1. Cell Based Model Galila Zaher, MRCPath Assistant Professor Consultant Hematologist KAUH

2. VIIa TF-BEARING CELL ACTIVATED PLATELET HEMOSTASIS THROMBIN FIBRIN HEMOSTATIC PLUG INITIATION OF HEMOSTASIS PROPAGATION OF HEMOSTASIS TF

3. X Xa Va II IIa TF-bearing cell VIII/vWFVIIIa VVa platelet activated platelet VIIa IX IXa VIIIa Va IXa X Xa II IIa TF XIa IX XIXIa Normal Hemostasis

4. IIa (THROMBIN) FIBRINOGEN FIBRIN (SOLUBLE FIBRIN MONOMERS) FXIIIa FIBRINOLYSIS TAFI STABILIZED, CROSS-LINKED FIBRIN (HEMOSTATIC PLUG) Thrombin FV FVIII FVa FVIIa

5. 0.60 U/mL Fibrin Structure 0.10 U/mL 0.05 U/mL 0.03 U/mL Blomback et al. 1994 (a) (b) (c) (d) Thrombin:

6. Thrombin Activity 0 0.005 0.01 0.015 0.02 0.025 0.03 0.035 0.04 0.045 0.05 020406080100120140 Time (min) Thrombin activity (dA405/min) With FVIII present (- FXI) FVIII-deficiency + 50 nM FVIIa + 150 nM FVIIa Kjalke et al. 1999

7. FACILITATE HEMOSTASIS Enhance thrombin generation Inhibit fibrinolysis WHY FVIIa? FVIIa not enzymatically active unless in complex with TF FVIIa not immediately inhibited by AT FVII present in plasma FVIIa added to hemophilia plasma with inhibitors normalized APTT

8. Potential Use of rFVIIa Increases thrombin generation Hemophilia (FVIII/FIX deficiency) Platelet disorders Diffuse bleeding triggered by surgery and trauma Impaired initial hemostasis FVII-deficiency Liver disease (low levels of FVII) OAC therapy (low levels of FVII)

9. TF X Xa Va II IIa TF-bearing cell VIII/vWFVIIIa VVa platelet activated platelet VIIa Va X Xa II IIa TF XIXIa Hemophilia

10. Haemophilia FDA-approved Hemophilia with inhibitors Efficacy in major surgery 90-100% (90-100 µg/kg q2 for first 48 hs, q4 hours on D3-D4then to q6 hours for another week (Shapiro et al 1998; Ingerslev et al 1997) Efficacy in serious bleedings 83-95% (Lusher et al 1998) Efficacy in home treatment 92% (Key et al 1998) Acute bleeds in hemophilia >5 BU No good laboratory markers for monitoring efficacy TEG or Trend of quantitative D-dimer levels as a blood counts and fibrinogen level

11. COST-EFFECTIVENESS in mild-mod HA bleeding – UK study Clinical effectiveness – rFVIIa: mean 2.3 doses of 90 ug/kg controlled 92% of all minor bleeds within 24 hrs (Key et al 1998). FEIBA (aPCC): mena 3 doses of 75 units/kg controlled 79% of minor bleeds within 36 hrs (Hilgartner)

12. COST EVALUATION MILD-MOD BLEEDINGS IN HAEMOPHILIA Average cost Time to resolve Mean number doses/epi sode Mean time to resolution Effective ness: OVERALL COST rFVIIa£11,79 4 30 hrs3.617.3 hrs 89.3%9,113 US$ FEIBA£20,4658 hrs4.843.666.7%12,542 rFVIIa is safe and has a higher efficacy relative to other treatment options”.

13. The FENOC study FEIBA (activated prothrombin complex concentrate (aPCC). Test equivalence of products in treatment of ankle, knee, and elbow joint bleeding. A prospective, open-label, randomized,crossover Data for 96 bleeding episodes contributed by 48 participants were analyzed. FEIBA and NovoSeven appear to exhibit a similar effect on joint bleeds, although the efficacy between products is rated differently by a substantial proportion of patients. 2007 ASH

14. FVII-DEFICIENCY Autosomal recessive 1/500 000 persons Genetic & clinical heterogeneity FVII activity <1% severe Prolonged PT; normal APTT There is only small number of patients available (case series) FDA-approved dose 15 -30µ g per kg, q6 -12 hs Monitored by PT & its correction correlate well with achievement of clinical hemostasis

15. USE OF rFVIIa IN FVII-DEFICIENCY N=32 treated in Compassionate and ER between 1988- 1999. Treated at 28 sites in 6 countries (AUS, DK, I,Malaysia, USA) Non-surgical episodes: 43 joint bleeds EFFECTIVE in 37/43 (86%) episodes independent on location of bleed. Surgical episodes: 26 EFFECTIVE in 25/26 (96%) episodes. 10 adverse events 2 pt developed Abs against FVII FDA-approved dose 15 to 30µ g per kg q 6-12 hours Monitored by the PT.

16. Preliminary guidelines for off-label use proposed in 2004 The consensus panel related use of rFVIIa as appropriate in : Cardiac, thoracic, aortic, and spinal surgery Hepatic resection Hysterectomy; postpartum bleeding Severe, multiple trauma substantial blood replacement ineffective. Non traumatic ICH <4 hours since onset of symptoms Anti-coagulated patients with expanding hematomas. Doses of 41 to 90 µg / kg recommended in adults for all scenarios. Correction of the pH value >7.2 Multitrauma patients is 100 - 140 µg/ kg repeat dose

17. European Recommendations on the use of rFVIIa as an adjunctive treatment for massive bleeding –

18. Trauma. Uncontrolled massive hemorrhage is 2 nd cause of death Massive hemorrhage : surgical / vascular and a coagulopathic component. ‘Lethal triad‘: consumption, dilution and metabolic disorders In cases of injury, TF is brought into contact with naturally occurring FVIIa, to initiate thrombin Pharmacological doses, rFVIIa bind activated platelets at the site of injury and activate FIX and X directly, leading to a thrombin burst

19. BluntTrauma Successful report for trauma in an Israeli soldier Case series of 36 patients stopped bleeding in 72% of cases Several case studies,case series, retrospective cohort Conventional hemostatic measures have failed. Promising addition to thrapeutic armamentarium Multicenter, randomized, double-blind, placebo controlled study by Boffard Initial dose of 200 µg/kg, then 100 µg/kg, at 1 and 3 hours Produced a significant reduction in the primary endpoint RBC transfusion requirements, need for massive transfusion, and incidence of respiratory failure Grade B Penetrating trauma are uncertain, no recommendations can be made for this indication. Grade B

20. Penetrating Boffard et al.: J Trauma 2005

22. Recommendations on the use of rFVIIa as an adjunctive treatment for massive bleeding – a European perspective Not be used in prophylactically in elective surgery (grade A) Use of rFVIIa in blunt trauma (grade B). Not be recommended for use in penetrating trauma (grade B) Not be recommended for use in liver surgery (grade B) Not be recommended for use in or in bleeding episodes in patients with Child–Pugh A cirrhosis (grade B). Bleeding after cardiac surgery (grade D). Postpartum hemorrhage (grade E) Uncontrolled bleeding in surgical patients (grade E) Monitoring of rFVIIa efficacy should be performed visually and by assessment of transfusion requirements (grade E), Critical Care 2006, 10:R120

23. Warfarin Reversal Dramatic increase in number of patients receiving OAC Interindividual variation (environmental and genetic) Incidence of fatal haemorrhage :1%/Y. Increased risk of ICH > 50 y compared with non- anticoagulated 10x Reversal :seriousness of bleeding, thrombotic risk and speed and completeness of reversal Options : dose omission,vit K & factors replacement FFP or PCCs

26. Warfarin Reversal PCCs Intermediate purity plasma products Only HTDEFIX is licensed in UK for warfarin reversal PCCs, (‘‘4 factor concentrates’’), OR low VII (3 ) Amounts of protein C and S Optimum dose not established. Thrombogenicity, exacerbation of DIC are dose related Current cost in UK (single treatment for a 70 kg individual £437 -£875). More expensive > FFP. ( unit of produced from UK plasma costs about £30). FFP that is methylene blue treated or produced from non-UK plasma is more expensive.)

27. Warfarin Reversal rFVIIa Advocated in the management of bleeding Studied in a small number of studies Normalises the INR in anticoagulated Dose range, 15–90 mg/kg Small numbers of patients with ICH successfully treated with rFVIIa have been reported recently.54–56 Lin J, J Neurosurg 2003;98:737–40. Sorensen B, Blood Coagul Fibrinolysis 2003;14:469–77 On the basis of this limited data, the role of rFVIIa in warfarin reversal remains unclear.

28. Use in intracranial hemorrhage. A recent report in ICH in adults Control the expansion of intracranial hematomas in elderly patients, improving neurologic outcome and significantly decreasing mortality. Serious thromboembolic events were higher in the treated groups (7% vs. 2% for placebo). Bijsterveld NR, Circulation 2002;106:2550-4.

29. SAFETY PROFILE Theoretical increased risk of thrombotic events rFVIIa bind to active PLTs, hemostatic activity should be restricted to vessel injury (TF is exposed & PLTs are locally activated) Experimental evidence for localized effect in rabbit model Dec 1995 -Jan 2005,total amount of rFVIIa released 680,245 standard doses :approved or “off-label” use, Over this postmarketing period, 123 thrombotic corresponding to a mean of 1/10000 thrombotic Review in patients with acquired and congenital hemophilia with inhibitors, incidence of thrombotic events was low

30. SAFETY PROFILE Review of 13 controlled clinical trials, 1178 patients with coagulopathy No significant association was found between exposure to rFVIIa and incidence of thrombotic events????. No inhibitors reported neither in HA nor off-label use. Two patients with FVII-DEFICIENCY (no FVII protein) developed transient inhibitors against FVII. Thrombotic complication: elderly with existing atherosclerotic disease. FDA report :Arterial and venous thromboembolic events.Half occurred in first 24 hours after last rFVIIa dose. Underlying medical conditions existed in some. Lack sufficient information dosage,concomitant medications, pre-existing medical conditions and the confounding indication;

31. Advantages Disadvantages Advantages Rapid onset of action Low-volume dosing Recombinant nature alleviating infectious disease transmission Low risk of thrombogenicity :increasing cases being reported of thromboembolic manifestations Disadvantages Substantial cost $1000 per milligram Risk of thrombosis Variability of current recommended dose and dosing intervals Short half-life Limited data pertaining to safety and efficacy, Problems with monitoring its efficacy.

32. SUMMARY Great potential in achieving hemostasis in patients refractory to traditional treatments. Significant cost and uncertain benefit in many clinical situations, it should not be used indiscriminately. Transfusion service, pharmacy OR content expert in hemostasis are appropriate gatekeepers The ordering physician must demonstrate to a gatekeeper that the patient meets established criteria For off-label use a maximum of two doses Further doses given only after additional expert consultation. FDA-approved indication :Hemophilia patients with inhibitors & Congenital FVII deficiency

33. Thanks

34. Hemostatic Defects Most common are: -Low platelet counts -Low levels of vit K-depandent coagulation factors (FVII, FX, FIX, FII, ProtC) -lowered fibrinogen -lowered FVIII and FV - increased fibrinolysis

35. Use in qualitative PLT disorders. Ability of pharmacologic doses to enhance rate of thrombin generation on activated PLTs Midlevel evidence and case reports exist. Glanzmann’s thrombasthenia :reports with good results. A report of 33 episodes in 7children 60% excellent response if treated within 12 hours of onset of bleeding. Surgical prophylaxis and excessive menstrual bleeding Doses of 90 to 120µ g per kg Approved for use in Europe Poon MC, international survey. J Thromb Haemost 2004;2:1096-103.