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 Home Advanced+Search Variants Structures AA+Alignments Resources Support Simple+Nucleo9de+Search ++++F8+Gene+Variants Haemophilia+A+is+caused+by+variants+in+the+gene+that+codes+for+coagula9on+factor+VIII.+There+are currently+2015+unique+variants+in+the+F8+gene+compiled+within+this+database+corresponding+to Nucleo6de% % select GO 5472+individual+cases. Simple+Amino+Acid+Search ++++Ci9ng+us If+you+find+this+website+useful,+please+reference+our+publica9on:+ Rallapalli+PM,+KemballBCook+G,+Tuddenham+EG,+Gomez+K,+Perkins+SJ+(2014)B+Manuscript+under HGVS% % select Legacy% GO % select GO Prepara9on Muta9on+type+Search ++++What+can+you+do+in+this+database+? You+can+search+for+all+the+variants+reported+in+the+F8+gene+from+1986B2010,+with+more+to+be added+during+2015.+ You+can+look+in+the+database+for+all+the+sequence,+structural+and+sta9s9cal+informa9on+on+the gene+variants.+You+can+also+submit+new+muta9ons/variants+and+contribute+to+the+gene9c services+provided+through+this+database. Type% % select GO Exon+and+Intron+based+search Exon% select % GO Intron% select % GO ++++Codon/AminoBacid+numbering:+HGVS+and+Legacy+++ ++++Classifica9on+of+Variant+Phenotype+++ ++++Have+you+or+someone+you+know+been+diagnosed+with+haemophilia+A?+++ +++Acknowledgements+++ ++++Latest+ReleaseB+Version+1.3+(November+2014)+++ The+informa9on+contained+on+this+web+site+is+provided+for+research+purposes+only.+All+informa9on+and+content+on+this+web+site+are+protected+by+copyright.+All+rights+are reserved. Thank you for visiting this site.% % Fri, 6 Mar 2015, 23:21 GMT Structural%Immunology%Group%,%University%College%London%,%Gower%Street,%London%WC1E%6BT Roza Chaireti april 7, 2015 3 Hemofili B Home ! 1: 30,000 Advanced+Search Variants Structures AA+Alignments Resources Support Simple+Nucleo9de+Search F9+Variants Haemophilia+ B+ is+ caused+ by+ Variants+ (muta9ons)+ in+ the+ F9+ gene+ which+ codes+ for+ coagula9on Nucleo6de% ---Select--- % Search factor+IX.+There+are+currently+1095+unique+variants+in+the+F9+gene+compiled+within+this+database corresponding+to+3713+individual+cases. Simple+Amino+Acid+Search Ci9ng+us HGVS% If+you+find+this+website+useful,+please+reference+our+publica9on:+ Rallapalli,+P.M.,+KemballBCook,+G.,+Tuddenham,+E.G.,+Gomez,+K.,+&+Perkins,+S.J.+2013.+An interac9ve+muta9on+database+for+human+coagula9on+factor+IX+provides+novel+insights+into+the % -- LEGACY% GO % -- GO Muta9on+type+Search phenotypes+and+gene9cs+of+haemophilia+B.+J.Thromb.Haemost.+available+from:+PM:23617593 Type% What+can+you+do+in+this+database? You+can+search+for+all+the+muta9ons+reported+in+the+F9+gene+prior+to+the+database+release+date. You+can+look+in+the+database+for+all+the+sequence,+structural+and+sta9s9cal+informa9on+for+the muta9ons.+You+can+also+submit+new+muta9ons+and+contribute+to+the+gene9c+services+provided through+this+database.+ ---Select--- % Search Exon+and+Intron+based+search Exon% -- % Intron% GO -- % GO ++++Codon/AminoBacid+numbering:+HGVS+and+Legacy+++ ++++Classifica9on+of+Variant+Phenotype+(Severity):+++ ++++Have+you+or+someone+you+know+been+diagnosed+with+haemophilia+B?+++ ++++Acknowledgements+++ ++++Latest+ReleaseB+Version+1.4+(November+2014)+++ The+informa9on+contained+on+this+web+site+is+provided+for+research+purposes+only.+All+informa9on+and+content+on+this+web+site+are+protected+by+copyright.+All+rights+are reserved. Thank you for visiting this site. Fri, 6 Mar 2015, 23:36 GMT Structural+Immunology+Group+,%University+College+London+,%Gower+Street,+London+WC1E+6BT Roza Chaireti april 7, 2015 4 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 £« v / >` { v « ë «`à >i« > «>ÌiÌð ®° ÃiÛiÀi >i« > 6£¯®Æ ® `iÀ>Ìi >i« > 6r£qx¯®Æ ` >i« > 6 x¯®Æ ®° À> VÌÀ ëÌ> VV> >LÀ>ÌÀiÃ] > à >ÀÛiÃÌi` À`iÀ Ì Ì Ì i «>ÌiÌð "ÕÀ ÀiÃÕÌà à Üi` Ì >Ì Ìi Vià «ÀiÃiÌ Ì i *** VÕ` iÃÕÌà >i« >Và >` i` Ì }iiÀ>Ì V>«>VÌÞ `>Ì> Ì Ì i Õ««iÀ ÓÉÎ v Ì i «>Ã> >ÞiÀ] ViÌÀvÕ}>Ì >Ì } iÀ ëii` ® Ì >Ì Ã vÌi ÃÕ}}iÃÌi` LÞ Ài µÕ>ÌÞ v *** LÌ>i` V> Li }iiÀ>Ì Ì i >LÃiVi v >Þ iÃi V`ÌÃ Ì ÀL }i >i« > «>ÌiÌà rÎ{®] ÕÃ} -«i>À> VÀ Ài>Ì ÌiÃÌ] Üi vÕ` > Ã}vV>Ì VÀÀi>Ì LiÌÜii «>à >ÌV 6 iÛià >` /* Àrä°xÎÆ «ä°ääÓ{®] «i> Àrä°ÈÆ «ä°äääÈ® >` Ìi Ì «i> Àr qä°xÓÆ «rä°ääÓÈ® LÌ>i` LÞ Ì ÀL }iiÀ>Ì i>ÃÕÀiiÌ }° Ó®° «>ÌiÌà ÜÌ >i « > r£Ó®] > Ã}vV>Ì VÀÀi>Ì Ü>Ã Ã Ü LiÌÜii 8\ >` /* Àrä°ÈÓÆ «rä°ä{®] >` «i> i} Ì Àrä°ÇxÆ «rä°ä£®° Ì Ã Ài>ÌÛiÞ Ã> >i« > ÃiÀiÃ] ÃÌ>Ìà ÌV>Þ Ã}vV>Ì Ài>Ìà « VÕ` Li iÃÌ>Là i` LiÌÜii 8\ >` Ìi Ì «i>° iëÌi Ì iÃi VÀÀi>Ìà LiÌÜii «>Ã> 6É8 VÌÌ} >VÌÛÌÞ >` // «>À>iÌiÀÃ] > Ài>ÌÛiÞ >À}i ëÀi>`} >ÀÕ` > }iiÀ> ÌÀi` VÕ` Li L ÃiÀÛi` }° Ó®° 7i VÃ`iÀi` >à > ÃiÛiÀi VV> Lii`} « iÌÞ«i Ì i VL>Ì v >Ì i>ÃÌ ÌÜ v Ì i vÜ} `V>ÌÀÃ\ ÃiÛiÀi À>`}V> >i« V >ÀÌ À«>Ì Þ >Ì i>ÃÌ i Ì ÜÌ À>`}V> *iÌÌiÀÃà ÃVÀi >Ì Îq{®] «>ÌiÌà Õ`iÀ «À« Þ>Ýà >vÌiÀ ÀiVÕÀÀiÌ ÃiÀÕà Lii`} i«Ã`iÃ Ó Ìià «iÀ Üii vÀ >Ì i>ÃÌ Î Ì Ã®] >i« >Và ÜÌ ÃÌÀÞ v ëÌ>iÕà >iÀÀ >}ià Îä i«Ã`iî° `i«i`iÌÞ v Ì i 6É8 «>Ã> iÛi] Üi vÕ` Ì >Ì > >i« > «>ÌiÌà «ÀiÃiÌ} > ÃiÛiÀi VV> Lii`} Ìi`iVÞ >` > /* Û>Õi ÜiÀ Ì > xä¯ v À> />Li Ó® «ä°ää䣮 iÝVi«Ì} i >i« > «>ÌiÌ «>ÌiÌ ° Ó£® Ü «ÀiÃiÌi` > ÃiÛiÀi Lii`} « i ÌÞ«i LÕÌ > /* >Ì x¯ v À>° ÜiÛiÀ] Ì Ã «>ÌiÌ >à iÝ LÌi` > `iÀ>Ìi >ÌÌ ÀL `ivViVÞ >Ì È¯ À> Û>Õià r näq£Ó䯮° / à >vÀ> /* Ü>à ÃÞÃÌi>ÌV>Þ LÃiÀÛi` >Ì 6É8 VViÌÀ>Ìà }Ài>ÌiÀ Ì > £ä¯° >À}>Õ`] iÌ >°\ / ÀL }iiÀ>Ì >i« > «>ÌiÌà ÛiÀÃiÞ] Üi vÕ` > /* } iÀ Ì > xä¯ v À> ÌÜ Ãi Trombingenerering hos patienter med hemofili à >à iÛ>Õ>Ìi`° 7 i *** Ü>à Üi `` Ì v` Ã}vV>Ì `vviÀ ` ÜÌ 6>VÕÌ>iÀ ÌÕLià VÌ>} >Ìi° / iÀi Ü>à >à Ã}vV>Ì >` ÛiÌÌi ÌÕLià VÌ>} ÜiÛiÀ] ÜÌ £« v /] Ì À iÌ 8 >` VÌ>VÌ >VÌÛ>Ì° Û>Ì] Üi ÕÃi` Þ`À« LV «Þ `ÕVi >VÌÛ>Ì Ì > «ÞÃÌÞ >Ài` Ì >À}iÀ £n ii`iÃ] >` ! Trombingenerering (TG) motsvarar svårighetsgrad i både hemofili A och hemofili B iÀÌi` >i« > >` ! TG avspeglar svårighet av blödningssymtom hos de flesta patienterna oavsett faktornivån ` ÌÜiÛi >i« > «>ÌiÌà iÛià À>}} LiÌÜii £ 1É` Õià v // «>À>iÌiÀà ÃiÛiÀi] >Và >Ài ÃÕ>Àâi` />Li £° >` Ìi Ì «i> ÜiÀi Vi>ÀÞ >L à }° £®° à iÀ ÌiÃÌ° « Û>Õi v ä°äx Ü>à VÃ`iÀi` ÃÌ>ÌÃÌV>Þ Ã} vV>Ì° iÀà v // ® >i VÌÀ Roza Chaireti *i> i>´-® ,iÃÕÌà >} /i /i Ì «i> /iÃÌ V`Ìà i>´-® i>´-® / i // «>À>iÌiÀà >Ài VÃiÞ `i«i`iÌ Ì i VViÌÀ>Ì v /° /ÜiÌÞ >i« V Ã>«ià ÜiÀi ÌiÃÌi` ÜÌ Ì Àii V -iÛiÀi >i« > ÓÎ Î{´£nÈ Óδ£Ó È´Ó v / x] Ó°x >` £´x ViÌÀ>Ìà £«® >` i v> « ë «` VViÌÀ>Ì {x®° 7i V Ãi > v> VViÌÀ>Ì v £« vÀ `iÀ>Ìi >i« > £ä ÈxÇ´Óäx xä´ÓÓ È´Ó £x´Î ÌÜ Ài>Ãð ÀÃÌÞ] >Ì Ì Ã / VViÌÀ>Ì] Ì ÀL }iiÀ >Ì È´Ó Ã >Þ `i«i`iÌ Õ« 6 >` 8 VÌÌ} v>VÌÀð ` >i« > £Î £änδÎnn £Óx´ÈÇ £Î´Î -iV`Þ] Ì ÀL }iiÀ>Ì VÕÀÛià Ài>i` v>Ì >Ì Ì Ã / VViÌÀ>Ì À> ÌÀ ÀÕ« {ä £{x´£Çx ÓnÇ´È£ x´ä°Ç ÃiÛiÀi >i« >VÃ] n´ä° Ì Õ} ÌÀ>Vià v Ì À L }iiÀ>Ì VVÕÀÀi` >vÌiÀ > «À}i` >} « >Ãi° / i ÃÌ VÀÌV> ÃÌi« >} Ì i «Ài>>ÞÌV> V`Ìà à ViÀÌ>Þ Ì i «Ài«>À>Ì v ***° 1ÃÕ>Þ] ëÌ> VV> >LÀ>ÌÀiÃ] > >ÝÕ ÛÕi v «>Ã> à >ÀÛiÃÌi` À`iÀ Ì Ì Ì i ÕLiÀ v Ã>«ià Ì>i vÀ «>ÌiÌð "ÕÀ ÀiÃÕÌà à Üi` Ì >Ì ÌÀ>Vià v «>ÌiiÌà >`ÉÀ Ü Ìi Vià «ÀiÃiÌ Ì i *** VÕ` Downloaded from www.thrombosis-online.com on 2015-03-08 | ID: 1000518979 | IP: 130.237.122.245 V«iÌiÞ V >}i Ì i // ÀiÃÕÌà >i« >Và >` i` Ì ÛiÀiÃÌ>Ìi Ì i Ì ÀL }iiÀ>Ì V>«>VÌÞ `>Ì> Ì For personal or educational use only. No other uses without permission. All rights reserved. à ܮ° v *** à LÌ>i` vÀ Ì i Õ««iÀ ÓÉÎ v Ì i «>Ã> >ÞiÀ] i V> Ì Ì i >``Ì> ViÌÀvÕ}>Ì >Ì } iÀ ëii` ÓÎäääÝ} `ÕÀ} £ ÕÀ >Ì {c ® Ì >Ì Ã vÌi ÃÕ}}iÃÌi` LÞ Ài Ãi>ÀV >LÀ>ÌÀià Ӯ° / i µÕ>ÌÞ v *** LÌ>i` V> Li V iVi` LÞ i>ÃÕÀ} Ì ÀL }iiÀ>Ì Ì i >LÃiVi v >Þ / >` « ë «`ð 1`iÀ Ì iÃi V`ÌÃ Ì ÀL }i iÀ>Ì Ã Õ` Li LÌ>i`° / i Ã>«} >ÌiÀ> Ü>à >à iÛ>Õ>Ìi`° 7 i *** Ü>à «Ài«>Ài` >à `iÃVÀLi` >LÛi] Üi `` Ì v` Ã}vV>Ì `vviÀ iVià LiÌÜii ÀiÃÕÌà LÌ>i` ÜÌ 6>VÕÌ>iÀ ÌÕLià VÌ>} £äx À £Ó ÌÀÃ`Õ VÌÀ>Ìi° / iÀi Ü>à >à Ã}vV>Ì `vviÀiVi LiÌÜii 6>VÕÌ>iÀ >` ÛiÌÌi ÌÕLià VÌ>} i>V £äx ÌÀÃ`Õ VÌÀ>Ìi° ÜiÛiÀ] ÜÌ £« v /] Ì À L }iiÀ>Ì Ã >à `i«i`iÌ 8 >` VÌ>VÌ >VÌÛ>Ì° À`iÀ Ì Ài`ÕVi VÌ>VÌ >VÌÛ>Ì] Üi ÕÃi` Þ`À« LV «Þ «À«Þii ÌÕLià iÃà «Ài Ì `ÕVi >VÌÛ>Ì Ì > «ÞÃÌÞ Àii®° Ó£ ii`ià ÜiÀi V«>Ài` Ì >À}iÀ £n ii`iÃ] >` `vviÀiVi Ü>à Ìi`° {ÇÇ /* i>´-® Dargaud et al. Thromb Haemost 2005; 93:475-80 ! }ÕÀi £\ / ÀL}À>à LÌ>i` ÜÌ > v> VViÌÀ>Ì v £« v / >` { v « ë «`à >i« > «>ÌiÌð ®° ÃiÛiÀi >i« > 6£¯®Æ ® `iÀ>Ìi >i« > 6r£qx¯®Æ ` >i« > 6 x¯®Æ ®° À> VÌÀ >i« > «>ÌiÌà rÎ{®] ÕÃ} -«i>À> VÀ Ài>Ì ÌiÃÌ] Üi vÕ` > Ã}vV>Ì VÀÀi>Ì LiÌÜii «>à >ÌV 6 iÛià >` /* Àrä°xÎÆ «ä°ääÓ{®] «i> Àrä°ÈÆ «ä°äääÈ® >` Ìi Ì «i> Àr qä°xÓÆ «rä°ääÓÈ® LÌ>i` LÞ Ì ÀL }iiÀ>Ì i>ÃÕÀiiÌ }° Ó®° «>ÌiÌà ÜÌ >i « > r£Ó®] > Ã}vV>Ì VÀÀi>Ì Ü>Ã Ã Ü LiÌÜii 8\ >` /* Àrä°ÈÓÆ «rä°ä{®] >` «i> i} Ì Àrä°ÇxÆ «rä°ä£®° Ì Ã Ài>ÌÛiÞ Ã> >i« > ÃiÀiÃ] ÃÌ>Ìà ÌV>Þ Ã}vV>Ì Ài>Ìà « VÕ` Li iÃÌ>Là i` LiÌÜii 8\ >` Ìi Ì «i>° iëÌi Ì iÃi VÀÀi>Ìà LiÌÜii «>Ã> 6É8 VÌÌ} >VÌÛÌÞ >` // «>À>iÌiÀÃ] > Ài>ÌÛiÞ >À}i ëÀi>`} >ÀÕ` > }iiÀ> ÌÀi` VÕ` Li L ÃiÀÛi` }° Ó®° 7i VÃ`iÀi` >à > ÃiÛiÀi VV> Lii`} « iÌÞ«i Ì i VL>Ì v >Ì i>ÃÌ ÌÜ v Ì i vÜ} `V>ÌÀÃ\ ÃiÛiÀi À>`}V> >i« V >ÀÌ À«>Ì Þ >Ì i>ÃÌ i Ì ÜÌ À>`}V> *iÌÌiÀÃà ÃVÀi >Ì Îq{®] «>ÌiÌà Õ`iÀ «À« Þ>Ýà >vÌiÀ ÀiVÕÀÀiÌ ÃiÀÕà Lii`} i«Ã`iÃ Ó Ìià «iÀ Üii vÀ >Ì i>ÃÌ Î Ì Ã®] >i« >Và ÜÌ ÃÌÀÞ v ëÌ>iÕà >iÀÀ >}ià Îä i«Ã`iî° `i«i`iÌÞ v Ì i 6É8 «>Ã> iÛi] Üi vÕ` Ì >Ì > >i« > «>ÌiÌà «ÀiÃiÌ} 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! [email protected]! Roza Chaireti april 7, 2015 23
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