Prothrombin Complex Concentrates - UCL Mont-Godinne€¦ · Antivitamin K...

Prothrombin Complex Concentrates

François Mullier, Bernard Chatelain, Christian Chatelain, Jean-Michel Dogné

GLEM Intensivistes, CHUMGMay 30th, 2011

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Outline•

Introduction

-

Overview

of blood

coagulation-

Targets

for anticoagulation-

Antivitamin

K antagonists-

Epidemiology-

INR

•

Prothrombin

complex

concentrates-

Indications: -

Management of severe

bleeding

on VKA-

Preoperative

management of patients on VKA requiring

an emergency intervention with

risk

of bleeding- Trauma-

PCC and new oral anticoagulants-

Reversal of AVK: Options-

Composition and mechanism

of action of PCC-

Recommendations-

Comparison

of concentrates-

How to use PCC?

•

Conclusions

Introduction: Overview

of blood coagulation

AG Turpie; C Esmon. Thromb Haemost 2011; 105: 586–596

Venous thromboembolism•

One of the leading

causes of mortality

and morbidity

•

12% of deaths

occurring

annually

in the European

Union are associated

with

venous

thromboembolism

(Cohen et

al., 2007)

•

Pulmonary

embolism

is

the most

common

preventable cause of hospital

death, and the prevention

of pulmonary

embolism

is

the number

one strategy

to improve

patient safety

in hospitals

(Geerts

et al., 2008).

T. Mavrakanas, H. Bounameaux / Pharmacology & Therapeutics 2011

Introduction: Targets

for anticoagulation

AG Turpie; C Esmon. Thromb Haemost 2011; 105: 586–596

I.Ahrens et al.Thromb Haemost 2010; 104: 49–60

Introduction: mechanism of action of vitamin K antagonists

Vitamine K

Vitamin K H2

Vitamin K oxyde

TargetsFactors

II, VII, IX, X

Proteins C et S

Glutamic

acid

-carboxyglutamique

acid

Reductase

Reductase

Oral anticoagulants

(warfarine, phenprocoumone, fluindione

et acenocoumarol) block the

2 first

reduction

steps

Adapted following Hirsh J, et al. Chest 1995; 108: 231–246

Introduction: disadvantages of vitamin K antagonists

•

Slow onset

and offset of action

•

Unpredictable

patient response

•

Monitoring and dose adjustment

required

•

Narrow

therapeutic

window

•

Multiple food

and drug

interactions

T. Mavrakanas, H. Bounameaux / Pharmacology & Therapeutics 2011

Vitamin

K antagonists

indications and epidemiology

•

Prevention

and treatment

of many

thrombotic

disorders: atrial fibrillation, venous

thromboembolic

disease

and mechanical

heart

valves

•

Atrial fibrillation:-

most

common

cardiac

arrhythmia

of clinical

significance

and a major

risk

factor for cardioembolic

stroke (Lloyd-Jones et al., 2004; Singer et al., 2004).

-

1% of the general

population, up to 10% of >=80 . -

Risk

of ischemic

stroke is

increased

four-

to fivefold

in patients with

AF (Wolf et al., 1991). -

Acetylsalicylic

acid

recommended

for patients with

AF who

have a

low

to intermediate

risk

of stroke, but only

modest

protection. -

VKA can

reduce

the risk

of atrial fibrillation-related

stroke by

approximately

70% (Singer et al., 2004; Hart et al., 2007)

Introduction: epidemiology

France Belgique Pays-Bas USA

Population 60 millions 10,5 millions 16,3 millions 280 millions

Anticoagulation orale

(% de la population)

600.000(1,0%)

200.000(2%)

325.072(2,0%)

2.500.000(0,9%)

Médicament principal Phéninidone

AcénocoumarolPhenprocoumone

Acénocoumarol Warfarine

Pengo et al. J Thromb Thrombolysis 2006; 21: 73–7

International Normalized Ratio (INR)

ISI : International Sensitivity Index

PT : Prothrombine

Time (sec.)

Patient PT

MNPTINR =

ISI

Normal

range:- Healthy

subject: 1,0 –

1,4

- AVK: 2,0 –

3,0

Quality

of antivitamin

K control in atrial fibrillation

•

Time in therapeutic

range:

b) AFBaker et al. JMCP April 2009 Vol. 15, No. 3-

8 studies: 22,237 warfarin-treated

AF patients with

41,199 years

of follow-up-

55% (95% CI = 51%-58%)

-

usual

care 11 lower

% (95% CI = 2%-20%) than

in anticoagulation

clinics.

Risk factors of bleedings

on

AVK

•

Bleeding

score includes:-

Age>=65-

History

of stroke-

History

of gastrointestinal

bleeding-

Presence

of one

or

more co-morbid

conditions

(recent myocardial

infarction, anemia, renal/hepatic

impairment, alcohol, hypertension, diabetes mellitus)

-

Sex-

Intensity

and variability

of anticoagulation-

Risk higher

during

1st year-

Duration

of anticoagulation-

Indication-

Concomitant drug therapies

Makris et al. J Thromb Thrombolysis 2010; 29: 171:181British Journal of Haematology 2001,114, 271-280

Risk

of bleeding

significantly

increases

when

the INR is

>=4.5

INR and hemorragic risk•

Italian Study on Complications of oral Anticoagulant Therapy:

risk of bleeding at an INR >7: -

40 times the risk at an INR in the range 2-2,9

-

20 times the risk at an INR in the range 3-4,4 (Palareti

et al, 1996).

Makris M. and WatsonHG. The management of coumarin-induced over-anticoagulation. British Journal of Haematology 2001;114: 271-280

PCC: Indications-

Management of severe

bleeding

on VKA

-

Preoperative


an emergency intervention with

risk

of bleeding

-

Bleedings

peri-operative

prevention

and treatment

in case of congenital

vitamin-K dependent

clotting

factor deficiency, when

no

specific

coagulation factor of high

purity

is

available

-

Trauma

-

PCC and new oral anticoagulants

Reversal of AVK: Options PCC

Leissinger et al. Role of prothrombin complex concentrates in reversing warfarin anticoagulation. A review of the literature Am.J.Hematol. 2008;83:137-143

•

Non activated

and concentrated

form

of vitamin

K dependent

clotting

factors

•

Rapid

and specific

method

for replacing

vitamine-K dependent

clotting

factors

and restoring

normal

hemostasis

in the context

of overcoagulation

•

Predictive

and measurable

effect


Leissinger et al. Role of prothrombin complex concentrates in reversing warfarin anticoagulation. A review of the literature Am.J.Hematol. 2008;83:137-143Pernod et al. French clinical pratice guidelines on the management of patients on vitamin K antagonists in at-risk situations (overdose, risk of bleeding and active bleeding). Thrombosis Research 2010; 126: e167-e174

•

In comparison

with

FFP:-

More effective in shortening

time to INR correction

-

Low

risk

of thrombotic

adverse events-

FFP fluid

overload

respiratory

distress

•

In comparison

with

vitamin

K:-

More rapid

correction than

vitamin

K alone

-

PCC: INR between

1.2 and 2 within

10 min in 79% to 100% cass, without

a clear

dose-effect

relationship

for

doses of between

25 and 50 U/kg


Pernod et al. French clinical pratice guidelines on the management of patients on vitamin K antagonists in at-risk situations (overdose, risk of bleeding and active bleeding). Thrombosis Research 2010; 126: e167-e174

•

Recombinant activated

factor VII (rVIIa, Novoseven®)-

Effective in reversing

excessive anticoagulation

in a few

non-controlled

small-sized

studies-

Cannot

be

recommended

due to insufficient

data and

lack

of information on the appropriate

dose

Recommendations: management of severe

bleeding

•

Severe, or potentially

severe, bleeding

during

VKA treatment

:

at

least one of the following:-

externalised

bleeding

that

cannot

be

stopped

by applying

conventional

measures;-

haemodynamic

instability

defined

by systolic

blood

pressure 90mm Hg, or 40 mm Hg lower

than

usual, or mean

arterial

pressureb65 mg Hg, or signs

of shock;-

need

for an emergency procedure

to stop bleeding

such

as surgery,interventional

radiology, endoscopy;-

need

for transfusion of red

cell

packs;-

life-threatening

bleeding

or bleeding

that

compromises function, e.g. intracranial

or intraspinal

haemorrhage, intraocular

or retroorbital

bleeding, haemothorax, haemoretroperitoneum, haemopericardium, deep

muscle haematoma

and/or neural compression syndrome, acute gastrointestinal

bleeding, and haemarthrosis.

•

None of these

criteria

non-severe.



bleeding

•

Patients with

severe

bleeding

must be

admitted

to hospital.

•

Surgeons and radiologists

should

rapidly

discuss whether

a surgical, endoscopic

or endovascular

procedure

is

needed

to stop bleeding.

•

The INR should

be

measured

immediately

on the patient's

admission to hospital.

•

However, the time needed

to obtain

the result

should

not delay

the treatment.



bleeding

•

If this

is

not possible, the INR should

be

measured

using

a self- management device

at

the patient's

bedside

(Professional

consensus). In this

case, the measurement

should

comply

with

good practices and the rules

for out-of laboratory

tests.

•

In cases of severe

bleeding, the return to a normal INR value (INR<1.5) should

be

achieved

as fast

as possible, i.e. within

a few

minutes.

•

Besides

VKA discontinuation, PCC should

be

administered immediately

in association with

10 mg vitamin

K supplement

(grade

C, level

3), and urgent management of massive haemorrhage

if present

(correction of hypovolemia, transfusion of red

cell

packs if

necessary, etc).



bleeding

•

Fresh

frozen

plasma should

be

used

only

when

PCCs are not available

(grade B, level

2).

•

The use of recombinant activated

Factor VII is

not recommended

(grade C, level

3).

•

If PCC is

not rapidly

available

in the emergency units, a few vials

of PCC should

be

kept

readily

available

in the

departments

concerned

(emergency department, intensive care unit, and some

operating rooms), with

the

agreement of the hospital

pharmacy

and with

a record of traceability

(Professional consensus).



bleeding

•

INR should

be

measured

within

30 minutes of PCC administration. If it

remains≥1.5, a further

PCC dose

should

be

administered. The second dose must be adjusted

according

to the INR and body weight, as

indicated

by the Summary

of Product Characteristics (SPC) of PCC.

•

The INR must be

measured

again

after

6 to 8 hours

and then

daily

while

the situation remains

critical.



bleeding


Recommendations: Preoperative


an emergency

intervention with

risk

of bleeding


•

An emergency procedure

is

defined

as a procedure

that

has to be carried

out before

the haemostatic

threshold

can

be

reached

(INR<1.5, or<1.2 for neurosurgery) by vitamin

K administration alone.

•

The INR must be

measured

on the patient's

admission to hospital.

•

The administration of PCC is

recommended

(grade C, level

3) as described

in the subsection

“Management of severe

bleeding”.

•

Administration of vitamin

K (5 mg) should

be

associated

with

PCC, unless

haemostasis

correction is

required

for<4 hours

(grade C,

level

3).

•

The enteric

route should

be

used

whenever

possible (grade A, level 1).



an emergency

intervention with

risk

of bleeding


•

The INR should

be

measured

30 minutes after

PCC administration and before

the intervention.

•

In cases of inadequate

correction, a further

dose of PCC should

be

given.

•

This dose depends

on the INR value and should

comply with

SPC recommendations.

•

The INR should

be

measured

6 to 8 hours

after anticoagulant reversal.

•

Postoperative

management is

the same

as for elective surgery.



an emergency

intervention with

risk

of bleeding


•

If the intervention can

be

delayed

to allow

anticoagulant reversal by vitamin

K alone

(6 to 24 hours

depending

on

the INR value), it

is

not necessary

to administer

PCC.

•

The vitamin

K dose recommended

is

5 to 10 mg, preferably

by the enteric

route.

•

INR should

be

measured

every

6 to 8 hours

until

the intervention. Postoperative

management is

the same

as

for elective

interventions.

Douketis JD. Blood 2011; 117(19): 5044-9

Recommendations: bleeding

in a trauma patient


•

Little

data available

recommendations

come from professional

consensus

•

INR should

be

measured

immediately

•

Depending

on the trauma, the management will

be

that proposed

for spontaneous

non-severe

or severe

bleeding

•

Head trauma: observation during

24h and brain

scan either

immediately

if neurological

symptoms

are present

, or within

4 to 6 hours

in other

cases (grade C, level

3)


in a trauma patient

Tanaka et al. Treatment of massive bleeding with prothrombin complex concentrate: arguments for. J Thromb Haemost 2010;8: 2589-91Godier et al. Treatment of massive bleeding with prothrombin complex concentrate: arguments against. J Thromb Haemost 2010;8: 2592-95

•

Multifactorial

deficiencies

in massive bleeding

may

not be

fully restored

by targeted

replacement of vitamin

K-dependent

factors

with

PCC:-

PCC does

not contain

fibrinogen, FV, FVIII, FXIII or plasminogen

(present

in PCC which

contains

also

albumin)-

Fibrinogen

may

fall

to critical

levels

before

other

factors

in patients

with

severe

bleeding-

Low

levels

of fibrinogen

are associated

with

increased

risk

of

hemorrhagic

severity-

Partial deficiency

in FXIII has been associated

with

perioperative

bleeding-

After

a loss

of > 200% of blood

volume, bleeding

may

result

from

thrombocytopenia

(< 50 ·

109 L-1) and low

FV (< 25%), for which platelet

or FFP transfusion may

be

necessary

.


in a trauma patient


•

In massive bleeding

without

DIC, PCC (20–25 IU kg-1) can

be administered

after

the primary

fibrinogen

replacement (1.5-2.0 g L-

1).


in a trauma patient


•

0,2-15 IU/ml heparin

in PCC:-

Influence coagulation assays

( decrease

ETP, increase

APTT,

changes in thromboelastography)-

Contra-indication

in patients with

history

of HIT

•

Fluid

volume:-

Low

fluid

volume of PCC : disadvantage

in massive bleeding

(profound

hypovolemia) PCC must be

associated

with

fluid therapy


in a trauma patient


•

Fluid

volume:

-

This may

promote

coagulopathy, through

dilution and alteration

of fibrin

polymerization

and stabilization

of the clot

if hydroxyethyl

starches

(HESs) are used.

-

The administration of fibrinogen

concentrate

can

correct the induced hypodysfibrinogenemia

related

to the combination

of PCC (without

fibrinogen) and HES [9].

-

Transfusion of FFP, which

adds

both

volume and fibrinogen,is

a simpler

and less

expensive

choice

than

the PCC–HES–

fibrinogen

combination.


in a trauma patient

Tanaka et al. Treatment of massive bleeding with prothrombin complex concentrate: arguments for. J Thromb Haemost 2010;8: 2589-91


in a trauma patient


•

Recent

retrospective

study

of 131 trauma patients-

Injury

Severity

Score, 38 ±

15

-

initially

administered

fibrinogen

concentrate

(median, 6 g) in 128 patients

-

then

four-factor PCC (median, 1800 IU) in 98 patients using thromboelastometry

as a point-of-care test.

-

Only

12 (9.2%) and 29 (22%) patients received

FFP and platelet transfusion, respectively, in the 24-h period.

-

Overall, the observed

mortality

was

24.4%, which

was

lower

than the predicted

mortality

(28–34%) based

on the injury

scale.


in a trauma patient


•

Although

these

data suggest

potential

hemostatic

efficacies

of fibrinogen

and PCC in patients receiving

10 U of RBCs

in 24 h, the

small

sample

size and retrospective

design preclude

extraction of any

safety

information.


in a trauma patient


•

The premise

underlying

the use of aforementioned

fibrinogen/ PCC interventions is

the immediate

availability

of factor concentrates

and

thromboelastometry.

•

The indication for and dose of each

factor concentrate

should always

be

guided

by laboratory

monitoring as well

as clinical

assessments

.

•

Administering

factor concentrates

without

appropriate

monitoringcan

be

both

potentially

dangerous

and costly. The therapeutic

response

to hemostatic

agents can

be

influenced

by coexisting

hypothermia

or hidden

surgical

bleeding.

Thus, it

is

important to carefully

assess

the cause(s) of bleeding.


in a trauma patient


•

A systemic

fibrinolytic

state may

be

diagnosed

in trauma patients using

thromboelastometry

, and antifibrinolytic

therapy

should

be

considered

in such

cases.

•

Thrombotic

complications are rare when

PCC is

administeredto reverse vitamin

K antagonists, but dosing

of PCC may

need

to be

reduced

to avoid

excess

thrombin

activity

because

the AT level

can be

below

40% in massive bleeding.

•

In overt

bleeding

associated

with

DIC or advanced

liver

disease, replacement of AT may

be

necessary

before

PCC is

administered


in a trauma patient


•

There are several

clinical

advantages

in the use of PCC overFFP:-

The risk

of transfusion-related

acute lung

injury

associated

with

FFP

can

be

minimized

by lack

of anti-HLA/antigranulocyte

antibodies

in PCCs.

-

PCCs

are derived

from

pooled

human

plasma, but multiple steps

of viral inactivation including

heat-treatment, solvent/detergent

and

nano-filtration are routinely

applied

in addition to the donor screening.

-

A non-lipid

enveloped, heat-resistant

virus including

ParvovirusB19 can

be

transmitted

by transfusion, but such

infections are

rare and of limited

clinical

consequences

in non-immunosuppressedpatients .


in a trauma patient


•

This sequence

of therapies

guided

by laboratory

monitoring seems to have FFP-sparing

effects

in trauma patients with

hemorrhage.

•

However, admittedly, there

are insufficient

prospective data at present

to support the efficacy

and safety

of (three-factor or

fourfactor) PCCs

(and their

use with

other

agents (e.g. antifibrinolytics)) in massive transfusion in trauma and surgery

.

•

Outside

the European

nations, PCCs

are generally

considered

off- label in the management of acquired

bleeding

•

Conversely, high-dose FFP therapy

is

increasingly

used

at

major trauma centres, but potential

long-term

complications are of great

concern.


in a trauma patient


•

In massive bleeding, rFVIIa

remains

an off-label agent. Two prospective randomized

trials of rFVIIa

in major transfusions (> 8

units

of RBCs) after

blunt

or penetrating

injury

(n = 143 and 134, respectively) revealed

no differences

in transfusion of FFP or

platelets

in 48 h between

patients who

received

rFVIIa

(400 lg kg-1 in three

divided

doses) and those

who

received

placebo.

•

In contrast

to rFVIIa, which

critically

depends

on endogenous

FX, FII and platelets

to increase

thrombin

generation, PCC restores

physiological

levels

of non-activated

FII, VII, IX and X at

the vascular injury

site.

•

The latter approach

with

fibrinogen

replacement seems

to lessen

the need

for rFVIIa.

Indications: PCC and new oral anticoagulants

JW. Eikelboom, JI. Weitz. BMJ 2011;342:224-227

Indications: PCC and new oral anticoagulants

Van Ryn et al. Dabigatran etexilate – a novel, reversible, oral direct thrombin inhibitor: Interpretation of coagulation assays and reversal of anticoagulant activity.Thromb.Haemost 2010; 104: 49–60

Comparison of PCC

Leissinger et al. Am.J.Hematol. 2008;83:137-143

Ideal PCC

Rapid response

time

Easy and rapid administration

Rapid correction

of coagulation

INR normalization

Balance between coagulation factors

and coagulation inhibitors

Viral- inactivation

Comparison of PCC•

3-factor (without

VII) or 4-factors

•

4-factors

differs

in:-

composition: coagulation factors

and inhibitors

-

Presence

of heparin

and antithrombin-

Purity

•

Does

not contain

fibrinogen, FV, FVIII, FXIII or plasminogen

Comparison of PCC

Kalina et al. Int.J.Clin.Practice 2008;83:137-14362(10):1614-22

•

Similar

levels

of coagulation factors

(exception: Uman Complex

no detectable

factor VII)

•

Considerable

differences

in their

coagulation inhibitory capacity

and purity

•

Beriplex: greater

thrombin

inhibition (high

levels

of the coagulation inhibitors

protein

C, protein

S, protein

Z, and

small

amounts

of antithrombin

III and heparin) and purity

therapeutic

protein

as a percentage

of total protein

•

All PCC negative

for activated

coagulation factors

Comparison of PCC

Kalina et al. Int.J.Clin.Practice 2008;83:137-14362(10):1614-22

Safety of PCC•

Immediate

allergic

reactions

•

Heparin-induced

thrombocytopenia

(for preparations containing

heparin)

•

Thromboembolic

complications:-

Leissinger

et al.:

*7/506 cases, 1.4%*Most cases: could

be

attributed

to the patients underlying

disease-

Lower

incidence over the last few years

due to

improvement

in the composition (inclusion of coagulation inhibitors, reduced

use of activated

coagulation factors

and improved

balance of coagulation factors)-

Beriplex: 0,9%

M.Franchini et G.Lippi. Blood Transfusion 2010; 8:149-154

PCC Dosage

Step 1:

Define the target INR• Moderate bleeding,

high thrombosis risk = 2,0–2,1

• Severe bleeding threatening the life, moderate thrombotic risk = 1,5• Severe bleeding , low thrombotic risk =

1,0

Step 2:

Transformation in prothrombin complex (%)INR %4,0 6%3,5 8%3,0 9%2,5 12%2,0 17%1,8 20%1,6 25%1,3 40%1,2 50%1,0 100%

Step 3:

Dosage calculation

(Target level [%] –

actual level [%])

x body weight (kg)

= PCC (UI)

Modified following Schulman S, New Engl J Med 2003 349 675-83Joost de Wolf Transfusieboek 2008

Confidex®

dosage

INR initial 2,0 – 3,9

4,0 – 6,0

> 6,0

Approximate dosage

(ml/kg)

1 1,4 2

Approximate dosage

(IU

factor IX/kg)

25 35 50

Pabinger et al. J Thromb Haemost 2008; 6:622-631Résumé des Caractéristiques du Produit Confidex. 11/2009

Main

objective: target INR < 1,3

54

•

First choice

in case of VKA overdosage

and preoperative management of patients on VKA requiring

an emergency

intervention with

risk

of bleeding

•

Massive bleeding

(without

VKA): debated

•

Improvement

of safety

due to improved

composition

Conclusions

Thank you for your attention

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