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

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

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.

with bleeding or significant drop in Fib levels within last 6h Fibrinogen Level* No Fibrinogen level is available 1.0 - 1.49 g/L with bleeding or significant drop in Fib levels within last 6h 0.5 - 1.0 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

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

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%)

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.

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

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

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

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

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  

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

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

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 0.5-0.99 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 0.51-0.99 20 6 14 10 1.67 1.0-1.49 19 5 12 17 1.69  Total cases 42 11 28 4 29 1.7 Percentage NA 25% 66% 9% 69%

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

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

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

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 0.5-0.99 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 0.51-0.99 16 9 3 2.10 1.0-1.49 26 14 10 17  Total cases 49 20 11 28 Percentage NA 41% 9% 57%  NA

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

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

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 0.51-0.99 7 2.10 10 1.67 1.0-1.49 17 1.69  Total cases 28/49 29/42 1.7 Percentage 57%  NA 69% NA

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

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

Appendix

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 +0.30. A weak uphill (positive) linear relationship +0.50. A moderate uphill (positive) relationship +0.70. A strong uphill (positive) linear relationship Exactly +1. A perfect uphill (positive) linear relationship

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 60-80 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%.

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%

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

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

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)

D-Dimer Level

Fibrinogen Levels - Pregnancy