1. NAC Meeting April 2018 - Calgary
FC (RiaSTAP) vs Cryo
M. Taher Shabani-Rad
Susan Nahirniak
Brian Muirhead
NAC Meeting April Calgary

2. Objectives
Evaluation of Fibrinogen increment after infusion of low dose RiaSTAP (1 gr) vs high dose (2 gr)
Is Cryo replaceable by RiaSTAP?
Development of dose recommendation based on clinical indications/companion Lab tests (Pending)
The Cost Impact of Cryo replacement by RiaSTAP

3. Methodology
An observation Study following implementation of FC protocol
Collecting retrospective clinical data of all cases with administration of FC (RiaSTAP) (2016 and 2017) that pre and post FC administration fibrinogen levels (up to 6 hours) were available.
Patients were categorized based on administered FC doses (1 gr, 2 gr and > 2gr) and underlying clinical indications (Bleeding, DIC, isolated hypofibrinogenemia or multi-factorial (>2 factors)) to calculate the delta-Fib (Post-FC fibrinogen minus Pre-FC fibrinogen) to evaluate the fibrinogen increment for each category.

4. with bleeding or significant drop in Fib levels within last 6h
Fibrinogen Level*
No Fibrinogen level is available
g/L
with bleeding or significant drop in Fib levels within last 6h
g/L
Less than 0.5 g/L
FC (RiaSTAP®) Dosing
**LT Bleeding
1 gram (1 vial)
Request collection for Fib levels prior to infusion and post-infusion Fib levels
Further vials requires Fibrinogen Level
Cardiac surgery pts
2 grams (2 vial) initially,
Request collection for Pre-infusion and post-infusion Fib levels
2 grams (2 vial)
All other patients
Request collection for post-infusion Fib levels
*Non-LT Bleeding
LT Bleeding
1 gram (1 vial) if ≤ one MTP or 6RCs transfused.
2 grams (2 vials) if > one MTP or 10RCs transfused.
2 grams initially, 2nd dose of 2 grams may be released without further Fib results if clinically indicated
2 gram (2 vials), Request collection for post-infusion Fib levels
4 grams (4 vials) ,
Further doses require post-infusion fibrinogen results
Notes: *Only pts with Fib. <1.5g/L are eligible for FC/Cryo
**LT = life threatening
Fib/FC = fibrinogen concentrate

5. Factor Levels of patients requiring Cryopercipitate/RiaSTAP (28 Pts)
Question: Which bleeding patients require Cryo vs RiaSTAP?
Patients with isolated Fibrinogen deficiency may require RiaSTAP
Patients with combined factor deficiency may require Cryo-Percipitate
Normal
Elevated
Low
Total
Fibrinogen 3 25 28
VWF 6 21 27
Factor VIII 12 11 5
Factor XIII
Not measured

6. Pre and Post infusion Feb Levels- CZ Based on RiaSTAP (1 gr vs 2 gr vs 4gr)
CLS-CZ
# Pts
# Pts (RSTP 1gr)
# Pts (RSTP 2gr)
# Pts (RSTP ≥4gr)
Pre Fib >1.5
57 (27%)
32 (25%)
23 (28%)
2 (18%)
Pre Fib <1.5
156 (73%)
98 (75%)
59 (72%)
9 (82%)
Total # of Patients
213
130 82 11
Post Fib <1.5
88 (41%)
62 (48%)
22 (27%)
4 (36%)
Post Fib >1.5
125 (59%)
68 (53%)
50 (73%)
7 (64%)

7. Categorization of Pts Based on Underlying Coagulopathic Conditions at The Time of Fib Administration
Patients with concurrent transfusion of Red Cells (>2 RCs within 12 hrs pre&post FC), Platelet>80,000 & PT/INR<1.2 or patients received =>1 MTP categorized as Active Bleeding patients (with or without Lab results).
Patients with abnormal coagulation profile [elevated INR, PTT & recent thrombocytopenia (<100,000) and elevated D-Dimer>3mg/L) or reconfirmed clinical diagnosis of DIC but transfusion of <3 RC units (within 12 hrs pre&post FC) included in DIC group.
Cases with low fibrinogen, Platelet>100,000, D-Dimer<3mg/L & transfusion of <3 RC units were included in isolated hypofibrinogenemia group.
The rest of cases were included within multi-factorial group.

8. Categorization of Pts Based on Underlying Coagulopathic Conditions at The Time of Fib Administration
A-BL MF
DIC
IHF
Fibrinogen dose
Active Bleeding
DIC
Isolated Hypofib
Multi-Factorial
Total 1g 75 18 10 27
130 2g 61 6 1 4 72

9. Four main categories of Fib utilization
Active Bleeding
Disseminated intravascular coagulation (DIC)
Multi-factorial
Isolated Hypofibrigenemia
Trauma
Leukemia/ Lymphoma
Liver failure
Familial
Cardiac Surgery
Leukemia
Solid tumor ; Pancreas Ca
Drug Overdose
Obstetric
Chemotherapy
Renal Failure
Multi organ Failure
Ruptured Aorta

10. Pts Received Low Dose FC (1 gr) Clinical Categories & Diagnosis (Death:18Pts)
Active Bleeding #N
DIC
Isolated Hypo Fib
Multi-Factorial
PPH 3
Liver Failure 4 2 17
Poly Trauma 14
Pregnancy
Cardiac surgery 1 11
Hematology Malignancy
Hematological Malignancy 6
Cardiac Surgery
GI bleeding 7
Dialysis/RF
Congenital
Vascular Surgery
Drug User
Multi-organ failure 23
Solid Tumor
Chronic RF
Septic shock
Sx/Ortho/ Urol
N/A
Total (130 Pts) 75 18 10 27

11. Pts Received High Dose FC (2 gr) Clinical Categories & Diagnosis (Death:6 Pts)
Active Bleeding #N
DIC
Isolated Hypo Fib
Multi-Factorial
Poly Trauma 4
Liver F 1
Solid Tumor
Pregnancy 3
pregnancy
PPH 2
GI bleeding
Cardiac Surgery
multi organ failure 34
Multiorgan Failure
Vascular 18
Septic Shock
Hip replacement
Total (72 Pts) 61 6

12. Pts Received FC (1 gr vs. 2gr) Active Bleeding Pts (75 pts vs. 61)
Two- Way ANOVA for Delta-Fib between bleeding subgroups (LD;1gr vs.  HD;2 gr) [p value =0.024]
FC provides a better increment among pts with Pre-FIB<1.0gr/L but not for pts with Pre-FIB>1.5  

13. Pts Received Low Dose FC (1 gr) Clinical Categories & Diagnosis (Death:18Pts)
Active Bleeding #N
DIC
Isolated Hypo Fib
Multi-Factorial
PPH 3
Liver Failure 4 2 17
Poly Trauma 14
Pregnancy
Cardiac surgery 1 11
Hematology Malignancy
Hematological Malignancy 6
Cardiac Surgery
GI bleeding 7
Dialysis/RF
Congenital
Vascular Surgery
Drug User
Multi-organ failure 23
Solid Tumor
Chronic RF
Septic shock
Sx/Ortho/ Urol
N/A
Total (130 Pts) 75 18 10 27

14. Pre-Fib vs Post-FC Delta Fib Pre-FC Fib vs Post-FC Fib
All Pts Received Low Dose FC (1 gr) Excluding Cardiac Sx/PPH (102/130 Pts)
Pre-Fib vs Post-FC Delta Fib
r=−0.6833
Pre-FC Fib vs Post-FC Fib
r=0.5448

15. Pts Received Low Dose FC (1 gr) Pre-FC Fib vs Post-FC Delta-Fib/Post-FC Fib Pts with Pre-Fib <1.5 gr/L (Excluding PPH/Cardiac SX)
Low Dose Group (1gr FC)
#Pts / Category
Delta<0.5 gr/L
Delta gr/L
Delta>1.0
gr/L
Post-Fib≥ 1.5 gr/L
Ave Post-Fib>1.5 gr/L
Pre-Fib ≤0.5 3 2 1
1.95
Pre-Fib 20 6 14 10
1.67 19 5 12 17
1.69
 Total cases 42 11 28 4 29
1.7
Percentage NA
25%
66% 9%
69%

16. Pre-Fib vs Post-FC Delta Fib Pre-FC Fib vs Post-FC Fib
Pts Received Low Dose FC (1 gr) Pts with Pre-Fib <1.5 gr/L Excluding Cardiac Sx/PPH (42 Pts)
Pre-Fib vs Post-FC Delta Fib
r=−0.3004
Pre-FC Fib vs Post-FC Fib
r=0.4063

17. Pts Received High Dose FC Clinical Categories & Diagnosis (Death:6 Pts)
Active Bleeding #N
DIC
Isolated Hypo Fib
Multi-Factorial
Poly Trauma 4
Liver F 1
Solid Tumor
Pregnancy 3
pregnancy
PPH 2
GI bleeding
Cardiac Surgery
multi organ failure 34
Multiorgan Failure
Vascular 18
Septic Shock
Hip replacement
Total Pts 61 6

18. All Pts Received High Dose FC (2gr) Excluding Cardiac Sx/PPH (34 Pts)
Pre-Fib vs Post-Delta Fib
r=−0.5974
Pre-Fib vs Post-Fib
r=0.2026

19. Pts Received High Dose FC (2 gr) Pre-FC Fib vs Post-FC Delta-Fib/Post-FC Fib Pts with Pre-Fib <1.5 gr/L (Excluding PPH/Cardiac SX)
High Dose (2gr FC)
#Pts / Category
Delta
<0.5 gr/L
gr/L
>1.0 gr/L
Post-Fib≥ 1.5 gr/L
Ave Post-Fib>1.5 gr/L
Pre-Fib≤0.5 7 2 1 4
2.15
Pre-Fib 16 9 3
2.10 26 14 10 17
 Total cases 49 20 11 28
Percentage NA
41% 9%
57%
 NA

20. Pre-Fib vs Post-Delta Fib
All Pts Received High Dose FC (2gr) Pts with Pre-Fib <1.5 gr/L (49 Pts)
Pre-Fib vs Post-Delta Fib
r=−0.2156
Pre-Fib vs Post-Fib
r=0.2341

21. Pre-FC Fib vs Post-FC Fib (1 Gram) Pre-FC Fib vs Post-FC Fib (2 Gram)
All Pts Received FC (1 gr vs. 2gr) Pts with Pre-Fib <1.5 gr/L Excluding Cardiac Sx/PPH
Pre-FC Fib vs Post-FC Fib (1 Gram)
r=0.5448
Pre-FC Fib vs Post-FC Fib (2 Gram)
r=0.2026

22. Ave PostFC-Fib>1.5 gr/L
Post-FC Fib - High Dose(2 g) vs.Low Dose(1 g) Pts with Pre-Fib <1.5 gr/L No significant Difference between groups (P value; 0.26)
High Dose (2gr FC)
Post-Fib≥ 1.5 gr/L
Ave PostFC-Fib>1.5 gr/L
Low Dose (1gr FC)
Ave Post-Fib>1.5 gr/L
Pre-Fib≤0.5 4
2.15
Pre-Fib ≤0.5 2
1.95
Pre-Fib 7
2.10 10
1.67 17
1.69
 Total cases
28/49
29/42
1.7
Percentage
57%
 NA
69% NA

23. Summary
Active bleeding patients with LD Fibrinogen concentrate achieve adequate increment
There is no statistical significant difference between LD & HD FC to achieve post-FC target Fib level of >1.5 gr/L
Patient with Pre-Fib of >1.5 did not show significant Fib increment by LD or HD FC
Addition of D-Dimer to coagulation assessment of bleeding patient may help better categorization of pts who are qualified for HD FC

24. Acknowledgement Sima Zolfaghari Deanna Dilabough Heather Holly Schack
Dr Dave Sidu
Dr Leland Baskin
Joanna McCarthy
Julia Hendry

25. Appendix

26. Correlation Coefficient r
Exactly –1. A perfect downhill (negative) linear relationship
–0.70. A strong downhill (negative) linear relationship
–0.50. A moderate downhill (negative) relationship
–0.30. A weak downhill (negative) linear relationship
0. No linear relationship
A weak uphill (positive) linear relationship
A moderate uphill (positive) relationship
A strong uphill (positive) linear relationship
Exactly +1. A perfect uphill (positive) linear relationship

27. D-Dimer
In adult patients with a clinically low pretest probability (Wells score) of developing DVT, a negative D-dimer test result yields a 99% negative predictive value (NPV) in patients aged years but only a 21%-31% NPV in patients older than 80 years
In pregnant patients, a negative D-dimer test results has a NPV of 100%.

28. Main Features of Disseminated Intravascular Coagulation in Series of 118 Patients
Affected Patients, %
Bleeding
64%
Renal dysfunction
25%
Hepatic dysfunction
19%
Respiratory dysfunction
16%
Shock
14%
Central nervous system dysfunction 2%

29. Diagnosis of DIC Moderate or Marked Thrombocytopenia
Down Trend Platelet count
aPTT and PT (Not INR) are typically prolonged (50%).
Fibrinogen (28% show Hypo Fib)
D-Dimer (80-90% Sensitivity)
Normal Range <0.45 mg/L (for Exclusion TE)
All ages > 3.0 mg/L
High D-Dimer> 10 mg/L

30. DIC Scoring System Score≥5  91-93% Sensitivity & 97-98% specificity International Society on Thrombosis and Haemostasis (ISTH)

31. JAMM DIC Score (Score≥ 4  DIC) Japanese Association for Acute Medicine (JAAM)
Platelet count (within 24 hours)
< 80 or >50 % decline  (3)
>80 and < 120 or >30% decline  (1)
>120  (0)
PT/INR
>1.2 (1)
<1.2  (0)
Fibrin/FDPs (mg/L)
>25  (3)
10-25  (1)
<10  (0)

32. D-Dimer Level

33. Fibrinogen Levels - Pregnancy