Blood, Vol. 93 No. 6 (March 15), 1999:
pp. 2129-2131
CORRESPONDENCE
Ex Vivo Factors Affecting Contact Phase Activation in Negatively
Charged Medical Devices
 |
LETTER |
To The Editor:
We read with interest the article by Scott et al1 on
contact system activation during platelet concentrate filtration. Several groups endeavoring to find a causative role for negatively charged filters in hypotensive/anaphylactoid reactions have reported activation of the coagulation cascade intrinsic pathway (contact phase)
by measuring changes in bradykinin and/or kallikrein activity before
and after filtration.2 Although a clear cause and effect relationship between clinical reactions and the use of negatively charged bedside filters has not been unequivocally demonstrated, there have been several case reports that support such a
hypothesis.3,4 The observations of Scott et al of minimal
high molecular weight kininogen and total kininogen adsorption to
negatively charged filters led them to conclude and generalize that
there is minimal, if any, contact phase activation during platelet
filtration using negatively charged filters. Others that have reported
significant activation of the contact system also observed a wide
variation in the levels of activation between platelet
concentrates.5 We believe these groups are missing
contributions from two critical components of this system: the pH of
the platelet or plasma being filtered and enhancement from dilution of
the products with crystalloids.
Hypotensive/anaphylactoid type or hypersensitivity reactions (HSR) were
reported during hemodialysis in the early 1990s with the use of ACE
inhibitor therapy (ACEI) and were found to be more frequent in
ACEI-treated patients dialyzed using AN69 (HOSPAL, Lyon,
France), a negatively charged dialysis membrane.6 In response to these reports, our HOSPAL group has been investigating the
role of contact phase activation in extracorporeal circuits, including
determination of key factors that affect this phenomenon. Potential
similarities between HSR in hemodialysis, transfusion medicine, and
therapeutic apheresis such as heterogeneity of occurrence, ACEI, and
exposure to negatively charged medical devices have been pointed out by
Owen and Brecher.7
We have seen a significant effect of perfusate pH (eg, platelet
concentrate pH) on contact phase activation. For in vitro activation, we see maximum kallikrein and bradykinin activation at
or below pH37°C of 7.1 (Fig
1). We believe this pH effect may have
significantly affected the results observed by Scott et al. Apheresis
platelet concentrates are known to have very large excursions in pH
over the course of storage, depending on storage bag type and the
number of platelets in the bag. An initial increase in pH is typically
seen during the first 2 days of storage, coinciding with the products
tested by Scott et al.
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| Fig 1.
Influence of pH on contact phase activation induced by
negatively charged dialysis membrane. Platelet-poor plasma pools were
diluted 1:20 in 0.9% saline (5% final plasma content). Pool pHs
(measured at 37°C) were adjusted as indicated and perfused (single
pass) through mini-hemodialysers constructed of AN69 membrane (250 cm2). At 4, 6, and 10 minutes of perfusion, aliquots of
effluent plasma were immediately frozen in methanol/dry ice bath.
Plasma kallikrein was determined by chromogenic assay using substrate
S2302 (Biogenic, Maurin, France) after modification of a method
described by De La Cadena et al.9 Means and standard
deviations (error bars) of six experiments are shown. Kallikrein in the
nonperfused pool remained at the baseline of less than 2 U/L over the
course of the experiment. Kallikrein for plasma perfused over
nonelectronegatively charged membranes (eg, cellulosic) remains at
baseline of less than 2 U/L (data not shown). ( ) pH 7.1; ( ) pH
7.4; ( ) pH 7.6; ( ) pH 7.8.
|
|
We have also observed a systematic increase in contact phase activation
when plasma is diluted with normal saline (0.9% NaCl, pH 5.5). These
observations were recently confirmed by Shimizu et al.8
They reported that bradykinin generation increases 30 times in platelet
concentrates diluted 85% with a storage solution (Seto sol; 115 mmol/L
NaCl, 4 mmol/L KCl, 3 mmol/L MgCl2, 10 mmol/L Na3PO4, 15 mmol/L acetate, 3 mmol/L
Na3citrate, 10 mmol/L glucose, pH 7.1) or
saline.8 We currently use 5% plasma in saline at a
pH37°C of 7.1 to maximize the activation signal as we
investigate various devices and components. Tests are conducted at
37°C, and we have found no differences at room temperature.
Blood interaction with an active foreign surface is multifaceted
with many interacting variables such as dilution, pH (which may be
6.0 to 7.6 for platelet concentrates), and physical properties of
materials. Effects on patients are potentiated not only by the
blood/material interactions, but also by predisposing factors in the
patient (bradykinin metabolism, acid/base status, and perhaps genetic
factors). Therefore, we would encourage investigators in this area
to pay special heed to ex vivo factors such as plasma content, pH,
and time effects. Understanding these effects may help to clarify a
phenomenon that occurs at an inconsistent frequency in the laboratory
and an elusive clinical complication rate when using leukocyte
reduction filters.
Jean-Louis Renaux
HOSPAL R&D
Int
Lyon, France
Larry J. Dumont
COBE BCT, Inc
Lakewood, CO
| |
REFERENCES |
1.
Scott CF, Brandwein H, Whitbread J, Coleman RW:
Lack of clinically significant contact system activation during platelet concentrate filtration by leukocyte removal filters.
Blood
92:616, 1998[Abstract/Free Full Text]
2.
Takahashi TA, Abe H, Hosada M, Nakai K, Sekiguchi S:
Bradykinin generation during filtration of platelet concentrates with a white cell-reduction filter.
Transfusion
35:967, 1995[Medline]
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3.
Hume HA, Popovsky MA, Benson K, Glassman AB, Hines D, Oberman HA, Pisciotto PT, Anderson KC:
Hypotensive reactions: A previously uncharacterized complication of platelet transfusion?
Transfusion
36:904, 1996[Medline]
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4.
Fried MR, Eastlund T, Christie B, Mullin GT, Key NS:
Hypotensive reactions to white cell-reduced plasma in a patient undergoing angiotensin-converting enzyme inhibitor therapy.
Transfusion
36:900, 1996[Medline]
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5.
Hild M, Söderström T, Egber N, Jundahl J:
Kinetics of Bradykinin levels during and after leucocyte filtration of platelet concentrates.
Vox Sang
75:18, 1998[Medline]
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6.
Tielmans C, Madhoun P, Lenaers M, Schandene L, Goldman M, Vanherweghen JL:
Anaphylactoid reactions during hemodialysis on AN69 membranes in patients receiving ACE inhibitors.
Kidney Int
38:982, 1990[Medline]
[Order article via Infotrieve]
7.
Owen HG, Brecher ME:
Atypical reaction associated with use of angiotensin-converting enzyme inhibitors and apheresis.
Transfusion
34:891, 1994[Medline]
[Order article via Infotrieve]
8.
Shimizu T, Nagae M, Mizuno S, Nakashima T, Kamira T, Ozawa K:
Increased bradykinin level in elutes from white cell-reduction filtration of platelets and red cells suspended with additive solutions.
Transfusion
37:11S, 1997
9.
De La Cadena RA, Scott CF, Colman RW:
Evaluation of a microassay for human plasma prekallikrein.
J Lab Clin Med
109:601, 1987[Medline]
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