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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 l.jpg

Fibrin sealants & components


Fibrin sealants l.jpg

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


Components of fibrin sealants l.jpg

Components of fibrin sealants

  • Fibrinogen

  • Thrombin

  • Factor XIII

  • Antifibrinolytic agent

  • Calcium chloride


Fibrinogen l.jpg

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


Thrombin l.jpg

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


Factor xiii l.jpg

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


Aprotinin l.jpg

Aprotinin

  • Source: bovine lung derived

  • Concentration range: 0–3000 KIU/mL

  • Function: inhibits plasmin, preventing fibrinolysis – prevents clot degradation


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Calcium chloride

  • Concentration: 40 mmol/L

  • Function: Ca2+ ions are required for thrombin and factor XIIIa activity


Mechanism of action l.jpg

Mechanism of action

Fibrinogen

Thrombin

Fibrin clot

Factor XIIIa

Anti-fibrinolytic [Aprotinin, tranexamic acid]

Cross-linked fibrin clot

X

Fibrin degradation


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Beriplast® P safety & tolerability


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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


Safety of beriplast p l.jpg

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


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Beriplast® P: integrated safety system

  • Safety at source

  • Controls/plasma verification and testing

  • Effective virus inactivation and elimination steps in production

  • Final product testing


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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


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Beriplast® P ISS: controls

  • Controls

    • plasma verification system

    • plasma pool testing

  • Rigorous testing of donated blood by serology and sensitive NAT/PCR techniques


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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


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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


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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


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Beriplast® P ISS: virus inactivation and elimination

  • Effective virus inactivation and elimination steps in production

    • pasteurisation

    • purification methods


Beriplast p v irus elimination and inactivation steps l.jpg

Beriplast® P: virus elimination and inactivation steps

Elimination

Inactivation

Cryoprecipitation

Adsorption

Ammonium sulphate precipitation

Ion exchange chromatography

Pasteurisation


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Validation of virus

Inactivation/elimination

  • Demonstrates inactivation/elimination of certain viruses potentially present in donated plasma


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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


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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


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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


Beriplast p log 10 viral reduction factors human fibrinogen l.jpg

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


Beriplast p log 10 viral reduction factors human factor xiii l.jpg

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


Aprotinin and transmissible spongiform encephalopathy tse risk l.jpg

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


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Beriplast® P ISS: final product testing

  • Sterility

  • Activity / Identity

  • pH

  • Appearance, colour and solubility


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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


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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


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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


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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


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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


Preclinical uses of fibrin sealant l.jpg

Preclinical uses of fibrin sealant


Experimental models l.jpg

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


Fibrin sealants enhance tensile strength of intraocular wounds l.jpg

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


Fibrin sealants increase the tensile strength of ruptured membranes in vitro l.jpg

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


Human plasma derived fibrin sealants produce strong wound closure l.jpg

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


Fibrin sealants strengthen colonic anastomoses l.jpg

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


Fibrin sealants strengthen watertight sutures l.jpg

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


Fibrin sealants strengthen vascular anastomoses l.jpg

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


Effect of fibrin sealant in a femoral artery injury model l.jpg

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


Fibrin sealant reduces suture hole bleeding in a pig vascular graft model l.jpg

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


Effective haemostasis in experimental atrial rupture l.jpg

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


Effective haemostasis with fibrin sealant in experimental liver injury l.jpg

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


Viscosity and delivery of fibrin sealants l.jpg

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


Comparison of two commercially available fibrin sealants l.jpg

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 XIII40–80 U

Human factor XIII10–50 U

Human albumin5–15 mg

Human fibronectin2–9 mg

Bovine aprotinin1000 KIE

Human plasminogen0.02–0.08 mg

Amino acids, salts

Bovine aprotinin3000 KIE

Glycine, albumin, heparin, creatine, triton, salts

Component 2

Component 2

Human thrombin400–600 IU

Human thrombin500 IU

CaCl2 dihydrate5.88 mg

CaCl2 dihydrate5.88 mg

NaCl, glycine

NaCl, Sodium citrate

Nagelschmidt, 1999


Viscosity of fibrin sealants l.jpg

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


Less force needed to deliver low viscosity fibrin sealants through delivery devices l.jpg

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


Fibrin sealant reduces rate of adhesion formation in a rat model l.jpg

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


Strength of adhesion is inversely related to treatment viscosity l.jpg

180

135

Adhesionstrength(g)

90

45

0

Control

Interceed®

Fibrin sealant

2% carboxy-methylcellulose

Strength of adhesion is inversely related to treatment viscosity

Harris et al, 1995


Fibrin sealant inhibits pericardial adhesions after cardiac surgery in dogs l.jpg

Adhesion to epicardiump<0.001

Adhesion to patchp<0.001

Control

8

Fibrin sealant

7

6

No. of animals

5

4

3

2

1

0

0

1

2

3

0

1

2

3

Adhesion score

Adhesion score

Fibrin sealant inhibits pericardial adhesions after cardiac surgery in dogs

Moro, 1999


Delivery devices l.jpg

Delivery devices


Fibrin sealants54 l.jpg

Fibrin sealants

  • Fibrin sealants are used in a variety of surgical procedures including:

    • open surgery

    • minimal invasive surgery

    • endoscopy

    • microsurgery

  • A range of delivery devices are used to ensure that fibrin sealant can be applied to the surgical site efficiently and effectively


Pantajet dual syringe in open surgery l.jpg

Pantajet® dual syringe in open surgery

  • Uses:

    • local haemostasis

    • suture support

    • tissue adhesion

    • assisting closure of small lung fistulae

    • sealing of body cavities


Application of fibrin sealant through spray tip in open surgery l.jpg

Application of fibrin sealant through spray tip in open surgery

  • Pantaject® with spray tip can be used in:

    • cardiovascular surgery

    • thoracic surgery

    • visceral surgery

    • plastic and reconstructive surgery

    • maxillofacial surgery

    • trauma surgery

  • 0.5 mL Beriplast® P covers 25–50 cm2; 1.0 mL covers 50–100 cm2; 3.0 mL covers 150–300 cm2


Application of fibrin sealant in minimal invasive surgery l.jpg

Application of fibrin sealant in minimal invasive surgery

  • Endoflex® spray catheter with Endoflex® spray tip (syringes with Luer Lok® connector needed)

  • Uses:

    • laparoscopy

    • thoracoscopy

    • video-assisted thoracic surgery

CE 0538


Application of fibrin sealant in minimal invasive surgery58 l.jpg

Application of fibrin sealant in minimal invasive surgery

  • The Catheject™ dual lumen endoscopic catheter (parallel channels)

  • Uses:

    • minimal invasive surgery

  • Pantaject ® 3 mL or Endoscopic Application Set


Application of fibrin sealant through double lumen probe in endoscopy l.jpg

Application of fibrin sealant through double-lumen probe in endoscopy

  • Endoflex® double-lumen probe ‘Neumühl’ and syringes with Luer Lok® connector

  • Use:

    • bleeding peptic ulcers


Application of fibrin sealant through double lumen probe in endoscopy60 l.jpg

Application of fibrin sealant throughdouble-lumen probe in endoscopy

  • Endoflex® double-lumen probe ‘Neumühl’ (syringes with Luer Lok® connector needed)

  • Use:

    • bleeding peptic ulcers


Double lumen probe no needle for use in endoscopy l.jpg

Double-lumen probe (no needle) for use in endoscopy

  • The Catheject™ dual lumen catheter (parallel channels)

  • Uses:

    • Fistulae - anastomotic insufficiencies of the gastrointestinal tract

  • Pantaject ® 0.5/1 mL, 3 mL or Endoscopic Application Set


Application of fibrin sealant with double lumen cannulae in microsurgery l.jpg

Application of fibrin sealant with double-lumen cannulae in microsurgery

  • The Catheject™ dual lumen cannula (parallel channels, malleable)


Flexible catheter for spray delivery l.jpg

Flexible catheter for spray delivery

  • Flexible PvB catheter, triple-lumen

  • Thrombin solution in one lumen, fibrinogen solution in one lumen

  • Compressed sterile gas delivered via large lumen


Flexible catheter l.jpg

Flexible catheter

  • Single-lumen plastic catheter

  • Pantaject ® 0.5/1 mL, 3 mL


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