TACTIC

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Project 2: The Role of Factor XI. . in TIC. Lead investigator: . Saulius. . Butenas. (University of Vermont). Co-Investigator: James H Morrissey (University of Illinois at Urbana-Champaign). Philadelphia, September 10, 2014. ID: 418813 Download Presentation

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TACTIC




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TACTIC

Project 2: The Role of Factor XI in TICLead investigator: Saulius Butenas (University of Vermont)Co-Investigator: James H Morrissey (University of Illinois at Urbana-Champaign)Philadelphia, September 10, 2014

a

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The Coagulation Cascade

Intrinsic Pathway

Factor XII

Prekallikrein

HMW Kininogen

“Surface”

Factor XIa

HMW Kininogen

Membrane

Ca2+, Zn2+

Intrinsic Tenase

AT-III

AT-III

IIa

XIa

Va

i

VIIIa

i

XIIa

IXa

Extrinsic Pathway

Factor VIIa

Tissue Factor

Membrane

Ca

2+

Factor IXa

Factor VIIIa

Membrane

Ca

2+

Factor Xa

Factor Va

Membrane

Ca

2+

Thrombin

ThrombomodulinMembraneCa2+

Fibrin Clot Formation

Extrinsic Tenase

Prothrombinase

Cross-Linked

Fibrin Clot

Soluble Fibrin Peptides

TFPI

AT-III

PAI-1

AT-III

TAFIa

Plasmin

APC

2

-AP

AT-III

XIIIa

Fibrin

IIa

Xa

Xa

IXa

TFPI

AT-III

Red =

Enzymes

Yellow = I

nhibitors

Vascular

Injury

Tissue Factor

IIa

Va

VIIIa

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FXIa-Initiated Clotting of Whole Blood

Initiator Concentration

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Assays for FXIa

Clotting and thrombin generation (TGA) assays were

developed.

Both assays are based on the response of

contact pathway-inhibited (corn trypsin inhibitor; CTI) plasma

to the inhibitory anti-FXI monoclonal antibody.

No exogenous initiator of thrombin generation is added.

No thrombin generation/clot formation is observed in plasma from healthy individuals

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Study #1(In collaboration with Dr. M. Park from Mayo Clinic)

Multiple time-points from 98 patients:

Burn 34

Blunt 47

Penetrating 17

Clotting assay was used for the quantitation of

FXIa

Supported by

DoD

and PO1 HL46703

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*ISS – injury severity score.**Average ± SD for patients with FXIa ≥ 10 pM. Detectabiliy limit of FXIa in this clotting time-based assay is 10 pM.S. Butenas, M. Park, K. Mann (unpublished data).

Active Factor XIa at Admission

Injury

ISS* > 25

ISS ≤ 25

XIa

Frequency

(

pM

)**

Frequency

(

pM

)

Burn

13/19 (68%)

38±36

3/15 (20%)

47±7

Blunt

19/31 (61%)

39±28

7/16 (44%)

37±26

Penetrating

3/7 (43%)

55±65

1/10 (10%)

160

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Conclusion #1

The

occurrence of

FXIa

correlates

with

the

severity of trauma

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Study #2 (In collaboration with Dr. J. Shupp from Washington Burn Center)

56 Burn patients

463 time-points

Up to 20 time-points per patient from 0 to 504 hours (3 weeks)

Thrombin Generation

assay was used for the quantitation of

FXIa

Supported by Systems Biology grant

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Conclusion #2

Of 56 burn patients analyzed:

62% had TF and 100% had

FXIa

at

at

least one time-point.

TF activity was observed in 21% and

FXIa

in 90% time-point samples.

Slide19

Study #3 (In collaboration with Dr. K. Freeman from FAHC, Burlington VT)

Multiple time-point plasma samples from

66 patients (no burn patients; 187 time-points)

56%

of them had TF and

94% had

FXIa

at

at

least one time-point.

TF activity was observed in

30%

and

FXIa

in

79%

time-point samples

.

Thrombin Generation assay was used for the quantitation of

FXIa

Supported by Systems Biology grant

Slide20

Final Conclusions

The majority of trauma patients have circulating

FXIa

, which correlates with trauma severity.

FXIa

concentration over observation time varies in a wide range.

The frequency of

FXIa

in burn patients is higher

than in

other trauma patient categories

FXIa

could be a potential marker of trauma severity

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