Mag. Herbert Maier Platelet Function Testing PFA-100 ® System Clinical Indications.

Mag. Herbert Maier

Platelet Function Testing

PFA-100® System

Clinical Indications

HM 2

Overview of the PFA-100® Test System

Overview

Introduction

Overview of the Test System

Test Principle

Intended Use and Clinical Performance

PFA-100® compared to Bleeding Time

VWD and DDAVP

Acetyl Salicylic Acid (ASA, Aspirin® - Bayer)

Use of PFA in:

Pre-surgical screening and Bleeding Risk management

Risk Stratification of CVD patients

Transfusion medicine

HM 3

PFA-100® Platelet Function Analyzer

Trigger solution container

Soft keys

LCD screen

Built-In Printer

Carousel

Cassette

Test Cartridge

HM 4

PFA-100® Test Principle

before after

apertureØ150 µM

cup

Platelet plug

Filter+

epinephrineor ADP

flash membrane

800 µl blood

capillaryØ 200 µM

collagen

p = -40 mBar

HM 5

high shear rate>5000 /s

high shear rate>5000 /s

PFA-100® Test Principle

PFA-100®

capillary 200µm

Epinephrine or

ADP membrane with

platelet

von Willebrand Factor

erythrocyte

FLOW

collagen coating

To: Poujol, Nurden, Paponneau, et al.

In Vivo Haemostasis

lumen

fibrinogen

platelet

collagen fibrils

erythrocyte

von Willebrand Factor

endothelial cell

HM 6

Simulates in-vivo conditions; high shear such as

present in small arteries (CVD)

High shear increases the sensitivity to vWF

abnormalities

Assesses the effect of anti-platelet agents under

physiological conditions*

*also recommendation of subcommittee on Biorheology - ISTH 1999

PFA-100® Test Principle - summary

HM 7

Col/EpiCol/ADP

3.8% (129mM) buffered Sodium citrate;90% Central Interval (sec)**: 85 - 165 71 -

118

** : data based on testing of 127 samples with normal platelet function in Germany

** Dade® PFA-100® System Package Insert

Expected Normal Ranges

Expected Values

HM 8

Comparison of the PFA-100® with skin Bleeding Time test

To : Mammen, Comp, Gosselin, et al..

0

1

0 1

Sen

siti

vity

1 - Specificity

PFA-100 ®

Bleeding Time test

PFA-100®

Area Under Curve 0.98 0.70Error 0.01 0.04

Bleeding Time test

Populations:

206 normals176 abnormals

PFA-100® Clinical Performance

HM 9

Sensitivity of PFA-100® System for Platelet Dysfunction

* with Dade® PFA-100® Col/Epi Cartridge (based on meta-analysis of 15 studies)

E.J. Favoloro. Haemophilia 2001; 7:170-179

GT

Cases

Sensitivity (%)

BSS SPD

Sensitivity for Platelet Dysfunction

14

100%

HPS ASA

2

100%

16

75%

11

91%

127

95%

Overall sensitivity for platelet disorders: 91%

HM 10

Sensitivity of PFA-100® System for vWD

1

Cases

Sensitivity (%)

2A 2B

Sensitivity for von Willebrand Disease Type

174*

88%

2M 3 Acquired

33

100%

36

92%

12

100%

31

100%

8/8

100%

Overall sensitivity for VWD: 92%

HM 11

Fressinaud et al. British Journal of Haematology 1999;106(3):777-783.

Correction of Primary Hemostasis in vWD patients

VWD patient management with DDAVP

HM 12

23% of 283 ACS patients Poulsen et al; ESC 2003

38% of 129 post-AMI patients Andersen et al., 2003

10% of 325 patients with CVD Gum et al., 2001

27% of 89 patients with CVD, CAD Santos et al; ISTH 2001

42% of 31 pts. with stable angina Crowe et al; ISTH 2001

25% of 105 pts. with CAD von Pape et al; ASH 2000

58% of 43 pts. undergoing PTCA von Pape et al; ASH 2000

45% of 100 pts. with ACS Sambola et al; ISTH 2001

= 25% of low-responders or non-compliants!

Review of the literature on 1,105 patients on ASAfrequency of normal Col/Epi result:

Cardiac Population

PFA-100® and ASA resistance

HM 13

• 33% of 118 cerebral ischemia patients Hanswillemenke et al; GTH 2002

• 37% of 129 cerebrovascular patients Alberts et al., 2004

• 23% of 53 cerebrovascular patients Grundmann et al., 2003

= 33% of low-responders or non-compliants!

Review of the literature on 300 patients on ASAfrequency of normal Col/Epi result:

Stroke Population


HM 14

There is a correlation between ASA non-responsiveness measured by PFA-100® and

clinical events!

Patients with AMI had 38% ASA non-responders compared to 18% for non

AMI patients

Poulsen et al., 2003

The event rates was 36% in the post-AMI group of ASA non-reponders,

compared to 24% for the responders

Andersen et al., 2003

Patients with recurrent cerebral ischemia attacks had 30% ASA non

responders, compared to 15% for patients with stable clinic

Hanswillemenke et al; GTH 2002

Symptomatic cerebral ischemia patients had 34% ASA non-responders,

compared to 0% for the asymptomatic group

Grundmann et al., 2003

Review of the literature on 552 patients with clinical data


HM 15

Conclusion: aspirin non-responders

Poor response to aspirin has been found in

1. Acute coronary syndromes, where it predicted deaths2. Late venous graft occlusion after bypass3. Recurrent TIA

ACS patients with aspirin home therapy could also profit from additional aspirin infusion (Fuchs & Jilma)

HM 16

Acesal Tbl., 500 mg Acesal-Calcium, 250 mgAcetylin Tbl., 500 mg Acetylsalicylsäure 500 PB, 500 mgAcetylsalicylsäure Tbl. Michallik, 500 mg Alacetan N Tbl., 250 mgAlka-Seltzer Brausetbl., 325 mg Antineuralgie Tbl. Scheurich, 250 mgAsasantin Tbl., 330 mg Aspirin Tbl., 500 mg, 300 mg, 100 mgAspirin direkt Kautbl., 500 mg Aspirin plus C Brausetbl., 400 mgAspirin protect, 100 und 300 mg Aspisol Amp., 500 mgAspro Tbl., 320 mg ASS-AbZ Tbl.ASS Bonfal Infarktschutz Tbl., 75 mg ASS 100/500 Hexal Tbl.ASS dura Tbl., 500 mg ASS Kreuz, 500 Tbl.ASS 100 Tbl. Lichtenstein ASS light 100 AzupharmaASS Kombi ratiopharm Brausetbl., 300 mg ASS mini Tbl., von CT, 50 mgASS ratiopharm Tbl., 100, 300, 500 mg ASS +C Braustbl. 500 mgASS Stada 100/500 Tbl.-Boxazin plus C Br.-tbl., 500mg ASS opt. Tbl., 500 mg

Boxonal Tbl., 210 mg CC-ASS-500 Tbl., 500 mg

CC-Cor Tbl., 30 mg CC-forte Tbl., 250 mgCebion Erkältungsbrausetbl., 50 mg Chephapyrin N Tbl., 250 mgCoffalon Tbl., 200 mg (Calicylamid) Coffetylin Tbl., 450 mg

Contradol Pastillen-Dolomo TN Tbl., 250 mg Dolviran N Tbl., 500 mgDoppel-Spalt compact Tbl., 500 mg Dorocoff-ASS plus Tbl., 400 mg

ASA-containing Medication in Germany (1)

(Koscnielny, personal communication)

*All medications are listed registered trade marks from various companies

HM 17

Gelonida NA supp. für Ki/Erw., 125 mg/500 mg Glutidal Tbl., 400 mg (Salicylamid)Godamed 100/500 Tbl., 100 /500 mg Godasal Tbl., 500 mg-HA-Tbl.N., 250 mgHerz ASS ratiopharm 50/100 Tbl., 50 mg/ 100 mg Hermes ASS plus Tbl., 400 mg

Malinert Tbl., 325 mg Melabon K Tbl., 250 mgMelanbon+C Brausetbl., 500 mg Menostabil-ASS Tbl.Mentopin Vit. C+ASS Brausetbl., 500 mg Micristin Tbl., 500 mgMiniasal Tbl., 30 mg Neuralgin Tbl., 250 mgNeuranidal Tbl., 300 mg Neuranidal Duo Brausetbl., 400 mgOrtoton Plus Tbl., 400 mg Pono-ASS Kaps. Praecineural Tbl., 350 mg und supp. 500 mg Pyracil N Tbl.Quadronal ASS comp. Tbl., 460 mg Ring N Tbl., 300 mgRio-Josipyrin N Tbl., 250 mg Romigal ASS 500 Tbl., 500 mg

Santasal N Tbl., 500 mg Spalt ASS Tbl., 600 mgSpalt A+P Tbl., 300 mg Spalt plus Tbl., 250 mg

Temagin ASS 600 Tbl., 600 mg Temagin PAC Tbl., 250 mgTempil N Kaps., 250 mg Thomapyrin Tbl., 250 mgThomapyrin C Brausetbl., 300 mg Togal Tbl., 250 mgTogal Kopfschmerzbrause + Vit.C, 500 mg Togal ASS Tbl., 400 mg

Werodon-ASS Tbl.

ASA-containing Medication in Germany (2)

(Koscnielny, personal communication)

*All medications are listed registered trade marks from various companies

HM 18

PFA-100® in Preoperative Screening

The Berlin Experience* - Set Up

During 2000, 5649 patients, filled in a questionnaire dedicated to bleeding observations

• Results pos.resp. pred.value

– prolonged bleeding 5.7% 8.2%

– high frequency of “blue spots” 5.1% 65.4%

– NSAID’s 3.6% 83.9%

– Menorrhagia 4,5%

• All patients were tested with a panel of screening tests:Platelet Count, APTT, PT, PFA-100 (Col/Epi and Col/ADP)

Patients, with a positive bleeding history (11.2%), were tested with two additional tests; BT (Surgicutt®), VWF:Ag.

* Koscielny J, et al. Clin Appl Thrombosis/Hemostasis 2004; 10(3): 195-204

HM 19


The Berlin Experience* - Results


All Patientsn=5.649

Negative Bleeding History n=5.021 (88.8%)

Abnormal Screening Tests n=9 (0.2%)

Positive Bleeding History n=628 (11.2%)

PFA-100® (C/Epi) n = 250 (97.7%) PFA-100® (C/ADP) n = 199 (77.7%) ‡BT n = 188 (73.4%)VWF:Ag n = 39 (15.2%) §APTT n = 24 (9.4%) #PT n = 10 (3.9%) ¶Platelet Count n = 2 (0.8%)

APTT n = 9 (0.2%) *Platelet Count n = 0 (0.0%) †

* all 9 patients had lupus inhibitors

† 1 patient had pseudothrombocytopenia

Not detected with PFA-100® (Col/Epi):

‡ 2 patients with hereditary thrombopathy

§ 2 patients with VWD

# 2 patients with VWD

¶ 1 pat. w. dysfibrinogenaemia, 1 w. F VII-deficiency

Abnormal Screening Tests n=256 (40.8%)

HM 20


Results 2 *


Patients with impaired hemostasisis n=256

Secondary haemostatic disorders; n = 2 (0.8%)

Congenital dysfibrinogenaemian = 1

Hereditary F VII deficiency n = 1

Combined haemostatic disorders; n = 67 (26.2%)

Von Willebrand disease

VWD:type 1 n = 40 VWF:Ag(%): 38 (27-49)

VWD: possible type 1 n = 12 VWF:Ag(%): 57 (50-65)

VWD:type 2a n = 2 VWF:Ag(%): 55 (35-62)

Liver cirrhosisVWD:type 1 n = 13

Acquired thrombocytopathiesuremia associated n = 7drug induced

acetylsalicylic acid n = 87diclofenac n = 29ibuprofen n = 7piroxicam n = 5ticlopidine n = 17clopidogrel n = 2valproic acid n = 5ciprofloxacin n = 3cefotaxin n = 2azlocillin n = 2benzylpenicillin n = 3

Hereditary thrombocytopathiesGlanzmann Thromb. n = 1Bernard-Soulier S. n = 1Secretion Defects n = 16

Primary haemostatic disorders; n = 187 (73.0%)

HM 21


Conclusions*

The vast majority of these patients could not be identified by routine screening for PT, APTT and Platelet Count

250 of these patients (256) are detected with the PFA-100® (Col/Epi)

A combination of all tests, without PFA-100® would miss up to 30% of the patients at risk for bleeding!

The PFA-100® (Col/Epi) demonstrated a PPV of 81.8% and NPV of 93.4% for impaired hemostasis

The PFA-100® system is clearly superior to the bleeding time.


HM 22


Recommendations*

For patients needing a pre-surgical work-up, a test panel without the PFA-100® (Col/Epi) is insufficient.

Patients with increased risk for bleeding complications can be identified using a standardized questionnaire and a test panel comprised of PFA-100® (Col/Epi), VWF-Ag, PT and APTT.

The PFA-100® (col/Epi) is important also for assessing the therapeutic efficacy of drugs such as aspirin and desmopressin acetate (DDAVP)


HM 23

Preoperative management of patients with impaired hemostasis

The Berlin Experience* - Results

The administration of DDAVP led to a correction of platelet dysfunction in 229 of the 254 patients treated (90.2%).

In patients with corrected impaired hemostasis the number of blood transfusions was non-significantly lower (9.4% vs. 12.2%; p = 0.202), than in patients without impaired hemostasis.

In a retrospective group of patients with non-corrected impaired hemostasis, the number of blood transfusions was significantly higher (89.3% vs. 11.3%; p < 0.001) than in patients without impaired hemostasis.


HM 24

Preoperative management of patients with impaired hemostasis

0

20

40

60

80

100

1999 retrospective 2000 prospective

Results * Retrospective study n=5102

Prospective studyn=5649

Corrected Impaired

n=256

Non-corrected normalsn=5393

transfusedn=24 (9,4%)

transfusedn=660 (12,2%)

Non-corrected Impairedn=317

Non-corrected normals

n=4785transfused

n=283 (89,3%)transfused

n=541 (11,3%)

Tra

nsf

use

d (

%)

p < 0.001

p = 0.202

Elective operations


HM 25

Platelet Function in Patients with Acute MI*

Set-up

Patients with acute chest pain or symptoms suggestive of acute coronary

syndromes (n=216) were prospectively examined at an emergency unit.

Results

COL/ADP-CT was significantly shorter in MI patients, than in other patient

groups (unstable angina, stable coronary artery disease), or controls.

Furthermore, COL/ADP-CT and COL/EPI–CT at presentation were

independent predictors of myocardial damage as measured by CK-MB or

TnT.

Patients with MI whose COL/ADP-CT values fell in the first quartile had

3-fold higher CK-MB and TnT levels than those in the fourth quartile.

* Frossard M, et al. Circulation. 2004;110:1392-1397

HM 26

Potential applications for PFA-100 in transfusion medicine

Quality control of platelet concentrates

– Collection (van der Boehlen et al. 2001, Feuring et al. 2001)– Storage (Beck et al. 2002, Borzini et al. 1999)– Cryo-Preservation (Borzini et al. 1999, 2000)

Therapeutic monitoring (e.g. DDAVP)

» Eriksson et al. Vox Sang 1996

Peri-operative transfusion management

– Platelet concentrates (Raman et al. 2001)

HM 27

Conclusion

INDICATIONS FOR PFA-100

BLEEDING Screening for VWD and platelet dysfunction Transfusion medicine: donor screening, transfusion efficacy Menorrhagia: screening for platelet defect / VWD Surgery: patients with high risk for platelet dysfunction or vWD

THROMBOSIS Detection of aspirin non-responsiveness and platelet hyperactivity

HM 28

The End

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Mag. Herbert Maier Platelet Function Testing PFA-100 ® System Clinical Indications.

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Transcript of Mag. Herbert Maier Platelet Function Testing PFA-100 ® System Clinical Indications.