Ma rc ia L . Zuc ke r, Ph.D. ZIVD L L C 1
E xpla in the I NR, wha t it is, ho w it is c a lc ula te d a nd whe n it sho uld b e use d De sc rib e re a so na b le e xpe c ta tio ns fo r I NR a g re e me nt a c ro ss pla tfo rms E va lua te diffe re nt I NR syste ms to ma ximize sta nda rdize d pa tie nt c a re 2
Mo nito ring he mo sta sis Bleeding Clotting 3
Picture courtesy of Helena Laboratories 4
Extrinsic Pathway Monitor Monitor with with PT WARFARIN ACT / aPTT X Xa LMWH & DXaI Common Pathway Monitor II IIa (thrombin) with ??? Hirudin & DTI CLOT 5
Mechan- Moni- Drug Action Effective ism toring Direct AT APTT Heparin Inhibition of Immediate cofactor ACT Thrombin Decreases Delay Warfarin Production Vitamin K PT 3-5 days of factors 6
Ra t po iso n Ca use o f “swe e t c lo ve r dise a se ” Ora lly a c tive a ntic o a g ula nt 7
8
F unc tio ns b y de c re a sing pro duc tio n o f Vita min K de pe nde nt c lo tting fa c to rs in live r › De la ye d o nse t o f a ntic o a g ula tio n Po te nc y ma y va ry b y ma nufa c ture r Do se re spo nse va rie s b y pa tie nt › Die ta ry inte ra c tio ns › L ife -style influe nc e s 9
Picture courtesy of Helena Laboratories 10
T hro mb o pla stin iso la te d fro m: › Diffe re nt spe c ie s pig ; c o w; huma n; e tc . › Diffe re nt o rg a ns b ra in; thymus; lung ; e tc . All yie ld diffe re nt re sults › Re sults va ry b y instrume nt syste m in use Ma nua l tilt tub e “g o ld sta nda rd” F ib ro me te r; a uto ma te d c o a g ula tio n syste ms PT ra tio s a do pte d to de te rmine the ra pe utic ra ng e 11
1977 – 1 st I RP de ve lo pe d › Inte rna tio na l re fe re nc e thro mb o pla stin pre pa ra tio n 1983 – K irkwo o d de sc rib e s me tho d to c a lib ra te lo c a l thro mb o pla stin to I RP › De fine re a g e nt ISI Inte rna tio na l se nsitivity inde x 1983 – WHO a nd I ST H re c o mme nd the use o f the I NR to sta nda rdize PT re sult re po rting 12
I nte rna tio na l No rma lize d Ra tio (I NR) › I SI = inte rna tio na l Se nsitivity I nde x › INR ta rg e t ra ng e s a re spe c ifie d b y pa tie nt po pula tio ns, e .g ., DVT , Afib , Atria l MHV: INR= 2.0 - 3.0 Mitra l me c ha nic a l he a rt va lve : INR= 2.5 – 3.5 Individua l va ria tio n 13
I SI › Initia lly de te rmine d b y re a g e nt ma nufa c ture r › T ra c e a b le to IRP Inte rna tio na l Re fe re nc e thro mb o pla stin Pre pa ra tio n › WHO de fine d pro c e ss Ca lib ra tio n up to INR = 4.5 ma nua l tilt tub e me tho d re fe re nc e › L o c a l c a lib ra tio ns c a n b e pe rfo rme d to de te rmine the 1 instrume nt spe c ific ISI Me a n no rma l PT › T he me a n no rma l PT sho uld b e de te rmine d fo r e a c h ne w b a tc h o f thro mb o pla stin with the sa me instrume nt 1 use d to a ssa y the PT Antithrombotic therapy and prevention of thrombosis, 9th ed: ACCP guidelines. CHEST 2012; 141(2)(Suppl):e44S–e88S 14
L o c a l c a lib ra tio n ma y intro duc e va ria b ility › Sa me sa mple yie lds diffe re nt re sults de pe nding o n c a lib ra tio n me tho d ISI and MNPT from Poller et. al., J Thromb Haemost 2012; 10: 1379–84. 15
Ma nufa c ture r a ssig ns I SI a nd me a n no rma l PT (MNPT ) › L o t spe c ific T ra c e a b le to I RP › Ofte n thro ug h se c o nda ry sta nda rd Ca nno t b e c ha ng e d b y e nd use r › Do e s no t va ry b y lo c a tio n o f te sting 16
b ut it WI L L Co rre la te 17
Po int o f Ca re L a b o ra to ry › Who le Blo o d › Pla te le t Po o r Pla sma › No Adde d › So dium Citra te Antic o a g ula nt Antic o a g ula nt › No Dilutio n › 1:9 Dilutio n › No Pre a na lytic a l › Va ria b le Pre a na lytic a l De la y De la y > Re a g e nt > I nstrume nt > Clo t de te c tio n 18
L a b Sa mple s › Blo o d c o lle c tio n ve nipunc ture te c hniq ue tub e und e rfill c itra te c o nc e ntra tio n he mo lysis 3.2% sho uld b e use d › T ra nspo rt te mpe ra ture e ffe c ts e xpo sure b e yo nd 18 - 24°C a ffe c ts re sult c o ld te mpe ra ture s sig nific a ntly re d uc e PT sa mple c lo tting d e la y in te sting va ria b le e ffe c ts d e pe nd ing o n a mb ie nt te mpe ra ture , c o nc o mita nt me d ic a tio ns a nd time o f d e la y CLSI documents H03; H21 and H54 19
Po int o f Ca re › Blo o d c o lle c tio n fing e rstic k te c hniq ue use o f c a pilla ry tub e fo r tra nsfe r 20
Co rre la tio n da ta fro m: Ple sc h e t. a l, T hro mb Re s 2008; 123:381–9 T hr omboplastin Analyze r c alibr ation T hr omboplastin Analyze r c alibr ation I nno vin CA1500 L o c a l vs rT F / 95 He pa to Quic k ST A-R Ma nufa c ture r Re c o mb ipla stin ML A1800 L o c a l vs rT F / 95 T hro mb o te st K C10 L o c a l vs OBT / 79 Ne o pla stin Plus ST A-R Ma nufa c ture r T hro mb o pla stin C Plus CA1500 Ma nufa c ture r 21
10 OAT pa tie nts a c ro ss 7 a na lyze r/ re a g e nt c o mb ina tio ns Mc Gla sso n, DL 2003: L a b Me d 34: 124 – 9. 22
36 pa tie nts o ve r 4 visits e a c h › 3 POC; 1 la b So lvik e t. a l., 2010: Clin Che m 56:1618–1626 (2010) INR % diff POC1-STA INR % diff POC 2-STA INR % diff POC 3-STA 23
Ob se rve d: › + 0.4 a t INR = 2.0 › + 0.8 a t INR = 3.0 › + 1.2 a t INR = 4.0 Sta nda rdiza tio n a s with g luc o se is unlike ly › disc re te a na lyte to b e te ste d › ve rsus a b io lo g ic pro c e ss Jacobson, J Thromb Thrombolysis (2008) 25:10–11 24
Re sults Ava ila b le While Pa tie nt is Pre se nt › Impro ve d Antic o a g ula tio n Ma na g e me nt Inc re a se d T ime in T he ra pe utic Ra ng e › Impro ve d Sta nda rd o f Ca re › Sta ff E ffic ie nc y I mme dia te Re te sting (if ne e de d) › F ing e rstic k Sa mpling 25
POCT 14A Co nse nsus Ca ndida te L imit Sourc e INR Range Agre e me nt L imits CL SI POCT 14A 1.0 to 2.5 + 0.4 CL SI POCT 14A 2.6 to 3.5 + 0.7 L ite ra ture 3.6 to 5.0 + 0.9 L ite ra ture Ab o ve 5.0 + 1.2 Supportive Literature Citations Lassen JF et al. INR for PT in patients ……Critical difference and probability of significant change in consecutive measurements, Clin Chem . 1995. Oral Anticoagulation Monitoring Study Group. POC PT measurement for professional and patient self-testing use, Am J Clin Path . 2001. Hobbs et al. Is the INR reliable? A trial ……..in hospital laboratory and primary care settings. J Clin Pathol, 1999. Jacobson A. Warfarin monitoring: POC INR limitations and interpretations. J Thromb Thrombolysis, 2008. Ansell J et al. Pharmacology and management of Vit K: Am Coll Chest Physicians Evidence Based Clinical Practice Guidelines. CHEST 2008. 26
L o we r do se ? K e e p sa me do se ? Ra ise Do se ? T e st Ag a in? T e st mo re o fte n? 27
Thrombotic and Hemorrhagic Reserve for a Patient with a target INR of 3.0 Increased 100 Increased Incidence per 100 Patient-Years Thrombotic Thrombotic Hemorrhagic Hemorrhagic Risk Reserve Reserve Risk 80 target 60 40 20 0 28 Adapted from Cannegeiter, et. al. N Engl J Med 1995; 333:11-17
a pe utic Ra ng e Goa l is to Ma inta in a T ig ht T he r Pra c tic a l Co nside ra tio ns › A-F ib c o mp lic a tio ns inc re a se fro m 4% a t a g e 65 to >15% a t a g e 75 29
1. Unde rsta nd limita tio ns in the I NR › Whe ne ve r a pa tie nt unde rg o e s duplic a te te sting o n diffe re nt syste ms, the re is the po te ntia l fo r disa g re e me nt 2. Atte mpt to ha ve pa tie nts ma na g e d with a c o nsiste nt me tho do lo g y Jacobson, J Thromb Thrombolysis (2008) 25:10–11 30
I NR wa s de ve lo pe d to mo nito r e ffe c t o f vita min K a nta g o nists (wa rfa rin, o the rs) I NR is ina ppro pria te sc a le fo r mo nito ring c o a g ulo pa thie s Mo st POC PT / I NR te sts c le a re d ONL Y fo r mo nito ring pa tie nts re c e iving o ra l a ntic o a g ula tio n the ra py suc h a s Co uma din o r wa rfa rin. 31
Mo nito ring he mo sta sis Bleeding Clotting 32
Marcia L. Zucker mlzucker.zivd@gmail.com 33
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