Cell Based ModelGalila Zaher, MRCPath

Assistant ProfessorConsultant Hematologist

KAUH

VIIa

TF-BEARING CELL

ACTIVATED PLATELET

HEMOSTASIS

THROMBIN

FIBRIN HEMOSTATIC PLUG

INITIATION

OF HEMOSTASIS

PROPAGATIONOF HEMOSTASIS

TF

TF

X

Xa Va

II

IIaTF-bearingcell

VIII/vWF VIIIa

V Va

platelet

activated platelet

VIIa

VIIaIX

IXa

VIIIaVaIXa

X

Xa

II

IIa

TF

XIa

IX

XI XIa

Normal Hemostasis

IIa (THROMBIN)

FIBRINOGEN FIBRIN(SOLUBLE FIBRIN MONOMERS)

FXIIIa

FIBRINOLYSIS

TAFI

STABILIZED,CROSS-LINKED

FIBRIN(HEMOSTATIC

PLUG)

Thrombin FV FVIII

FVa FVIIa

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:

Thrombin Activity

0

0.005

0.01

0.015

0.02

0.025

0.03

0.035

0.04

0.045

0.05

0 20 40 60 80 100 120 140

Time (min)

Th

rom

bin

act

ivity

(dA

405

/min

)

With FVIII present(- FXI)

FVIII-deficiency

+ 50 nM FVIIa

+ 150 nM FVIIa

Kjalke et al. 1999

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

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)

TF

X

Xa Va

II

IIaTF-bearingcell

VIII/vWF VIIIa

V Va

platelet

activated platelet

VIIa

VIIa

VIIa Va

X

Xa

II

IIa

TF

XI XIa

Hemophilia

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

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)

COST EVALUATION MILD-MOD BLEEDINGS IN HAEMOPHILIA

Average cost

Time to resolve

Mean number doses/episode

Mean time to resolution

Effectiveness:

OVERALL COST

rFVIIa £11,794

30 hrs 3.6 17.3 hrs

89.3% 9,113US$

FEIBA £20,46 58 hrs 4.8 43.6 66.7% 12,542

rFVIIa is safe and has a higher efficacy relative to other treatment options”.

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

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

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.

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

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

–

Trauma.• Uncontrolled massive hemorrhage is 2nd

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

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

0

5

10

15

20

25

30

35

Blunt Penentrating

Trauma: % Patients Requiring > 20 Units RBC

rFVIIaPlacebo

%Pts

P=0.03

P=0.08

PenetratingBoffard et al.: J Trauma 2005

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

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

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.)

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.

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.

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

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;

Advantages DisadvantagesAdvantages • Rapid onset of action• Low-volume dosing• Recombinant nature alleviating infectious disease

transmission • Low risk of thrombogenicity :increasing cases being

reported of thromboembolic manifestationsDisadvantages • 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.

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

Thanks

Hemostatic DefectsMost 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

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.