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Fibrin sealants & components

Fibrin sealants & components . Fibrin sealants. Surgical haemostatic and adhesive agents derived from plasma products Designed to reproduce the final steps of the physiological coagulation cascade and form a stable fibrin clot

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Fibrin sealants & components

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  1. Fibrin sealants & components

  2. Fibrin sealants • Surgical haemostatic and adhesive agents derived from plasma products • Designed to reproduce the final steps of the physiological coagulation cascade and form a stable fibrin clot • Fibrin clot arrests blood loss, seals physiological compartments and aids normal wound healing • Clot degraded by naturally occurring fibrinolytic enzymes over several days to weeks

  3. Components of fibrin sealants • Fibrinogen • Thrombin • Factor XIII • Antifibrinolytic agent • Calcium chloride

  4. Fibrinogen • Source: human plasma derived • Concentration range: 65–115 mg/mL • Structure: soluble monomeric form of fibrin • Function: forms basis of clot along with platelets – forms covalent cross-links with factor XIII which stabilizes the clot

  5. Thrombin • Human plasma derived • 4–1000 IU/mL • Enzymatically cleaves fibrinogen to initiate polymerisation • Cleaves b2-subunits and a-chain of factor XIII • Initiates fibroblast division in wound healing

  6. Factor XIII • Source: human plasma derived • Concentration range: 0–80 U/mL • Function: activated by thrombin in the presence of Ca2+ to factor XIIIa. Factor XIIIa participates in fibrin cross-linking and stabilisation

  7. Aprotinin • Source: bovine lung derived • Concentration range: 0–3000 KIU/mL • Function: inhibits plasmin, preventing fibrinolysis – prevents clot degradation

  8. Calcium chloride • Concentration: 40 mmol/L • Function: Ca2+ ions are required for thrombin and factor XIIIa activity

  9. Mechanism of action Fibrinogen Thrombin Fibrin clot Factor XIIIa Anti-fibrinolytic [Aprotinin, tranexamic acid] Cross-linked fibrin clot X Fibrin degradation

  10. Beriplast® P safety & tolerability

  11. Clinical safety of Beriplast® P • Beriplast® P has been shown to be clinically useful across a range of surgical procedures, and has an excellent safety and tolerability profile • Rigorous donor selection and testing on all plasma used in Beriplast® P is designed to ensure an extremely low risk of pathogen transmission

  12. Safety of Beriplast® P • Worldwide safety record – many years’ experience with Beriplast® P • more than 6 million milliliters applied to date • Data from post-launch period (July 1991-Dec 2002) show: • no confirmed reports of HIV or hepatitis transmission attributable specifically to Beriplast® P • only 1 in 156264 uses was associated with a suspected adverse drug reaction • in most cases the adverse reaction was not related to Beriplast® P

  13. Beriplast® P: integrated safety system • Safety at source • Controls/plasma verification and testing • Effective virus inactivation and elimination steps in production • Final product testing

  14. Beriplast® P ISS: safety at the source • Safety at the source • plasma collection • donor centre selection • qualified donor selection • donation testing • plasma inventory hold • Careful selection of plasma donors meeting or exceeding regulatory requirements • viral marker rates lower than other plasma suppliers

  15. Beriplast® P ISS: controls • Controls • plasma verification system • plasma pool testing • Rigorous testing of donated blood by serology and sensitive NAT/PCR techniques

  16. Beriplast® P ISS: safety at the source • Careful donor selection • screening criteria more rigorous than non-paid donors • Rigorous testing of donated blood or plasma by serology and sensitive NAT/PCR techniques

  17. Beriplast® P: NAT/PCR used to test plasma donations • Hepatitis viruses • hepatitis C virus (HCV) • hepatitis B virus (HBV) • hepatitis A virus (HAV) • Retrovirus • human immunodeficiency virus-1 (HIV-1) • Parvovirus • parvovirus B19

  18. Beriplast® P: window period reduction by PCR Window period (days) Reduction Virus Serology PCR Days % HIV HBV HCV 22 56 82 11 31 23 11 25 59 50 45 72

  19. Beriplast® P ISS: virus inactivation and elimination • Effective virus inactivation and elimination steps in production • pasteurisation • purification methods

  20. Beriplast® P: virus elimination and inactivation steps Elimination Inactivation Cryoprecipitation Adsorption Ammonium sulphate precipitation Ion exchange chromatography Pasteurisation

  21. Validation of virus Inactivation/elimination • Demonstrates inactivation/elimination of certain viruses potentially present in donated plasma

  22. Beriplast® P: viruses used in validation studies Test Virus Relevant virus or Model virus for HIV-1 Bovine viral diarrhoea virus (BVDV) Herpes simplex virustype-1 (HSV-1) Hepatitis A virus (HAV) Canine parvovirus (CPV) Relevant virus, specific model for Retroviruses Specific model for HCV, HGV and non-specific model for other medium-sized enveloped RNA viruses Non-specific model for enveloped DNA viruses Relevant virus and non-specific model for other non-enveloped small RNA viruses Specific model for Parvovirus B19

  23. Viral reduction in Beriplast® P production Pasteurisation process • Between 1.2 and  9 log10 reduction Overall • Between  12 and  20 log10 reduction of HIV-1 • Between  11 and  13 log10 reduction of model enveloped RNA virus • Between  5 and  9 log10 reduction of HAV • Between  9 and  20 log10 reduction of model enveloped DNA viruses (herpes simplex 1) • Between 4.3 and 5.5 log10 reduction of model parvovirus

  24. Beriplast® P log10 viral reduction factors: human thrombin Production step HIV-1 BVDV HSV-1 HAV CPV Ion exchange chromatography Pasteurisation Precipitation, absorption Activation of prothrombin Mean overallreduction factor 2.7 6.9 6.5 3.5 19.6 - 8.5 1.9 2.2 12.6 1.7 7.0 6.6 5.0 20.3 - 4.0 1.7 2.6 8.3 1.1 (0.5)* 1.2 3.2 5.5 *Data not used in overall reduction factor calculation

  25. Beriplast® P log10 viral reduction factors: human fibrinogen Production step HIV-1 BVDV HSV-1 HAV CPV Cryoprecipitation Adsorption,precipitation Pasteurisation Precipitation Lyophilisation Mean overallreduction factor - 2.8 5.7 3.9 - 12.4 - (1.5)* 9.0 2.0 - 11.0 - (0.9)* 8.0 1.0 - 9.0 1.4 - 4.1 (0.8)* (2.2)* 5.5 1.7 - 1.2 1.6 - 4.5 *Data not used in overall reduction factor calculation

  26. Beriplast® P log10 viral reduction factors: human factor XIII Production step HIV-1 BVDV HSV-1 HAV CPV Adsorption,defibrination Ion exchange chromatography Pasteurisation Lyophilisation Mean overallreduction factor 5.6 4.6 7.0 - 17.2 7.4 - 7.2 - 14.6 2.8 2.6 7.9 - 13.3 1.3 3.1 4.2 (2.3)* 8.6 (0.4)* 3.3 1.0 - 4.3 *Data not used in overall reduction factor calculation

  27. Aprotinin and transmissible spongiform encephalopathy (TSE) risk • Derived from bovine lungs • class III organ • Cattle from countries with no reported cases of BSE according to WHO information • Reduction of scrapie agent (causative agent of TSE in sheep and goats) during the manufacture of aprotinin

  28. Beriplast® P ISS: final product testing • Sterility • Activity / Identity • pH • Appearance, colour and solubility

  29. Beriplast® P: adverse reactions • Basic prescribing information for Beriplast® P lists: • rare reports of hypersensitivity or allergic reaction (dyspnoea, flushing/rash) • isolated cases of anaphylactic shock • Repeated exposure or hypersensitivity to bovine proteins (or other product constituents) can contribute to an adverse event • Thromboembolic complications • Risk for tissue adhesion at undesired sites • Transmission of infective agents

  30. Beriplast® P: drug surveillance • >6 million mL of Beriplast® P distributed worldwide • 41 cases of drug reactions have been reported with Beriplast® P - approximately 1 suspected adverse reaction per 156264 applications of Beriplast® P in the reporting period from Jul 1991 to Dec 2002 • No confirmed reports of transmission of viral hepatitis or HIV related to use of Beriplast® P

  31. Estimated risks of adverse events in clinical practice • 10-20% of hospital patients suffer an adverse reaction to therapy • 0.24-2.9% of deaths in hospital inpatients are due to adverse reactions to drugs • 0.3-5.0% of hospital admissions are due to adverse drug reactions • For Beriplast® P the estimated reporting rate of suspected adverse event is 1 case for every 156264 standard applications (0.0000063%) Aronson, 1996

  32. Safety of Beriplast® P • Greatly reduced risk of viral transmission compared with blood transfusion • Safer than blood bank produced sealants • reduced risk of virus transmission • reduced risk of antibody response with human thrombin compared with bovine thrombin • consistency of product

  33. Beriplast® P: conclusions • The manufacturer’s integrated safety system confers a high degree of clinical safety to Beriplast® P • Beriplast® P is a safe, valuable and reliable adjunct to surgery supported by: • virus validation studies • clinical trials data • long-term drug surveillance reports

  34. Preclinical uses of fibrin sealant

  35. Experimental models • Used to determine the mechanical and biochemical properties of fibrin sealants • Mechanical properties • support strength of seal • evaluate bursting pressure of wound closure • Biochemical properties • models of haemostasis • studies of the viscosity of fibrin sealants

  36. Vertical suture Infinity suture 350 Self-sealing sutures 300 Fibrin sealant 250 Cyanoacrylate closure Mean tensilestrengthgf/mm2 200 150 100 50 0 Postoperative days Fibrin sealants enhance tensile strength of intraocular wounds Day 0 Day 4 Day 28 Shigemitsu and Majima, 1997

  37. 180 160 140 Rupture tension (g/cm) * 120 100 * 80 60 40 20 0 Intact Punctured Fibrin sealant *p<0.05 Harmanli et al, 1998 Fibrin sealants increase the tensile strength of ruptured membranes in vitro Fibrin sealant increases the strength of punctured chorioamniotic membrane in vitro but does not restore tissue strength to pre-puncture levels

  38. Human fibrin sealant Bovine fibrin sealant 14 Treated Treated 12 Control Control 10 Breakingstrength(kg) 8 6 4 2 0 Day 10 Day 30 Day 10 Day 30 Human plasma derived fibrin sealants produce strong wound closure Human fibrin sealant provides a stronger cutaneous wound closure than sutures alone (controls) or bovine fibrin sealant Scardino et al, 1999

  39. 120 * 100 Burstingpressurecm H2O 80 60 40 20 0 Sutures Sutures +fibrin sealant Fibrin sealants strengthen colonic anastomoses Bursting pressure of colonic anastomoses closed with fibrin sealant and sutures is significantly (p<0.05) higher than with sutures alone *p<0.05 Byrne et al, 1992

  40. Fibrin sealant 100 Control Burstingpressurecm H2O * 75 * 50 * 25 0 Day 0 Day 3 Day 6 Postoperative days Fibrin sealants strengthen watertight sutures Hydrostatic leak pressure is significantly higher (p<0.1) after skin tube closure with sutures and fibrin sealant compared with sutures alone *p<0.1 Oosterlinck et al, 1993

  41. 3.5 Treated 3.0 Control 2.5 Bleedingg/30 s 2.0 1.5 1.0 0.5 0 Normotensive 150 mmHg 200 mmHg 250 mmHg Blood pressure Fibrin sealants strengthen vascular anastomoses Fibrin sealant significantly (p<0.01) reduces bleeding following vascular anastomoses even in hypertensive animals Isogai et al, 1992

  42. Treated Control 120 100 * 100 75 Meanblood flow(mL/min) Meanblood loss(mL) 80 60 50 40 25 20 0 0 Effect of fibrin sealant in a femoral artery injury model *p=0.0005 Jackson et al, 1997

  43. 200 150 Mean blood loss (mL) 100 50 * 0 Fibrinsealant Control Fibrin sealant reduces suture hole bleeding in a pig vascular graft model * p=0.016 Dickneite et al, 2000

  44. Effective haemostasis in experimental atrial rupture Mean atrial pressure prior to clamp release (cmH2O) Haemostasis Right atrium 10.4 5/5 Left atrium 10.8 5/5 Kjaergard et al, 1995

  45. Fibrinsealant Suture 0 100 200 300 400 Time tohaemostasis (s) Effective haemostasis with fibrin sealant in experimental liver injury Hot aircoagulation Tovar et al, 1998

  46. Viscosity and delivery of fibrin sealants • Used increasingly in minimally invasive surgical techniques such as endoscopy • repair damaged tissue • haemostasis • promoting healing process • Delivered through twin-lumen injection catheters • <180 cm in length • force needed to inject fibrin sealant increases with increasing catheter length

  47. Comparison of two commercially available fibrin sealants Beriplast® P Competitor Component 1 Component 1 Human fibrinogen 65–115 mg Human fibrinogen 70–110 mg Human factor XIII 40–80 U Human factor XIII 10–50 U Human albumin 5–15 mg Human fibronectin 2–9 mg Bovine aprotinin 1000 KIE Human plasminogen 0.02–0.08 mg Amino acids, salts Bovine aprotinin 3000 KIE Glycine, albumin, heparin, creatine, triton, salts Component 2 Component 2 Human thrombin 400–600 IU Human thrombin 500 IU CaCl2 dihydrate 5.88 mg CaCl2 dihydrate 5.88 mg NaCl, glycine NaCl, Sodium citrate Nagelschmidt, 1999

  48. Beriplast® P Competitor 900 750 Batch 1 Viscosity(mm2/s) 600 Batch 2 450 Batch 3 300 150 0 18ºC 25ºC 37ºC 18ºC 25ºC 37ºC Viscosity of fibrin sealants Nagelschmidt, 1999

  49. Beriplast® P Competitor 4000 3000 Batch 1 Force(g) Batch 2 2000 Batch 3 1000 0 Short Long Short Long Catheter length Less force needed to deliver low viscosity fibrin sealants through delivery devices Nagelschmidt, 1999

  50. 100 75 Rate ofadhesionformation(%) 50 25 0 Control Interceed® Fibrin sealant 2% carboxy-methylcellulose Fibrin sealant reduces rate of adhesion formation in a rat model Harris et al, 1995

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