefin) or PL 1240 (BTHC) containers.

These studies indicate that DEHP plasticised bags could be used for platelet storage if higher permeabilities are ensured.

In vitro studies showed that DEHP reduced platelet functions such as aggregation responses and the percentage of hypotonic shock responses. It also prevented morphological changes in platelets which are frequently seen in TOTM and BTHC plasticised PVC bags. These changes have been explained on the basis of the DEHP leached into the plasma stabilising platelet membrane and thereby preventing changes as in the case or RBC.

Trimellitate Plasticised PVC

Grode et al studied the storage of platelet concentrates in PVC bags plasticised with tri octyl tri mellitate plasticiser and showed that such bags possessed sufficient gas permeability to be suitable for extended storage of platelets for at least 5 days. They also found a 30 fold reduction in plasticiser accumulation in platelet concentrates as compared to DEHP plasticised bags. Studies made subsequently confirm that such bags may be used for storing platelet concentrates for at least 5 days at 22oC. While TOTM plasticised containers were found satisfactory for storage of most platelet concentrates, it may be desirable to use more permeable containers if platelet yields are routinely very high.

A distinct advantage ofTOTM is its low migration and volatility characteristics. Baxgter Health Care Corporation, USA (PL-1240), M/s Cutter Laboratories, USA (CLX), M/s Tuta Laboratoties, Australia and others have been using TOTM as plasticiser for platelet storage bags.

BTHC plasticised PVC

Blood bags made with n-butyrul, tri n-hyxyl Citrate plasticisers have been shown to be effective for storing platelets and their behaviour is similar to TOTM plasticised bags. Measurements of pH, pO2, pCO2, glucose, lactate, ATP, total adenine nuecleotide, lactate dehydrogenase and platelet factor-4 )pF4) showed similar results for BTHC and TOTM plasticised bags during five day storage of platelets. Results of in vivo studies were similar.

An interesting observation, however, has been made that while statistically significant higher values have been obtained for BTHC plasticised containers than for TOTM, for pH, pO2, amd g;icpse/ The jogjer pH levels obtained for BTHC is similar to the high pH levels observed during the storage of platelets in blow moulded polylefin bags which have high permeability. This observation indicates that while BTHC and polyolefin containers ensures sufficient oxygenation to maintain an aerobic metabolism, the carbon dioxide permeability is too high and allows too much escape of the gas as indicated by the low pCO2.

Modified Polyolefins

This material introduced by M/s Baxter health Care Corporation, USA (PL-732 Plastic) is suitable for the storage of platelets for up to 7 days because of its higher gas permeability. However, aberrant morphology has been observed after 2-3 days. The actual composition of the plastic is not disclosed. It is reported to be free of plasticisers but possibly it contains an antioxidant to prevent oxidative deterioration. Even polyolefin materials have been shown to give rise to leaching. Thus polypropylene releases many low molecular weight oligomers while polyethylene releases higher molecular weight oligomers.

Di, n-decyl phthalate plasticised PVC (DnDP)

M/s Trumo Corporation, Japan has developed a new PVC blood bag (X-331S) incorporating a less leachable phthalate ester – di, n-decyl phthalate (DnDP) which has better has permeabilities. The leachability of this plasticiser into plasma is 1/80th that of DEHP. The LD50 values of DnDP is around ten times that of DEHP. This makes DnDP more than 800 times safer than DEHP. The new bag has been shown to be suitable for the five day storage of platelet concentrates.

source: http://www.medicalplasticsindia.com/mpds/2002/jan2002/technology.htm 14apr02