Coagulare exercitii

7/30/2019 Coagulare exercitii

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International Sensitivity Index [ISI] & TheInternational Normalised Ratio [INR]

IntroductionThe Prothrombin Time (PT) in an individual with one or more

deficiencies of a clotting factor will vary with the type of thromboplastin

(e.g. rabbit, human, bovine etc) used in the assay. This difference in

sensitivities is known as the sensitivity index. Individual thromboplastins

can be calibrated against an international WHO reference

thromboplastin (International Reference Preparation or IRP) to assign

them an International sensitivity index or ISI. The first WHO referencethromboplastin was assigned an ISI of 1.0 and it is against this (and

subsequent reference preparations) that all other thromboplastins are

calibrated.

The first WHO IRP was a human brain extract to which adsorbed bovine

plasma was added to optimise the content of the non-vitamin K

dependent coagulation factors. Subsequent WHO IRPs contain no

adsorbed bovine plasma.

Principles & Methodology1. Calculating the ISIThe calibration of a test thromboplastin must be against a reference

thromboplastin of the same species e.g. human against human, rabbit

against rabbit etc.

Prothrombin Times are performed in duplicate for each thromboplastin

and the mean for each pair of tests derived. Tests are historically

performed on 20 normal donors not on anticoagulants and 60 patients

who have been on oral anticoagulant treatment for at least 6 weeks. If


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there is more than a 10% difference in the clotting times between

duplicate samples, the tests on that plasma sample should be repeated.

The mean of each pair of of PT results are plotted on double-log paper

with the reference sample on the Y axis and the test plasma on the X-axis. The use of the double-log paper removes the necessity to derive

the log for each PT result. A line of best fit is drawn and the slope of this

line is the ISI.


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The ISI can be calculated in (at least) two ways:

Deriving the ISI

The preferred method The PTs of all the plasma samples are converted to the corresponding

logarithms, an orthogonal regression line is calculated and from whichthe ISI can be derived. For more information relating to the derivation of

the ISI - see References.

The simpler method A best fit line is drawn with points above the highest recorded PT and the

lowest PT (see figure above). The slope of the line is calculated and thisrepresents the ISI.

In the example shown above -

Distance A to C = 125mm and distance B to C = 110mm

So the ISI of the test thromboplastin is calculated from the formula:

So if the ISI of the Reference Thromboplastin is 1.1 and the ISI derived

from the slope is 1.14, the ISI of the Test Thromboplastin is 1.1 x 1.14 =

1.25.

Thromboplastins should be chosen with an ISI close to 1.0.

Thromboplastins with high ISIs are less sensitive to small changes in the

PT. The table below under INR illustrates this. Using a thromboplastin

with an ISI of 1.0 the PT can range from 15s - 35s but the INR is still inthe therapeutic range. In contrast if the ISI of the thromboplastin is 2.0 an

increase in the PT from 15s to 30s results in an INR outwith the

therapeutic range.

Local Calibration


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Whilst the development of an International Reference Thromboplastin

resulted in significant improvements in the standardisation of

anticoagulant control, the use of different coagulometers for the PT and

the differing methods of end-point detection can lead to significantvariations in PT. For these reasons, a local calibration of

thromboplastins is recommended. This involves testing a set of plasma

samples with known INRs with the a laboratory-specific thromboplastin

and on the coagulometers which will be used to derive the PT.

2. The International Normalised Ratio[INR]

The International Normalised Ratio (INR) is the PT ratio of a test sample

compared to a normal PT (derived from the log mean normal

prothrombin time (LMNPT) of 20 normal donors) corrected for the

sensitivity of the thromboplastin used in the test. It is the value for the

Prothrombin Time Ratio which has been obtained using the first WHO

Reference Thromboplastin with an ISI of 1.0.

or as below:

So for a patient on warfarin with a PT of 23 seconds and a mean normal

PT of 12 seconds using a thromboplastin with an ISI of 1.2, the INR is

2.18:


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The table below illustrates a number of patients with varying PTs and in

whom the INR was calculated using three thromboplastins with varying

ISIs. The Geometric Mean Normal Prothrombin Time (GMNPT) for a

group of 20 normal donors not on anticoagulants was 12.1s.

Patient PT [s] Thromboplastin 1

[ISI 1.0]

Thromboplastin 2

[ISI 1.5]

Thromboplastin 3

[ISI 2.0]

15 1.25 1.39 1.5420 1.67 2.15 2.78

25 2.08 3.00 4.3

30 2.5 3.95 6.25

35 2.91 4.98 8.51

The simplest way to calculate the INRs is to use an electronic

calculator!

A nomogram for correcting prothrombin time ratios to INR can be used

for any thromboplastin where the ISI is known. This LINK will take to a

publication which demonstrates the nomogram.

Reference RangesThe INR reference value for a patient not taking a vitamin K antagonist

is 1.0. The therapeutic range for anticoagulation varies according to the

precise indication - see BCSH Guidelines and ACCP Guidelines.

Data InterpretationClick HERE to go to the Data Interpretation Exercises.COMMENTS

1. The INR is used for monitoring patients on warfarin and whilst it isfrequently used in other areas e.g. for assessing the severity of liverdysfunction this is incorrect and the PT should be used for this.
http://www.practical-haemostasis.com/References/WHO_LAB_98.3-3.pdfhttp://www.practical-haemostasis.com/Data%20Interpretation/Data%20Questions/data_interpretation_miscellaneous_tests.htmlhttp://www.practical-haemostasis.com/References/WHO_LAB_98.3-3.pdfhttp://www.practical-haemostasis.com/Data%20Interpretation/Data%20Questions/data_interpretation_miscellaneous_tests.html


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2. The INR is widely used in various models for end-stage-liver-diseasee.g. the MELD score [Model forEnd-stage LiverDisease] or the theChild-Pugh score - and is a mathematical score that is used to prioritisepatients for liver transplantation.

Amongst the variables included in this score is the INR. The INR in thisscore was used to minimise any variation in PT that might result fromusing thromboplastins with varying reagents and therefore patients fromdifferent centres could be prioritised.However, the INR evolved to monitor patients on oral anticoagulantsand not with liver disease and the variables that affect the INR inpatients with liver disease are different from those that affect the INR inpatients on drugs such as warfarin.For these reasons it has been proposed that thromboplastins becalibrated to establish their ISILiverand that this ISILiver is then used toconvert PT into INR. This alternative thromboplastin calibration usingplasmas from patients with cirrhosis instead of from patients on vitaminK antagonists may resolve the variability of these scores in prioritisingpatients for transplantation.REFERENCES

1. Hermans, J., et al., A collaborative calibration study of referencematerials for thromboplastins. Thromb Haemost, 1983. 50(3): p. 712-7.

2. Kovacs MJ, Wong A, MacKinnon K, Weir K, Keeney M, Boyle E, et al.

Assessment of the validity of the INR system for patients with liverimpairment Thromb Haemost. 1994;71(6):727-30.

3. Kitchen S, Walker ID, Woods TA, Preston FE. Thromboplastin relateddifferences in the determination of international normalised ratio: acause for concern? Steering Committee of the UK National ExternalQuality Assessment Scheme in Blood Coagulation. Thromb Haemost.1994 Sep;72(3):426-9.

4. Thomson, J.M., J.A. Tomenson, and L. Poller, The calibration of the

second primary international reference preparation for thromboplastin(thromboplastin, human, plain, coded BCT/253). Thromb Haemost,1984. 52(3): 336-42.

5. Kirkwood, T.B., Calibration of reference thromboplastins andstandardisation of the prothrombin time ratio. Thromb Haemost, 1983.49(3): 238-44.


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6. Tripodi, A., et al., International collaborative study for the calibrationof a proposed reference preparation for thromboplastin, humanrecombinant, plain. On behalf of the Subcommittee on Control of

Anticoagulation. Thromb Haemost, 1998. 79(2): 439-43.

7. Tripodi, A., et al., A simplified procedure for thromboplastincalibration--the usefulness of lyophilized plasmas assessed in acollaborative study. Thromb Haemost, 1996. 75(2): 309-12.

8. Poller L. International Normalized Ratio (INR): the first 20 years. JThromb Haemost 2004;2:849-860.

9. Floden A, Castedal M, Friman S, Olausson M, Backman L.Calculation and comparison of the model for end-stage liver disease(MELD) score in patients accepted for liver transplantation in 1999 and2004. Transplant Proc. 2007 Mar;39(2):385-6.

10. Londono MC, Cardenas A, Guevara M, Quinto L, de Las Heras D,Navasa M, et al. MELD score and serum sodium in the prediction ofsurvival of patients with cirrhosis awaiting liver transplantation. Gut.2007 Sep;56(9):1283-90.

10. Baglin et al. Guidelines on oral anticoagulation (warfarin): third

edition - 2005 update. Brit J Haem 2005;132(3):277-285.

11. BCSH Website

12.ACCP Guidelines

LINKS

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----------------------------------Data Interpretation:Miscellaneous Tests

IntroductionThis section covers many of the tests that were outlined in the section

on 'Miscellaneous tests' - some questions do cross over into some of

the other sections.

Question 1


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You are provided with prothrombin times using two different thromboplastins on a number of

patients stably anticoagulated on warfarin as well as several normal healthy individuals.

One thromboplastin is the WHO rabbit reference material and the other is an 'in-house' rabbit

material you have prepared in your laboratory.Plasma Sample PT [s] WHO Reference Preparation PT [s] In-House Preparation

1 32 15.5

2 46 16

3 50 19.5

4 46 16

5 15 12

6 43 16

7 13 12

8 45 18.5

9 32 15.5

10 13 11

11 55 18

12 48 17

13 13 11

14 14 12

15 55 18

16 55 20

17 29 15

A. What is the ISI of the home made material?

B. Would you use this thromboplastin in your laboratory? If not, why not?

Question 2


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From the data shown in the attached graph derive the ISI (roughly) for thromboplastin. If you clickHEREyou

graph in a new window.

The WHO Reference thromboplastin has an ISI of 1.0. Points A, B and C are designed to help you.
http://www.practical-haemostasis.com/images/Images-2/Data%20Interpretation/Miscellaneous%20Tests/isi.jpghttp://www.practical-haemostasis.com/images/Images-2/Data%20Interpretation/Miscellaneous%20Tests/isi.jpghttp://www.practical-haemostasis.com/images/Images-2/Data%20Interpretation/Miscellaneous%20Tests/isi.jpg


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Question 3

A 20-year-old woman is 32/40 weeks pregnant. She attends the antenatal clinic for a routine check

up. You are asked to see her because of the following results:

Test Patient Reference Range

Hb 10.1g/dL 11.5-13.5 g/dL

WCC 6.2 x 109/L 6 - 10 x 109/L

Platelets 80 x 109/L 150-400 x 109/L

MPV 13.1 fL 7.5-9.2 fL

1. What would you do immediately and what investigations would you request?

2. What are the possible diagnoses?

Click here for Part 2


Question 4

A 23-year-old man is investigated for a possible bleeding disorder whilst living in Paris. He has a

bleeding time performed and this is found to be significantly prolonged at 26 minutes (NR:


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Briefly explain the principles of the Activated Clotting Time and the Thrombin Time

1. What factors can affect the ACT?

2. What factors can affect the thrombin time?

2. Why do we use the ACT and not the thrombin time to monitor patients on cardio-pulmonary

bypass?

Question 6

A 64-year-old man undergoes an aortic valve replacement. Prior to coming off bypass he is given

protamine sulphate to reverse the unfractionated heparin. His BP falls and he becomes profoundly

hypotensive.

1. What is protamine sulphate and how does it work?

2. What do you think might have happened?

Question 7

A 56-year-old man with a long history of COPD is admitted for surgery.

His pre-operative investigations show a Hb of 19g/dL and an Hct of 0.58 .


PT 20s 11-14s

APTT 47s 23-35s

1. What might explain these findings and what would you do next?

Question 8

Outline the mechanism of action of tranexamic acid and DDAVP.

Question 9


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A 45-year-old female presents with a spontaneous proximal DVT. She is anticoagulated with

initially a low molecular weight heparin and subsequently warfarin with a target INR of 2.5.

Shortly after starting warfarin she complains of bruising and presents 5 weeks later to Accident and

Emergency with a large haematoma in her right calf. Her investigations on admission are shown

below:


INR 2.3 1.0

APTT 117s 28-34.5s

Fibrinogen (Clauss) 3.9 g/dL 2-4 g/dL

Haemoglobin 12.2g/dl 13.5-16.2 g/L

Platelets 298 x 109/L 150-400 x 109/L

1. What additional tests might you request and why?



Question 10

A 67-year-old man with no previous history of note requires an aortic valve replacement. He has a

pre-operative screen performed and this shows the following:


PT 13s 11-14s

APTT >120s 28-34.5s

Fibrinogen (Clauss) 3.9 g/dL 2-4 g/L

Thrombin Time 14s 11.5-13.5s

Platelets 358 x 109/L 150-400 x 109/L

1. What would you do next?




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Question 11

A 56-year-old woman is admitted thorough Accident and Emergency having been found confused

at home by her partner.

Investigations show:


PT 14s 11-14s

APTT 35s 28-34.5s

Fibrinogen (Clauss) 2.1 g/dL 2-4 g/L


Hb 8.6 g/dL 7.3 g/dL

Platelets 23 x 109

/L 150-400 x 109

/L

WCC 11.2 x 109/L 6-10 x 109/L

LDH 2342 U/L


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A 45-year-old woman is on treatment for pulmonary TB and develops a large abdominal

haematoma. Laboratory investigations show:


PT 14s 11-14s

APTT 35s 28-34.5s

Fibrinogen (Clauss) 4.2 g/L 2-4 g/L


Platelets 387 x 109/L 150-400 x 109/L

PFA-100 [Collagen:ADP] Normal closure times

1. What additional tests would you request?


Question 13

A 67-year-old male is admitted to CCU with unstable angina. He undergoes an emergency coronary

angioplasty and receives in addition to 5000 units of unfractionated heparin, Abciximab to prevent

re-occlusion of the coronary artery. 3 days after the procedure he is noted to be bruising and his

platelets are found to be 5 x 109/L having been 189 x 109/L at the time of his admission.

i. What are you going to do

ii. What do you think has happened

iii. What is Abciximab

Question 14


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A 23-year-old man is referred for investigation of prolonged bleeding after dental extraction.

Shown below are the results of his premilinary tests. Comment upon the results of these tests andsuggest other other that you think would be of value.


PT 11s 11-14s

APTT 45s 28-34.5s



Platelets 387 x 109/L 150-400 x 109/L

PFA-100 [Collagen:ADP] 155s 60-133s


Click HERE for Part 2


Question 15


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A 57-year-old man is transferred to ITU following coronary artery bypass grafting. He has a

'routine' post-operative clotting screen performed which shows:


PT 11s 11-14s

APTT 34s 28-34.5s


Thrombin Time >120s 11.5-13.5s

Platelets 187 x 109/L 150-400 x 109/L

1. What do you think might provide an explanation for these results and what would tests would

you like to perform?



Question 16


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A 47-year-old man is see in the Emergency Department with a 2 week history of easy bruising and

more recently of a prolonged epistaxis. His past medical history was unremarkable, he had notcommenced any new drugs and there was no family history of note.

He had a full blood count performed together with the results of some 'basic' clotting tests. Shown

below are the results of his preliminary tests.

Comment upon the results of these tests and suggest other investigations that you think would be of

value in reaching a diagnosis.


PT 15.9s 11-14s

APTT 21.3s 28-34.5s


D Dimer >60,000 ng/mL 0-230 ng/mL

Platelets 14 x 109/L 150-400 x 109/L

Hb 7.2 g/L 11.5 -15.5 g/dL

WCC 276 x 109/L 5-16 x 109/L



Comment upon the results of the blood films?

Why do patients with this particular problem bleed?

ClickHEREfor the AnswersTry to avoid looking at the answers until you have worked

through the questions.COMMENTS

1. You will gain maximum educational value if you work through eachpart of each answer before you look at the second and subsequentparts or indeed the answers.

2. The answers will give you some help as to the reasoning behind
http://www.practical-haemostasis.com/Data%20Interpretation/Data%20Answers/data_interpretation_miscellaneous_tests_answers.htmlhttp://www.practical-haemostasis.com/Data%20Interpretation/Data%20Answers/data_interpretation_miscellaneous_tests_answers.html


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some of the questions.

3. The questions span disorders from common to exceptionally rare butinteresting.REFERENCES

LINKS

HOME PAGE

Site Map Graph Paper

SEARCH THIS SITE

Search

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