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Globala hemostatiska metoder vid
hemofili
Roza Chaireti
Specialistläkare, med dr
Hematologiskt Centrum
Karolinska Universitetssjukhuset
Hemofili
!  αιµοφιλία (αιµορροφιλία)
!  X-linked recessiv blödningssjukdom
!  Hemofili A orsakas av faktor VIII brist
!  Hemofili B orsakas av faktor IX brist
!  Spontana och posttraumatiska blödningar
Roza Chaireti
april 7, 2015
2
Hemofili A
!  1: 5,000
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Kliniska utmaningar vid hemofilivård
!  Diskrepans mellan faktornivå och blödningssymtom
!  Förutsäga blödningsrisken hos patienter med hemofili med olika
svårighetsgrader
!  Monitorera behandling
!  Med faktorkoncentrat
!  Med ”bypassing agents”
Roza Chaireti
april 7, 2015
5
PPP and PRP is normal.
Thrombin generation assays (TGA)
Roza Chaireti
april 7, 2015
6
such as the rate of clot formation, the
nd stability of the clot are thereby recorded by
, and are dependent on the interaction of the
n factors, platelets and fibrinogen. The traced is called the thromboelastogram as shown
the same instrument.
In order to ensure that the instruments were in good
working order it was determined that the date of the last
maintenance check was within 6 months of running the
test.
Since PRP is more stable during storage and transportation, this was determined to be the sample of
choice. A pool of normal as well as FVIII deficient
plasma was provided by Center for Hemophilia and
Tromboelastografi (TEG, ROTEM)
G! and ROTEM! although similar have
erences in the mechanical aspects. This is
d in Table 1.
2
hromboelastography trace.
Chitlur et al. Haemophilia 2011;17:532-37!
kwell Publishing Ltd
Roza Chaireti
BOLLIGER ET AL
counterbalanced or at least questioned [2]. Screening for coagulation abnormalities and application of
hemostatic interventions based on classical coagulation tests such as prothrombin time (PT) and
activated partial thromboplastin time (aPTT) are of
limited value in perioperative and acutely ill
patients [3]. Whole blood testing by thromboelastography may offer advantages in these clinical
settings. Originally invented in 1948 [4], its concept
predates the introduction of the aPTT test in plasma
[5]. Recent methodological improvements of
thromboelastography have widely expanded its
use from preclinical hemostasis research to pointof-care use in the emergency and the operation
room. Two commercially available devices are
TEG (Thromboelastograph; Haemoscope/Haemonetics, Niles, Ill) and ROTEM (Rotation Thromboelastometry; TEM International, Munich,
Haemophilia (2011), 17, 532–537
Germany). The TEG system has been available
for many years in the United States, whereas the
ROTEM system has been recently approved by the
Food and Drug Administration for clinical use. In
this review, the term thromboelastography will be
used to describe general principles of the common
technology, but the differences between the 2
Fig 1. Working principle of TEG (panel A) and ROTEM (panel
In TEG, the cup with the blood sample is rotating, whereas the
systems will be specified as TEGBollinger
or ROTEM, B). et
Med
2012;26:1-13
torsion wireal.
is fixed. InTransf
ROTEM, the cup is fixed,
whereas theRev
pin is
respectively.
rotating. Changes in torque are detected electromechanically in
Technical and methodological aspects of throm- TEG and optically in ROTEM. The computer-processed signal is
boelastography have been recently discussed in finally presented as a tracing. Panel C shows typical tracings from
(lower tracing) and ROTEM (upper tracing). For a detailed
detail [6-10], but practical aspects of its clinical TEG
description of the terms used and the reference values of the
applications have not been fully appreciated. In various thromboelastographic parameters, see Tables 1 and 2. april 7, 2015
7
this article, we review the working principles,
In the original description [4], a metal pin
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Trombingenerering hos patienter med
hemofili
à >Ãœ iÛ>Õ>Ìi`° 7…i˜ *** Ü>Ã
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>Ài` ̜ >À}iÀ £n ˜ii`iÃ] >˜` ˜œ
!  Trombingenerering (TG) motsvarar svårighetsgrad i både
hemofili A och hemofili B
…iÀˆÌi` …>i“œ«…ˆˆ> >˜` !  TG avspeglar svårighet av blödningssymtom hos de flesta
patienterna oavsett faktornivån
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˜ˆvˆV>˜Ì°
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Vœ˜ÌÀœ
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i˜Vià LiÌÜii˜ ÀiÃՏÌà œLÌ>ˆ˜i` ܈̅ 6>VÕÌ>ˆ˜iÀ ÌÕLià Vœ˜Ì>ˆ˜ˆ˜}
£äx œÀ £Ó™“ ÌÀˆÃœ`ˆÕ“ VˆÌÀ>Ìi° /…iÀi Ü>à >Ãœ ˜œ È}˜ˆvˆV>˜Ì
`ˆvviÀi˜Vi LiÌÜii˜ 6>VÕÌ>ˆ˜iÀ >˜` œ˜œÛiÌÌi ÌÕLià Vœ˜Ì>ˆ˜ˆ˜}
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Lˆ˜ }i˜iÀ>̈œ˜ ˆÃ >Ãœ `i«i˜`i˜Ì œ˜ 8 >˜` Vœ˜Ì>VÌ >V̈Û>̈œ˜°
˜ œÀ`iÀ ̜ Ài`ÕVi Vœ˜Ì>VÌ >V̈Û>̈œ˜] Üi ÕÃi` …Þ`Àœ«…œLˆV «œÞ‡
«Àœ«Þi˜i ÌÕLià ­iÃà «Àœ˜i ̜ ˆ˜`ÕVi >V̈Û>̈œ˜ ̅>˜ «œÞÃÌއ
Ài˜i®° Ó£ ˜ii`ià ÜiÀi Vœ“«>Ài` ̜ >À}iÀ £n ˜ii`iÃ] >˜` ˜œ
`ˆvviÀi˜Vi Ü>à ˜œÌi`°
{ÇÇ
/*
­“i>˜´-®
Dargaud et al. Thromb Haemost 2005; 93:475-80 !
ˆ}ÕÀi £\ /…Àœ“Lœ}À>“à œLÌ>ˆ˜i` ܈̅ > vˆ˜> Vœ˜Vi˜ÌÀ>̈œ˜ œv
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Ài>̈œ˜ ÌiÃÌ] Üi vœÕ˜` > È}˜ˆvˆV>˜Ì VœÀÀi>̈œ˜ LiÌÜii˜ «>Ç
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̅Àœ“Lˆ˜ }i˜iÀ>̈œ˜ “i>ÃÕÀi“i˜Ì ­ˆ}° Ó®° ˜ «>̈i˜Ìà ܈̅ …>i‡
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8\ >˜` ̈“i ̜ «i>Ž° iëˆÌi ̅iÃi VœÀÀi>̈œ˜Ã LiÌÜii˜
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Ài>̈ÛiÞ >À}i ëÀi>`ˆ˜} >ÀœÕ˜` > }i˜iÀ> ÌÀi˜` VœÕ` Li œL‡
ÃiÀÛi` ­ˆ}° Ó®°
7i Vœ˜Ãˆ`iÀi` >à > ÃiÛiÀi Vˆ˜ˆV> Lii`ˆ˜} «…i˜œÌÞ«i ̅i
Vœ“Lˆ˜>̈œ˜ œv >Ì i>ÃÌ Ìܜ œv ̅i vœœÜˆ˜} ˆ˜`ˆV>̜ÀÃ\ ÃiÛiÀi
À>`ˆœœ}ˆV> …>i“œ«…ˆˆV >À̅Àœ«>Ì…Þ ­>Ì i>ÃÌ œ˜i œˆ˜Ì ܈̅
À>`ˆœœ}ˆV> *iÌÌiÀÃܘ ÃVœÀi >Ì Îq{®] «>̈i˜Ìà ՘`iÀ «Àœ«…ޏ>݈Ã
>vÌiÀ ÀiVÕÀÀi˜Ì ÃiÀˆœÕà Lii`ˆ˜} i«ˆÃœ`ià ­€Ó ̈“ià «iÀ ÜiiŽ vœÀ
>Ì i>ÃÌ Î “œ˜Ì…î] …>i“œ«…ˆˆ>Và ܈̅ …ˆÃ̜ÀÞ œv 뜘Ì>˜iœÕÃ
…>i“œÀÀ…>}ià ­€Îä i«ˆÃœ`iî° ˜`i«i˜`i˜ÌÞ œv ̅i 6É8
«>Ó> iÛi] Üi vœÕ˜` ̅>Ì > …>i“œ«…ˆˆ> «>̈i˜Ìà «ÀiÃi˜Ìˆ˜}
april 7, 2015
8
10
5
Rate
ETP
1000
800
600
400
200
0
2.5
0
20
10
1
0
30
1
0
0
10
20
30
40
50
0
60
10
5
2.5
10
20
30
FVIII %
(c)
40
50
60
FVIII %
(d)
FEDP 1 pM
200
FEDP 1 pM
35
50
30
150
5
2.5
50
0
Lag time
Peak
Vilka markörer passar bäst?
0
25
100
10
20
15
1
0
10
20
30
40
50
1 2.5
5
10
10
50
5
0
60
0
FVIII %
10
20
30
FVIII %
40
50
60
!  ETP och peak korrelerar till blödningstendens/svårighetsgrad
Fig. 1. Thrombin generation in FVIII-deficient plasma (FEDP) when spiked with human factor VIII (FVIII) 1–50% (0.01–0.5 IU mL)1) at
1 pM tissue factor (TF). Similar results were observed at 2 pM TF (data not shown). All parameters [endogenous thrombin potential
(ETP), rate and peak] of thrombin generation rise (a–c) and lag-time decreases (d) when FVIII levels rise.
(a)
***
1400
1600
1200
1400
1000
1200
ETP (nM min)
ETP (nM min)
(b)
*
1600
800
600
400
**
1000
800
600
400
200
200
0
0
Sev
Mod
Sev
Mild
Clinical severity
(c)
Mild
(d)
200
180
160
140
120
100
80
60
40
20
0
**
***
Peak (nM)
Peak (nM)
Mod
Clinical severity (FVIII:C)
Sev
Mod
Clinical severity
Mild
200
180
160
140
120
100
80
60
40
20
0
***
*
*
Sev
Mod
Mild
Clinical severity (FVIII:C)
Fig. 2. Comparison of thrombin generation between groups of severity categorized either by clinical bleeding score [clinical severity (a, c)]
or according to FVIII:C [severity FVIII:C (b, d)] in both cases. Peak thrombin shows best discrimination. Thrombin generation showed
similar values at 1 pM and 2 pM tissue factor (TF) (data not shown).
!  Lagtime visar ingen/tveksam korrelation till faktornivån
! 2005 Blackwell Publishing Ltd
Haemophilia (2005), 11, 326–334
Beltran-Miranda CP et al. Haemophilia 2005;93:326-34!
Dargaud et al. Thromb Haemost 2007;97:675-76!
Roza Chaireti
april 7, 2015
9
Trombingenerering – preanalytiska variabler
!  Kontaktaktivering
!  Centrifugera en gång eller två gånger eller …?
!  ”Spår” av trombocyter och leukocyter kan leda till falska resultat
ER
300
Thrombin (nM)
250
50
200
150
a (control)
c(FVIII = 2% )
60
h severe FXII defiand in the absence
CTI on FXII actived on the coaguy.
Dargaud et al Haemophilia 2010;16:223-30!
b(FVIII = 2%)
100
50
0
0
5
10
15
20
25
Time (min)
30
35
40
45
Fig. 2. The presence of platelets and/or white cells in PPP samples
can completely change TGT results in haemophiliacs and lead to
overestimation of the thrombin generation capacity.
es, a maximum
olytic activity of the calibrator with a known,
the number of
constant
thrombin-like activity of 600 nm is directly
remarked thatRoza
Chaireti
compared to the activity of an unknown amount of
y dependent on
thrombin in another sample of the same plasma. The
mpared double
april 7, 2015
10
Monitorera effekten av behandling med
faktorkoncentrat
!  Patienter med svår hemofili har olika doseringsbehov av
faktorkoncentrat
!  Samma faktornivå – olika trombingenereringspotential?
!  Samma koncentratdos – korrigerar i olika grader?
!  Skillnader i farmakokinetik?
Roza Chaireti
april 7, 2015
11
Monitorera effekten av behandling med
faktorkoncentrat
!  TG är känslig även när mindre doser FVIII koncentrat användes
(in vitro)
!  Ibland korrigeras inte TG när FVIII adderas – antikroppar pga.
multipla transfusioner?
Salvagno et al. Haemophilia 2009;15:290-96!
Roza Chaireti
april 7, 2015
12
Thrombin generation measurements with 1 pM tissue
factor trigger in the absence of thrombomodulin
Thrombin generation measurements in the absence of
thrombomodulin are presented in Table 1(B), and the
ETP and peak height are depicted in Figure 2 (panels A
and B, respectively; solid lines). Correlations of the
thrombin generation parameters with FVIII levels are
presented in Table 2. The effects of FVIII administration
and the addition of thrombomodulin on the thrombin
generation curve are depicted in Figure 3. The lag time
showed no significant changes upon FVIII administration
and the lag time and FVIII levels were not correlated.
The ETP increased significantly after FVIII infusion to
a peak value of 114.5% after 15 min. Forty-eight hours
after FVIII administration, the ETP returned to the baseline value of 40.0%. FVIII levels correlated with the ETP
in the group of patients as a whole (R=0.79, p<0.0001).
However, when data were analyzed per individual
patient, correlations were markedly higher. Despite
these correlations, there was a wide range of ETP at
higher FVIII levels. Prior to FVIII administration, the peak
height was relatively low compared to the ETP (24.0 vs.
40.0%), but became greater after 15 min: 126.0%. The
Monitorera effekten av behandling med
faktorkoncentrat
!  Bättre resultat än med traditionella metoder
Yu and Millar. JTH 2014;12:62–70
Table 1. FVIII levels (A) and thrombin generation at 1 pM tissue factor in the absence (B) and presence (C) of thrombomodulin at baseline and upon recombinant FVIII replacement.
0 minutes
15 minutes
1 hour
3 hours
6 hours
24 hours
48 hours
!  Stor variation mellan patienter, men förutsägbar effekt i samma
Lewis et al. Br J Haematol 2007;138:775-82
patient
A
FVIII (%)
0.9
B
Lag time (min)
ETP (%)
Peak height (%)
Time to peak (min)
Slope (nM/min)
4.5 [3.7-5.5]
4.7
[4.3-5.2]
5.3
40.0 [30.3-48.5] 114.5a [91.5-147.5] 113.0a
24.0 [20.0-30.8] 126.0a [89.3-205.3] 119.5a
16.9 [15.3-17.5] 10.3a [8.5-11.4] 11.2a
1.0 [0.8-1.2] 10.5a [7.1-22.8] 11.0a
[4.2-6.1]
[77.3-129.8]
[79.0-148.3]
[9.3-12.2]
[6.1-16.2]
C
Lag time (min)
ETP (%)
Peak height (%)
Time to peak (min)
Slope (nM/min)
3.7b
16.9b
13.6b
12.8b
0.8
5.1a
64.6ab
105.9ab
10.0ab
12.2ab
[4.3-5.8]
[35.4-73.9]
[50.9-136.2]
[8.0-10.3]
[5.5-18.2]
[0.1-5.1]
105.0a [86.0-115.9] 82.9a [74.0-91.1] 65.5a [59.6-73.6] 47.5a [43.2-57.1] 14.5a [11.5-21.8]
5.4
97.5a
91.0a
11.8a
7.5a
[4.3-5.9]
[82.3-106.8]
[75.0-117.0]
[9.9-12.5]
[5.1-11.3]
5.3a
47.6ab
75.5ab
10.2ab
8.0ab
[4.6-5.7]
[33.7-59.4]
[50.5-98.3]
[8.6-10.8]
[5.2-11.5]
6.0a
[2.5-8.6]
5.0
[4.2-5.9] 5.4
[4.3-6.1]
84.5a [57.8-104.3] 56.5a [50.8-72.5]
80.5a [50.5-102.3] 45.5a [39.5-58.0]
11.7a [10.8-13.4] 13.7a [12.7-14.9]
5.7a [3.6-8.6] 2.8a [2.2-3.5]
5.7
[4.3-6.2]
40.0 [37.58-56.0]
29.0 [27.0-38.0]
15.2a [14.3-16.9]
1.6
[1.3-1.9]
4.8ab [4.2-5.8] 4.9b [3.8-5.4]
36.3ab [26.0-62.4] 24.4ab [18.6-33.2]
57.7ab [33.8-94.7] 29.8ab [23.0-37.6]
10.3ab [8.9-11.0] 11.2ab [9.8-12.0]
6.2a [3.3-8.4] 2.5a [2.0-3.0]
4.2b [3.8-4.9]
16.1b [13.3-27.6]
15.3b [12.7-27.3]
12.2b [10.7-13.3]
1.2b [0.8-2.0]
!  Resultaten är mer pålitliga om trombomodulin adderas
Thrombin generation with thrombomodulin in hemophilia A
[3.1-4.4]
5.0
[11.3-19.2] 67.0ab
[9.0-17.9] 110.5ab
[10.9-14.6] 9.2ab
[0.5-1.2] 13.0ab
[4.2-5.4]
[46.2-101.0]
[62.9-190.9]
[7.9-10.2]
[7.2-25.5]
140
120
80
60
40
ue factor-triggered
d with the calibrated
20
Thrombinoscope BV,
Measurements were
0
0
60
120
180 360
1200 2040 2880
nal concentrations of
time (min)
w, Thrombinoscope
absence and presence
Figure 1. FVIII levels at baseline and upon recombinant FVIII
ombomodulin (Asahi
administration. Data are presented as the median [interquartile
Japan). The concenrange].
sen such as to inhibpooled plasma by
as obtained from
relation between thrombin generation and FVIII levels,
ce was read in a
mo Labsystems OY, multiple linear regression analysis was performed with
FVIII as the dependent variable and the lag time, ETP,
390/460 filter set and
peak height, time to peak, slope, age and product dose
calculated with the
infused as independent variables. For each model, the
binoscope BV).
R2 and the standardized regression coefficients
m the thrombin genRozaadjusted
Chaireti
hase of coagulation),
(β) of the independent variables were calculated. The β
d slope (propagation
indicates the change of the dependent variable,
e was defined as the
expressed in standard deviations (SD), when the inde-
ETP (%)
100
240
220
200
180
160
140
120
100
80
60
40
20
0
peak height (%)
Data are presented as medians [interquartile range]. adenotes p<0.05 compared to baseline; bdenotes p<0.05 compared to thrombin generation in the absence of thrombomodulin.
FVIII (%)
ding to the manufacenic assay on BCS
any) using a chroemployed standard
alibrated against the
d.
s
peak height returned to baseline by 48 hours (29.0%).
Similar to the ETP, the peak height correlated with FVIII
levels in the whole group of patients (R=0.79, p<0.0001),
although stronger correlations were found in individual
patients. Administration of FVIII significantly shortened
the time to peak (from 16.9 to 10.3 min after 15 min).
The time to peak was the only thrombin generation
parameter still significantly decreased after 48 hours
(15.2 vs. 16.9 min at baseline). The time to peak was
inversely correlated with FVIII levels (R=-0.75,
p<0.0001). In contrast to the ETP and peak height, the
time to peak values were within a narrow range across
all FVIII levels.
The slope was calculated from non-normalized peak
height data, a method that yields comparable data to the
slope calculated from normalized peak height data
(R=0.997, p<0.0001, data not shown). The slope increased
significantly upon FVIII infusion, reaching a peak of 11.0
nM/min after 1 hour. After 48 hours the slope returned
to baseline: 1.6 nM/min. The slope correlated with FVIII
levels in the group of patients as a whole (R=0.74,
p<0.0001).The ETP, peak height and slope were strongly
correlated in all patients.
0
60
120
180 360
time (min)
1200
2040
2880
240
220
200
180
160
140
120
100
80
60
40
20
0
Dielis et al. !
Haematologica 2008;93:1351-57 !
0
60
120
180 360
time (min)
1200
2040
2880
Figure 2. ETP (A) and peak height (B) at 1 pM tissue factor in the absence (solid line) and presence (dashed line) of thrombomodulin
at baseline and upon administration of recombinant FVIII. Data are presented as medians [interquartile range]. * denotes p<0.05.
| 1354 | haematologica | 2008; 93(9)
april 7, 2015
13
Monitorering av behandling med bypassing
agents
!  FEIBA ® (Baxter) NovoSeven ® (NovoNordisk) +/faktorkoncentrat
!  Olika behandlingsprotokoll, olika stora kohorter
!  De flesta studier har gjorts på patienter med hemofili A
Roza Chaireti
april 7, 2015
14
Monitorering av behandling med bypassing
agents
!  Tillägg av FVIII koncentrat till behandling med bypassing agents
ökar TG ytterligare
!  Kombination av rFVIIa och FEIBA leder till bättre hemostas
!  De flesta studier visar bra korrelation
Klintman et al. Br J Haematol 2010;151:381–386 !
Livnat et al. Haemophilia 2013;19:782–789 !
Varadi et al. JTH 2003;1:2374-2380 !
Roza Chaireti
april 7, 2015
15
Tromboelastografi – preanalytiska variabler
!  Provtagning
!  Provrör/nål
!  Multipel sampling
!  Resting time
!  Blodstatus (anemi? trombocytopeni?)
Roza Chaireti
april 7, 2015
16
10 millimeters
(b)
1
10 millimeters
10ml
10 millimeters
Kaolin
Sample time: 17-Jun-05 03:36:30 PM - 05:33:40 PM
Kaolin
Sample time: 0
2
Ramesh Girap 2.6.5
10 millimeters
SP
mm
34.2
(b)
R
mm
36.8
7 17
K
mm
5.2
1 7
Angle
dec
56.4
47 74
MA
mm
67.0
55 73
TPI
/sec
19.7
32 527
A
mm
58.9
CI
–8.3
–3 3
EPL
%
1.4
15
0
LY30
%
1.4
0 8
SP
mm
6.3
736
R
mm
25.3
7 17
1
Kaolin
Sample time: 17-Jun-05 03:36:30 PM - 05:33:40 PM
Angle
deg
45.3
47 74
MA
mm
79.5
55 73
K. GHOSH et al.
TEG vid hemofili
10ml
K
mm
4.0
1 7
2
Pankaj Kulkarni 1/12/5
(a)
Ramesh Girap 2.6.5
TPI
/sec
48.5
32 527
A
mm
60.7
SPCI
mm
34.2
–3.6
–3 3
KLY30 Angle
MA
EPL
REPL
LY30
A
CI
TPI
mm%
mm%
mm
dec
mm
%
/sec
%
5.2
36.8
–8.3
1.4
56.4
19.7
1.4
58.9
67.0
5.2
5.2
0 15
0 8
–3 3
55 73 32 527
7 0 1715 1 0 7 8 47 74
Angle
R
LY30
K
MA
TPI
A
SP
EPL
CI
deg
%
mm
%
mm
mm
/sec
mm
mm
–39.3
25.4
25.4
96.0
106.8
19.3
22.5
42.5
1.9
0.8
–3 3
0 8
0 15
1 7
47 74 55 73 32 527
7 17
Kaolin
2
Kaolin
time:
01-Dec-05
12:46:41
PM - 02:38:51
PM
10ml
Sample Sample
time: 02-Jun_05
11:10:52
AM - 12:21:47
PM
1
(b)
SP
mm
13.5
7
Angle
deg
45.3
47 74
K
mm
4.0
1 7
R
mm
25.3
7 17
R
mm
14.3
17
K
mm
1.7
7
1
MA
mm
79.5
55 73
Angle
deg
77.3
47 74
2
Kaolin
Kaolin
Mahendra
(severe)3/5/5
Sample time:
03-May-05
SampleBagadiya
time: 17-Jun-05
03:36:30 PM - 05:33:40 PM
Ramesh
Girap11:29:05
2.6.5 AM - 01:01:15 PM
(c)
10 millimeters
10 millimeters
10 millimeters
SP
mm
6.3
1
Parth Amin 30-01-0610 millimeters
TPI
/sec
48.5
32 527
MA
mm
69.0
55 73
A
mm
60.7
A
mm
19
TPI
/sec
66.9
32 527
Kaolin
Sample time: 02-J
2
Kaolin
Sample time: 30-Jan-06
10:41:41 AM - 01:06:11 PM
10 millimeters
10 millimeters
!  TEG korrelerar till sjukdomens svårighetsgrad
SP
mm
96.0
736
(a)
R
mm
106.8
7 17
K
mm
19.3
1 7
Angle
deg
22.5
47 74
K. GHOSH et al.
MA
mm
42.5
55 73
TPI
/sec
1.9
527
A
mm
0.8
CI
EPL
%
25.4
0 15
LY30
%
25.4
0 8
32
–39.3
–3 3
(c)KaolinParth Amin 30-01-06
2
Pankaj Kulkarni 1/12/5
SP
mm
13.5
1
Sample time: 01-Dec-05 12:46:41 PM - 02:38:51 PM
(d)
(b)
R
mm
36.8
7 17
K
mm
5.2
1 7
Angle
dec
56.4
47 74
R CI
K EPL AngleLY30 MA
TPI SP A
%
/sec mm mm mm
%
1.4
19.7 *288.8*58.9 *288.8*–8.3
1.4
7 17
0 15
0 8
32 527
–3 3
MA
mm
67.0
55 73
2
Mazhar Qureshi 30-01-06
1
10ml
K
Angle
MA
TPI
mm
Angle
decMA
mmTPI
/sec A
5.2deg
mm
56.4mm
19.7
67.0/sec
527
1 77.3
7
47 69.0
74
55 66.9
73 32 19.6
47 74 55 73 32 527
Kaolin
2
Sample
time:
30-Jan-06(severe)3/5/5
10:41:41 AM - 01:06:11 PM
10ml
Mahendra
Bagadiya
(b)
Kaolin
Sample time: 30-Jan-06 01:11:31 PM - 04:20:36 PM
Kaolin
Sample time: 17-Jun-05 03:36:30 PM - 05:33:40 PM
10 millimeters
TPISP
mm
6.3
A R
CI
RK
SP
mm
mm
mm
mm
mm
0.225.3
96.0
106.8
4.0
7 17 7 117 7
10 millimeters
10 millimeters
LY3C
EPL
K
MATPI
TPIA
Angle Angle
MA
deg
mm
/sec
mm
deg
mm
mm
/sec
19.3
22.5
42.5
1.9
79.5
60.7
48.5
1 4745.3
7 74 47 55 74 73 5532 7352732 527
1
Chetan 20/04/05
2
Ramesh Girap 2.6.5
(c) (d)
R
mm
255.2
R
7mm17
106.8
7 17
K
mm
*121.0*
K
1mm7
19.3
1 7
Angle
deg
3.2
Angle
47deg74
22.5
47 74
MA
TPI
/sec
mm
*0.1*
*18.0*
MA
TPI
55mm73 32/sec527
42.5
1.9
55 73 32 527
(e)
(c)
A
mm
18.2
A
mm
0.8
CI
EPL
LY30
CI
EPL
%
25.4
0 15
LY30
%
25.4
0 8
–39.3
–3 3
10ml
Parth Amin 30-01-06
1
SP
mm
42.0
SP
mm
13.5
K
mm
20.3
K
1mm7
1.7
1 7
Angle
deg
20.3
Angle
47deg 74
77.3
47 74
MA
mm
43.5
MA73
55mm
69.0
55 73
Citrated native
Sample time: 29-Sep-04 01:51:14 PM - 03:25:59 PM
Mazhar Qureshi 30-01-06
1
Kaolin
(d)
Sample time: 30-Jan-06 10:41:41
AM - 01:06:11 PM
10 millimeters
Ghosh et al. Haemophilia 2007;13:734–739 !
Roza Chaireti
R
mm
50.8
R
7 mm17
14.3
7 17
SP
MA
mm
mm
13.5
*18.0*
55 73
RK
SP R
Amm
TPI
mm
mm
mm
/sec
mm
*288.8*
14.3 *288.8*
1.7
*0.1*
17 7 18.2
117 7
32 7 527
10 millimeters
TPI
/sec
1.9
TPI527
32/sec
66.9
32 527
LY30
Angle
%
deg
5.2
8
0 77.3
47EPL74
MA
mm
69.0
LY3C
55 73
(d) !
Kaolin
Sample time: 20
A CI
EPL
MATPI
TPIA
CI
K
LY30AngleLY3C
Angle Angle
MA
EPL
MA
EPLmm
CIdeg
R
LY30
mm SP mm
/sec
%
% K
mm
19.6 mm 0.21.5 mm 36.9 mm 36.9 deg
66.9
77.3
69.0
43.5
42.0–3 350.8 0 1520.3 0 820.3
47 74 55 73 32 527
1 7
47 74 55 73
7 17
(e)
A
mm
19.6
TPI
/sec
66.9
32 527
(c) !
2
Kaolin
1
Kaolin Sample time: 30-Jan-06 01:11:31 PM - 04:20:36 PM
Sample time: 10ml
30-Jan-06 10:41:41 AM - 01:06:11 PM
10 millimeters
10 millimeters
EPL
%K
mm
5.2
15
0 1.7
CI
1 7
10 millimeters
10 millimeters
10 millimeters
(b) !
1
CI
R
mm
–3.6
–314.3
A3
7 mm
17
0.2
1
Kaolin
Kaolin
2
Sample
time: 30-Jan-06
AM - 01:06:11
PM 1
Parth
Sample time:
02-Jun_05
11:10:5210:41:41
AM - 12:21:47
PM
Ramesh
GirapAmin
2.6.530-01-06
2
Kaolin
Sample time: 30-Jan-06 01:11:31 PM - 04:20:36 PM
Chetan 20/04/05
LY30
A CI
EPL
CIEPL
Angle
R %LY30 K %
SP %
mm
% mm
deg
mm
mm
–39.3
25.4
25.45.2
0.8
–3.6 208.3
5.2 255.2
*121.0*
3.2
–3 3 –3 0 3 157 0 17015 8 1 0 7 8 47 74
Kaolin
Sample time: 20-Apr-05
11:22:02
- 01:28:57 PM
Mazhar
QureshiAM
30-01-06
Parth Amin 30-01-06
Kaolin
Sample time: 02-Jun_05 11:10:52 AM - 12:21:47 PM
A
SP
mm
mm
60.7
13.5
TPI
(c)
(d)
10 millimeters
SP
mm
208.3
SP
mm
96.0
Angle
K
MA
SP
R
TPI
LY30
MA
TPI
degEPL
mm A
mm
mm CI
/sec
mm/sec
%
mm
79.5%
25.3mm
48.5
4.0
45.3
6.3 1.9
25.4 55 25.4
42.5
0.8
73 32 527
1 –39.3
7
MA
K15
–3 R 3 47 0 74
0Angle
8
55 73 32 527 7 17SP
mm
mm
*288.8*
*288.8*
7 17
EPL
LY30
A
CI
Angle
REPL
K
SPCI
LY30
mm
%
%
deg
mm
mm%
mm%
–8.3
1.4
1.4
58.9
96.0
1.5 –3106.8
36.9
36.9
0 19.3
15
022.58
3
–3 3 7 0 1715 1 0 7 8 47 74
1
Kaolin
Kaolin
Sample
time: 17-Jun-05
PM - 05:33:40
PM
Sample time:
03-May-05
11:29:0503:36:30
AM - 01:01:15
PM
Mazhar Qureshi 30-01-06
10 millimeters
(a) !
10 millimeters
SP
mm
34.2
R
SP
mm K
mm R
mm
36.8
34.2mm
14.3 7 17
1.7
7 17
1 7
!  Olika grupper med olika fenotyper identifieras
1
Citrated native
Chetan time:
20/04/05
Sample
29-Sep-04 01:51:14 PM - 03:25:59 PM
10 millimeters
10 millimeters
32
TPI
/sec
1.9
527
A
mm
39
Kaolin
Sample time: 20-A
10 millimeters
(n)!
MA
Angle
A
KLY30 Angle
REPL
LY30 mm
SPCI
MA
TPI A SP A CI R CI EPL KEPL LY3C
mm
deg
mm
mm
mmSP mm R mm% K
mm%Angle deg MA mm TPI /sec mm
mm
mm 255.2
mm –21.3
49.5
7.3
17.7
0.9
22.0
44.0
39.6
0.9
*0.1*
*121.0*
*18.0*
3.2
LY30
A
0.2 18.2 19 55
*288.8*
*288.8*208.3
4 18
0
22 58 44 64
–3 CI
3 7 0EPL
7 8 47 74 55 73 32 527
17
mm
% 15 1 %
7
17
19.6
1.5
36.9
36.9
0 15
0 8
–3 3
TPI
SP
/sec
mm
6.7
3 42.0
20
AR
CI K
mm
mm
mm
–0.5
39.2
50.8
20.3
7 17 –3 1 3 7
EPL
Angle LY30
MA
%deg
% mm
5.3
5.343.5
0 4720.3
15 74 0 558 73
32
TPI
/sec
1.9
527
A
mm
39.6
Fig. 1. Spectrum of thromboelastographic (TEG) patterns in different groups.
2
Kaolin
Sample time: 30-Jan-06 01:11:31 PM - 04:20:36 PM
10ml
Chetan
20/04/05
(e)
10 millimeters
Haemophilia (2007), 13, 734–739
11
Citrated native
Kaolin
Sample
time: 29-Sep-04
01:51:14
PM - 03:25:59
Sample
time: 20-Apr-05
11:22:02
AM - 01:28:57
PM PM
10 millimeters
10 millimeters
Journal compilation ! 2007
april 7, 2015
17
Monitorering av behandling med bypassing
agents
!  rFVIIa och aPCC visar liknande, dosberoende effekter på TEG
(förkortning av initieringsfasen, accelerar klotbildning)
!  TEG i närvaro av kaolin visar behovet av olika doser rFVIIa för
normalisering av hemostas beroende på sjukdomens
svårighetsgrad
!  Effekten av behandlingen identifieras
bäst vid patienter med grav avvikande
hemostatisk profil (TEG kurva)
280 Blood Coagulation and Fibrinolysis 2008, Vol 19 No 4
Fig. 3
(a)
0 ug/ml
1.2 ug/ml
1.6 ug/ml
2.0 ug/ml
2.6 ug/ml
3.0 ug/ml
3.5 ug/ml
10 milimeteres
!
Sorensen et al. JTH 2004;2:102-10!
Viuff et al. Thromb Res 2010;126:144–149 !
Young et al. Blood Coagul Fibrinol 2009;19:276 – 282 !
Roza Chaireti
(b)
0 ug/ml
1.2 ug/ml
1.6 ug/ml
2.0 ug/ml
2.6 ug/ml
3.0 ug/ml
3.5 ug/ml
10 milimeteres
and thromboelastography parame
from haemophiliacs with inhibito
Ex-vivo addition of rFVIIa at a
equivalent to the expected plas
dose of 90 mg/kg led to improved
ever, increasing the concentration
any additional improvements i
parameters with the exception o
104; Fig. 3a). Thus, only this pa
boelastographic pattern consistent
tration–response relationship. Th
the fact that while the TEG/ROT
were abnormal, they were not suffi
able to detect a concentration–res
that this unexpected finding wa
selection criteria, which mandat
tration of any kind for a minimum
their potential impact on baselin
results. This restriction, however,
by precluding the enrolment of p
quently and would likely have a m
curve, and by preferentially select
relatively infrequently (mean num
in the year prior to the study), and
baseline coagulation profiles. Whi
have demonstrated nearly flat cu
abnormal parameters for haemoph
that these patients bled more than
that allowed differentiation of the
[12,13,18,19].
Changes in individual TEG coagulation profiles following ex-vivo
addition of rFVIIa. Data shown are for a patient with a concentration–
response relationship (a) and for a typical profile representative of the
majority of patients (b). rFVIIa, recombinant activated factor VII; TEG,april 7, 2015
Thromboelastograph.
In addition,
19
we believe that the l
was also due to the choice or con
Conclusion
4 Luddington R
eration by ca
factor inhibit
5 Dargaud Y,
factor activa
thrombin gen
low-concentr
1160–1.
6 Riddell A, A
Monitoring l
with severe
Haemost 201
7 Lippi G, Fra
Guidi GC. Q
can we trust
513–9.
8 Zambruni A
AK. Throm
with native
repeated sam
9 Sorensen B,
Whole blood
minimal tiss
551–8.
10 Sorensen B,
april 7, 2015
20
patient requ
This WP makes the following recommendations for the
use of TEG/ROTEM as it relates to the clinical manageTromboelastografi
vid hemofili-rekommendationer
ment and clinical trials in patients with hemophilia:
1 Investigators and treaters may use either device (TEG
or ROTEM).
2 For clinical care, we recommend the use of intrinsic
pathway activation with kaolin (TEG) or INTEM (ROTEM).
3 For clinical trials, we recommend intrinsic pathway
activation as the primary method. Extrinsic pathway
activation can be used in an exploratory fashion,
although we cannot endorse any specific method.
Last, while progress has been made over the past
10 years in the study of TEG/ROTEM in hemophilia,
Chitlur et al. Recommendations for performing thromboelastography/
they are notinin
wide clinical
use.from
Totheachieve
thromboelastometry
hemophilia:
communication
SSC of the this
ISTH. aim,
JTH
2014;12:103–106
!
further
research
directly linking laboratory results to
clinical outcomes are needed. As we enter an era of personalized medicine, we believe that it will be possible in
Roza Chaireti
the near future to individualize approaches to the
TGA eller TEG?
!  Tran et al: både metoder avspeglar effekten av bypassing agents.
MEN TGA visar även skillnader mellan använda preparaten. Kliniska
studier? Tran et al. Haemophilia 2015;21: 275–283
!  TGA är känsligare är TEG för hemofilidiagnos
van Veen et al Thromb Res 2009;123:895–901
!  Eller både och?
"  Qi et al hittade ingen skillnad mellan metoderna vid monitorering av
behandling med rFVIIa
Qi et al. Blood Coagul Fibrinol 2014;25:754–760
Roza Chaireti
april 7, 2015
21
Slutsats
!  Lovande resultat från farmakokinetiska studier och mindre
kohorter
!  Standardisering är viktig
!  Svårt att evaluera den kliniska relevansen i små kohorter
!  Multicenter studier, dock med liknande behandlingsprotokoll?
Roza Chaireti
april 7, 2015
22
Tack!
Roza.Chaireti@ki.se!
Roza Chaireti
april 7, 2015
23