Immunohematology

Titration Procedures
A Guide to Good Laboratory Practices
Identification
Document
Titration Procedures - A Guide to Good Laboratory Practices
2019/10

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Contents
Titration Procedures
Identification 2

Chapter 1: Introduction 4

Chapter 2: Good Laboratory Practices 5

2.1 Preparation of Dilutions 5

2.2 Controls 5

2.3 Choice of the Red Cell Reagents 6

2.4 Antibody Should Be Identified Prior to Titration 6

2.5 Results Interpretation 6

2.6 Scoring and Reporting of Results 7

2.7 Examples 7

Chapter 3: Frequently Asked Questions (FAQ) 14

 Introduction

1 Introduction
n

Antibody titration is a semiquantitative method of To determine the relative specificity of autoantibodies in
n

determining antibody concentration; it may be undertaken Warm Antibody Immune Hemolytic Anemia (WAIHA), e.g.
for a number of reasons: in an eluate.
In Cold Agglutinin Syndrome (CAS), titration may help in
n To monitor alloantibodies of potential importance in
elucidating the specificity of autoanti-I exhibiting a broad
pregnant women. This is the most common reason for
thermal range.
antibody titration.
n To determine the antigen status of direct antiglobulin
n Titration of ABO antibodies is undertaken to allow
test (DAT) positive cells when reagents are unavailable or
clinical assessment of the feasibility of ABO mismatched
unsuccessful in removing IgG from the cells to be typed.
transplant, and monitoring of treatment to reduce
antibody titre in preparation for ABO mismatched n To assess the antigen site density of red cell reagents,
transplant. although this has largely been superseded by more
accurate methods such as flow cytometry.
n To investigate so-called High Titre Low Avidity “HTLA”
antibodies. For example, antibodies now known to n To assess the characteristics of a new antiserum or
belong to the Knops blood group system. compare a new batch with a previous one.

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 Good Laboratory Practices

2 Good Laboratory Practices

n

Titration usually is described as an “inherently imprecise interfere with an accurate and meaningful result. The results
procedure”. also depend on the equilibrium constant of the antibody
itself in addition to its concentration, making control of the
As for any other laboratory method, standardization is
test parameters very important. Key factors to consider
therefore imperative in order to minimize variables that may
include the following items.

2.1 Preparation of Dilutions

Titration uses a two-fold serial dilution of the sample from A properly calibrated and regularly maintained volumetric
neat (undiluted), 1:2, 1:4, … to 1:2048 (12 tubes). The pipette with a clean tip should be used to prepare each of
number of dilutions prepared can be adapted to what is the dilution in the series.
most convenient for the method to be followed.
On IH-500, a dedicated ID-Titration Rack is used. The
Titrations are more accurate when larger volumes are used instrument contains a “properly calibrated and maintained
when preparing the dilutions. pipette” and the needles are properly washed when making
the serial two-fold dilutions.
The tubes - as contained in the racks in the ID-System -
should be unused, clean and large enough to allow proper
and thorough mixing of each dilution in the series.

2.2 Controls
It is recommended to titrate a standard antibody of known Samples should be stored frozen (at -20°C or lower).
concentration or better with an “expected” titre to validate Special attention should be taken when thawing samples:
the titration procedure (see tables in the examples on next concentration gradients are produced during thawing, as the
pages). This can be performed as a routine control of the concentrated solution melts first and then runs down inside
method as well. It will help to minimize variability affecting the tube along the inner wall.
the technical performance.
After thawing, the tube should be inverted several times.
When the titration is being performed in the context of Before testing, the tube should be examined for presence of
pregnancy follow-up, the first sample - usually from around any undissolved material. When present, it usually helps to
the 12th week - establishes the base line titre. All subsequent carefully warm the sample at 37°C to redissolve this1.
titrations should be carried out in parallel with the previous
sample. Again this will minimize variation inherent to the
technique and it will provide for a more accurate reflection
of the antibody status.

1
 oung DS. Effects of Preanalytical Variables on Clinical Laboratory Tests. 2nd ed. Washington, DC: AACC Press; 1997:
Y
4- 180, 181,533

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 Good Laboratory Practices

2.3 Choice of the Red Cell Reagents

Whenever possible, the same antigen source should be Whether the red cells used for titration should be single or
used each time, as there is great heterogeneity of antigen double dose, in particular during pregnancy, is a debate.
expression even among cells of apparently the same Most but not all countries would recommend the use of
phenotype. single dose cells (heterozygous expression). The reasoning
behind this is that the fetus of an allo-immunized mother will
For instance, R1R2 cells (DCcEe, RH:1,2,3,4,5) can have
never be homozygous for the gene in question. Therefore
between 23,000 and 31,000 copies2 of the D-antigen.
the use of single dose cells will more closely mimic the in
Because it is impossible for most laboratories to have the
vivo situation.
same red cells available for the follow-up during a whole
pregnancy, it is recommended to use a pool of three cells Two things are clear:
(volume by volume) of the same phenotype. Together with n Laboratories should use the cells recommended by their
performing the titration in parallel with the previous sample,
local guidelines
this minimizes variability.
n The key to standardization is to use the same phenotype
The selected cells should be prepared accurately according
as a standard procedure each time
to the test method used, e.g. 0.8% in the appropriate diluent
for the ID-System. The appropriate volumes should be
dispensed using a calibrated volumetric pipette.

2.4 Antibody Should Be Identified Prior to Titration

It does not make sense to perform titration just on the basis If more than one antibody is present, the selection of the red
of a positive antibody screening test. cell reagents for titration must be done carefully, to ensure
that the titre of each antibody is assessed independently.
As explained in section 2.3, a proper choice of the red cell
reagents can only be made when the antibody is properly For example, for a mixture of anti-K+Fya (anti-KEL1+FY1),
identified. two independent titrations should be done, the first using
K-;Fy(a+b+) / (KEL:-1;FY:1,2) red cells and the second using
In addition there may be multiple antibodies present, and if not
K+k+;Fy(a-) / (KEL:1.2;FY.-1) red cells.
properly identified they may interfere with the titration result.

2.5 Results Interpretation

When dispensing the properly prepared dilutions, it is There usually are weaker reactions observed beyond this
recommended to start with the highest dilution ending with dilution showing a 1+ (+ in ID) reaction: these are looked at
the neat undiluted sample, to prevent any possibility of carry when reporting a score instead of a titre (see tables in the
over due to a strong antibody. examples on next pages).
Clear endpoints should be defined. Usually the last dilution
that produces a 1+ (+ in the ID-System) is considered to be
the endpoint. The reciprocal of this defined end point is then
the titre of the antibody in the sample: if this dilution is 1:32
than the titre is 32 (and not 1:32).

2
Daniels, G., 2013. Human Blood Groups. 3rd ed. Chichester, UK: John Wiley & Sons

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 Good Laboratory Practices

2.6 Scoring and Reporting of Results

Titres are often simply reported as the reciprocal of the from 5 to 0. The actual method is not important, as long as
define endpoint, e.g. a titre of 64. However, this does not the same system is always used. The scoring system should
always reflect the true strength of an antibody or point to be incorporated in the laboratory SOP, together with the
a significant rise in titre. Scoring the reactions may help to definition of what is a significant rise in titre, a significant rise
overcome this problem. Scoring methods differ, some using in score.
scores from 12 to 0 (most commonly), others more simply

2.7 Examples
Example 1 n Titres and Scores

Sample Dilution
Neat 1:2 1:4 1:8 1:16 1:32 1:64 1:128 1:256 1:512 Titre Endpoint Score

Sample Strength 3+ 3+ 3+ 2+ 2+ 2+ 1+ +/- +/- - 64

1 Score 10 10 10 8 8 8 5 2 2 0 1:256 63

Sample Strength 4+ 4+ 4+ 3+ 3+ 3+ 2+ 1+ +/- - 128

2 Score 12 12 12 10 10 10 8 5 2 0 1:256 81

Sample Strength 1+ 1+ 1+ 1+ +/- +/- +/- +/- +/- - 8

3 Score 5 5 5 5 2 2 2 2 2 0 1:256 30

In the above example, all three samples are showing Assigning scores to all of the individual reaction strengths
reactions up to and including dilution 1:256. leads three different scores.
The last dilution showing a clear 1+ reaction is different for each Sample 3 is an example of an HTLA-antibody (see example 4
one of them, leading to different titres reported for each sample. at page 10).

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 Good Laboratory Practices

Example 2 n Interpretation: Significant Rise in Titre e.g. in Pregnancy

Titre of standard,
Titre of “today’s” sample Titre of “previous” sample Conclusion
expected titre = 32
No titre increase
a 4 4 32 Q 3
Titre of 4
Significant titre increase from
b 32 4 32 Q 3
4 to 32
No titre increase
c 16 16 64 Q 3
Titre of 16
No titre increase
d 8 4 32 Q 3
1 step is no increase

It is necessary for a laboratory to establish a baseline titre using Note: In UK3, some antibodies are quantified (IU/ml) rather
a standard with an expected titre specific to the method. than titred.
In the above example the expected titre of the standard n Anti-D (RH1) less than 4 IU/ml Q HDFN unlikely
is 32; this titre should be reproducible within ±1 dilution, n Anti-D (RH1) between 4-15 IU/ml Q Moderate risk of
i.e. 16-32-64 are acceptable titres, as illustrated.
HDFN
Note that the “previous” sample, stored frozen, is titrated again
in parallel to the newly drawn sample (e.g. 2 weeks later). n Anti-D (RH1) More than 15 IU/ml Q High risk of hydrops
fetalis
Sample a: the standard shows a titre of 32 Q 3; both the
previous sample and the newly drawn sample show a titre of 4. n Anti-c (RH4) less than 7.5 IU/ml Q continue to monitor
Conclusion: no titre increase. n Anti-c (RH4) between 7.5 to 20 IU/ml Q Risk of moderate
HDFN, refer to specialist unit
Sample b: the standard shows a titre of 32 Q 3; the
previous sample shows a titre of 4, the new sample has a
n Anti-c (RH4) more than 20 IU/ml Q Risk of severe HDFN,
titre of 32. refer to specialist unit

Conclusion: a significant (more than 2 dilutions) titre increase.

Sample c: the standard shows a titre of 64 Q 3; both the

previous sample and the newly drawn sample show a titre
of 16.
Conclusion: no titre increase.

Sample d: the standard shows a titre of 32 Q 3; the first

sample shows a titre of 4, the new sample has a titre of 8.
Conclusion: a 1 step increase is not significant, no titre
increase.

3
https://www.transfusionguidelines.org/red-book (accessed Jan 24, 2018)

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 Good Laboratory Practices

Example 3 n ABO Titration in the context of ABO incompatible (ABOi) organ transplants (kidneys and others).
ABOi haemopoetic stem cell transplants and ABO HDFN
In most countries there is a lack of available kidneys for Reports from exercises in the UK (NEQAS reference to be
transplantation. The use of ABOi kidneys was investigated added October 2014 workshop) are showing:
as a possible solution: generally speaking HLA matching n A standard technique is recommended using ID-Cards
is more important than ABO matching and there is now
IAT and Neutral:
a consensus that “ABOi-Kidney Transplant (KT) outcome
is comparable to ABO compatible KT”4. Assessment of - it allows more reproducible results
anti-A/B antibody titre is crucial in ABOi-KT. It guides the
- the results show a tighter range, i.e. closer to method
effectiveness of operative preconditioning and determines
median
the period to permit transplantation. In addition, post-
transplant monitoring helps early detection of antibody- n IAT is more reproducible than DRT
mediated rejection by antibody rebound. n DTT introduces variability
Transplant protocols are different between transplantation n It is recommend to develop a standard
centres, between regions, between countries. Efforts are on-
going to establish minimum transplant candidate ABO titres. That standard has been developed and is available at
Overall titres are ranging from 32 to 128 (Gel method). When the NIBSC (High titre anti-A and anti-B in serum - WHO
titres are above these limits, patients are treated to “desensitize” Reference Reagent 14/3005).
to ABO with medication, antigen-specific immunoadsorption,
plasma exchange, or double-filtration plasmapheresis. The testing of replicate dilution series of both 14/300 and
the samples is recommended to take into account intra-
When performing titrations on ABO antibodies, it is laboratory variation in repeat titrations.
important to realize that samples will always contain
mixtures of IgM and IgG. Most laboratories will perform the Finally, it is important to make sure an antibody detections
titrations in both at room temperature (usually referred to as test is done. Any alloantibody present may interfere with the
DRT, Direct agglutination at Room Temperature) and in IAT. ABOi titration should the antigen toward which the antibody
is directed be present on the cells used for titration.
It is imperative to understand that:
For example, when an alloanti-K (KEL1) is present, one
n DRT will preferentially detect IgM, but that some IgG will should make sure the red cell reagents are K-, when titrating
occasionally directly agglutinate using the IAT:
n IAT will preferentially detect IgG, but occasionally there For example, when a cold reactive alloanti-P1 (P1PK1) is
will be some agglutination by IgM present, one should make sure the red cell reagents are P1-
Some laboratories want to specifically measure IgG. In that (P1PK:-1), when titrating using DRT.
case, the sample should be treated with DTT (or 2-ME).
These molecules will inactivate IgM molecules without
affecting the IgG molecules. At the negative side, it needs to
be understood the method itself introduces another cause of
variability to the system.

4
 uramatsu M et al., 2014. ABO incompatible renal transplants
M
5
http://www.nibsc.org/products/brm_product_catalogue/detail_page.aspx?catid=14/300 (accessed Jan 24, 2018)

Titration Procedures n © Bio-Rad | 9

 Good Laboratory Practices

Example 4 n HTLA (High Titre, Low Avidity)

The “term” HTLA is a colloquial statement intended to Most of the antibodies in this “group” are clinically
describe “rather roughly” the serological results of this group insignificant. Specificities include anti-Ch, anti-Rg, anti-JMH,
of antibodies and not intended to define antibody specificity anti-Csa, anti-Yka, and others.
(quote from the late JJ Moulds).
Titrations can provide a clue to whether the antibody is likely
Common characteristics are: weak, variable reactions in to be one that exhibits HTLA characteristics, i.e. usually 1+
IAT and in some cases hard to reproduce. The antigens are reactions (Low Avidity) in IAT and titres > 32.
of high frequency, so almost always the identification panel
shows weak reactions in IAT with all cells, making it difficult
to draw conclusions.

Dilution Neat 1:2 1:4 1:8 1:16 1:32 1:64 1:128

Low Titre
+/- 0 0 0 0 0 0 0
Low Avidity
Low Titre
2+ 2+ 1+ 0 0 0 0 0
High Avidity
High Titre
1+ 1+ 1+ +/- +/- +/- +/- 0
Low Avidity
High Titre
3+ 3+ 3+ 2+ 2+ 1+ 1+ +/-
High Avidity

In this table, the HTLA characteristic (dark blue) is clearly

demonstrated: it is “unexpected” to observe that a weakly
reactive antibody shows reactions up to the dilution 1:64.

Example 5 Autoantibodies6 n Reactions of a Typical Auto-Anti-I associated with CAS

Titre
Temp Cells from 2 4 8 16 32 64 128 256 512 1024 2048 4096
Adult 4+ 4+ 4+ 4+ 4+ 4+ 4+ 3+ 3+ 2+ 1+ 0
4°C
Cord 4+ 4+ 4+ 4+ 4+ 4+ 3+ 3+ 2+ 1+ 0 0
Adult 4+ 4+ 3+ 3+ 3+ 2+ 1+ 0.5+ 0 0 0 0
RT
Cord 1+ 1+ 0.5+ 0 0 0 0 0 0 0 0 0
Adult 1+ 0.5+ 0 0 0 0 0 0 0 0 0 0
37°C
Cord 0 0 0 0 0 0 0 0 0 0 0 0

In this example, 6 titrations are performed at three different The titres with both cells are highest at 4°C, lower at RT,
temperatures, using adult (I+s, i+w) and cord (I+w, i+s) cells. and lowest at 37°C. At each of the different temperatures,
the titre versus the adult cells is higher than the titre versus
the cord cells.

6
Petz, LD and Garratty G, 2004. Immune Hemolytic Anemias. 2nd ed. Philadelphia: Churchill Livingstone

10 | www.bio-rad.com/immunohematology n Titration Procedures

 Good Laboratory Practices

Example 6 n Reactions of an Eluate or Serum/Plasma showing Anti-e (RH5) “Relative Specificity”

Titre
Rh Phenotype 2 4 8 16 32 64 128 256
dce/dce
rr 4+ 3+ 3+ 2+ 2+ 1+ 0 0
RH:-1,-2,-3,4,5
DCe/DCe
R1R1 4+ 3+ 3+ 2+ 2+ 1+ 0 0
RH:1,2,-3,-4,5
DcE/DcE
R2R2 3+ 2+ 1+ 0 0 0 0 0
RH:-1,-2,3,4,-5

In this example, the sample is titrated versus E-e+ (rr and Such reaction should confirmed by testing against more
R1R1) and E+e- (R2R2) cells. examples of, in this case, e+ (RH:5) and e- (RH:-5) cells.
The results can be interpreted as showing “relative
specificity” for the e (RH5) antigen.

Example 7 n Phenotyping DAT+ Red Blood Cells when using IAT Reactive Reagents
As a first step, laboratories would try to dissociate the IgG In such cases, typing can be carried out by measuring the
autoantibodies e.g. using chloroquine. Sometimes such amount of specific antibody left in the typing reagent after
treatment will be unsuccessful. adsorption with the patient’s red blood cells, and comparing
it using adsorptions on known single and double dose red
blood cells.

Dilutions of adsorbed anti-Fya reagent

Red blood cells used to adsorb
Neat 1:2 1:4 1:8 1:16 1:32 Score
anti-Fya reagent
Fy(a+b+) / Fy:1,2 2+ 1+ 1+ +/- 0 0 21
Fy(a+b-) / Fy:1,-2 1+ 1+ 0 0 0 0 10
Fy(a-b+) / Fy:-1,2 3+ 3+ 2+ 2+ 1+ 0 41

Patient 2+ 1+ 0 0 0 0 13

These results indicate that the patient is probably Fy(a+) / (Fy:1).

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 Good Laboratory Practices

Example 8 n Microtitration of Anti-D (RH1) expressed in ng/ml

Microtitration of anti-D (RH1) allows to distinguish allo-anti-D n An incoherent reaction strength relative to the date of
from passively acquired anti-D (RH1) after injection of Ig anti-D injection of the Ig anti-D (RH1) (e.g. > 3+ for more than 1
(prophylaxis). month, > 2+ if more than 50 days post-injection, > 1+ if
more than 70 days post-injection)
Particularly in France, this microtitration is indicated when
pregnant women or women who recently delivered present
with: In this method, both a known standard, usually 28 ng/ml is
titrated along with the sample.
n No decrease in reaction strength between two
consecutive antibody detection test (antibody screening) Calculations are then performed based on Brossard et al.7.
n No information available on a possible antenatal injection
with Ig anti-D (RH1)

Calculations
Dilutions 1:4 1:8 1:16 A x B = C
Concentration Reciprocal of the last Concentration of the
Standard
28 ng/ml

7 3.5 1.75 Concentration of anti-D

(ng/ml) reactive dilution of the standard showing the same
(RH1) in the sample
Strength ++++ +++ + sample (< ++++)* reaction strength as (A)

1 + 0 0 4 1.75 7 ng/ml
2 ++++ ++++ +++ 16 3.5 56 ng/ml
Sample

3 ++++ ++++ ++++ > 16 7 > 112 ng/ml

4 +++ + 0 8 1.75 14 ng/ml

n Note, that in this procedure the samples and the n The calculated values are interpreted using tables with
standard are not tested to the normal titration endpoint the expected concentrations of anti-D (RH1), taking into
of +; the reaction strength of the last reactive dilution of account:
the sample is related to the concentration of the dilution
- The concentration of the anti-D (RH1) injected, e.g.
of the standard exhibiting the same reaction strength.
200 μg or 300 μg
- Sample 1: the “last” reactive dilution is 1:4 with a
- The number of doses injected
reaction strength of + and the concentration of the
dilution of the standard exhibiting the same reaction - The delay (days) between the date of injection and the
strength of + is 1.75 ng/ml. draw date of the sample
Logically, the concentration in the sample is:
4 x 1.75 ng/ml = 7 ng/ml.
- Sample 3: reaction strengths of the sample dilution
are ++++. To observe reaction < ++++, the sample
would have to be diluted further. That is not done; the
conclusion is simply > 16, and the calculation than
becomes: > 16 x 7 ng/ml = > 112 ng/ml.

7
Brossard, Y, 2002. M. Diagnostic et suivi prénatals des allo-immunisations érythrocytaires. Feuill Biol, 43, 11-17

12 | www.bio-rad.com/immunohematology n Titration Procedures

 Good Laboratory Practices

n The graph (Figure 1) below represents the expected In case there is no information on the exact date of injection
values post-injection after 1 dose of anti-D (RH1) of of the prophylactic dose, care should be taken on how the
200 μg (dark red) and 300 μg (grey). result is reported. Ultimately a new sample - with proper
information on the dates - should be tested.
n Possible interpretations:
- Finally, as indicated in chapter 2.4, it is important to
- If the concentration of anti-D (RH1) in the sample is
make sure the presence of any other alloantibody is
clearly < the expected value, then it is quite probable
tested
that the anti-D (RH1) is the passively acquired antibody
- If the concentration of anti-D (RH1) in the sample is
clearly > the expected value, a new sample should be
tested a few weeks later (usually 2 weeks), because an
allo-immunisation anti-D (RH1) may be taking place

Figure 1

50
45
40
35
30
ng/ml

25
Dose of 200 µg
20
Dose of 300 µg
15
10
5
0
0 10 20 30 40 50 60 70 80 90 100
Days after injection

Titration Procedures n © Bio-Rad | 13

 Frequently Asked Questions (FAQ)

3 F
 requently Asked Questions
n

(FAQ)
Questions Answers
Will I obtain different titres when performing It is good laboratory practice to review and redefine the
titration on IH-500 diluting the samples with the “normal” values when there is a significant change in a
ID-Titration Solution? test procedure. There may implications on the actions the
treating physicians may decide on.
This accounts for titrations as well.
This means that critical titres for antibodies detected during
pregnancy, or ABO titres in case of an ABOi mismatch, must
be reviewed and communicated to the clinicians.

Why in a context of pregnancy is it so important to The titration of the previous sample in parallel with the new
compare the titres from previous sample and the one must be done to verify that the change in titre is not due
new one? to the variability in the method.

Why two titres obtained in different test conditions As explained before, the variability in titration is reality,
cannot be compared? both between and within techniques used. Titres obtained
in different tests are inherently biased and should not be
compared.

Why should I reset my threshold values if I change The technology used will impact the titre; as titres obtained
my titration method? with different test methods should not be compared,
threshold titres (or critical titres) should be reestablished.

If I want to reestablish my threshold titres, how Titration should be carried out with a significant number of
should I proceed? antibodies with the old and the new method. Care should
be taken to properly select the antibodies by Ig class, IgG or
IgM (if relevant like in ABOi transplants). It is also important
to include antibodies with titres close to the threshold titre.

 hy should I perform a new antibody identification

W Immunized patients are more prone to producing new
on each new sample? antibodies. These newly formed antibodies may interfere
with the titration as explained in section 2.4 on page 6;
therefore it is important to confirm or exclude their presence
or absence.

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