Frank W.G. Leebeek, MD PhD

Dept of Hematology

Erasmus MC Rotterdam, The Netherlands

5 juli 2012

Indicaties voor recombinant factor VIIa (Novoseven)

Regionaal Bloedtransfusieoverleg Zuidwest: Kliniek van Bloedtransfusie

coagulation

NEJM 2001,344:1527

Recombinant Factor VIIa

Activated eptacog alpha, Novoseven®

Developed for use in haemophilia patients with inhibitors against FVIII

or IX

First clinical use in 1983

Dose: 90 microgram/kg i.v. every 2-3 hours, or continuous infusion

Half-life 2 -3 hours

Excellent efficacy in haemophilia patients with inhibitors

Rarely thrombo-embolic events in these patients

Recombinant Factor VIIa

Tissue factor dependent mechanism of action

Activates FX on activated platelets

Inhibits fibrinolysis by upregulating TAFI by generation of thrombin

Mannucci, PM .NEJM 2007;356:2301

Current indications of rFVIIa

Bleeding (spontaneous and surgical) in patients with congenital and

acquired haemophilia A or B with inhibitors against FVIII or FIX

Glanzmann thrombasthenia

Factor VII deficiency

rFVIIa in Haemophilia

Other possible indications for rFVIIa

Without pre-existing coagulopathy

Excessive, uncontrollable bleeding post-surgery, trauma

Major surgery (prostatectomy, cardiac surgery)

Acute intracerebral hemorrhage

With coagulopathy

Liver surgery, transplantation

Thrombocytopenia

Gastro-intestinal bleeding

Bleeding associated with anticoagulant treatment

Extensive study program has been done

Trauma: reduction in RBC transfusion in severe blunt trauma

Liver transplantation: no reduction in blood loss, number of patients

requiring RBC transfusion was lower

Hepatectomy: no reduction in blood loss

Upper gastrointestinal bleeding: rVIIa showed no advantage over

standard treatment

Randomized-controlled trials rFVIIa: Efficacy

Boffard J Trauma 2005;59:8 Planinsic Liver transpl 2005;11:895

Shao Am J Surg 2006;191:245; Lodge Anestesiology 2005;102:269Lodge

Liver transpl 2005;11:973, Bosch Gastroenterology 2004;127:1123

Recombinant Factor VIIa use in the US

O’Connell et al. JAMA 2006;295:293-298

Recombinant Factor VIIa for excessive bleeding

Several case series on succesful use of rVIIa in excessive bleeding

rFVIIa not registered for this indication

>90 % of rVIIa use in the US is off-label

What is excessive blood loss

Several definitions of massive blood loss

Replacement of total blood volume with RBC in<24 hrs

Blood loss of > 50% within 3 hrs

Blood loss of > 150 ml/min

rVIIa in treatment of excessive bleeding

Retrospective, uncontrolled chart audit

196 non-hemophilic individuals in 21 US academic centers

Surgical bleeding 37%

Gastro-intestinal 31%

Intra-cranial 13 %

Pulmonary 11 %

Others 8 %

75 % of patients was treated once

MacLaren et al Transfusion 2005;45:1434-1442

Outcome after rVIIa

52.6 % of patients bleeding stopped

26 % of these rebled

37 % of patient died from bleeding < 48 hrs

Dependent upon acidosis (pH<7.20 neg. predictor, OR 0.2; 0.1-0.51)

MacLaren et al Transfusion 2005;45:1434-1442

Effectiveness of rFVIIa and acidosis

Laffan, NM et al Blood Coagul Fibrinolysis 2003:14(suppl 1): S35-S38

Adverse events off-label vs trial patients:

O’Connell et al. JAMA 2006;295:293-298

Considerations regarding adverse events rFVIIa

Thrombo-embolic events hardly occur in haemophilia patients

Thromboembolic events in studies are low, comparable to controls

rFVIIa might be more thrombogenic in patients predisposing to

thrombosis, as is seen in ICU patients

FDA adverse event reporting system does not mention the total number

of patients treated. Not all SAE may have been reported

Most patients will also have been treated with other prohaemostatic

drugs

Deaths due to trauma

Pharmacological measures to reduce blood loss

Desmopressin

Fibrinolysis inhibitors

Plasminogen inhibitors Tranexamic acid

Epsilon-amino-caproic acid

Serine protease inhibitors Aprotinin

Recombinant factor VIIa

Topical agents (thrombin//collagen/fibrin sealants)

Coagulation factor concentrates

Desmopressin (DDAVP)

Increases VWF and FVIII in plasma

Improves platelet function

Improvement of primary hemostasis

Hardly any randomized trials available

Effect in cardiac surgery (+ aspirin) (several studies)

No effect in scoliosis surgery (Spine 1999)

No effect in hepatectomy (Can J Anaesthesia, 2003)

No effect in variceal bleeding (Hepatology 1993)

Antifibrinolytics in excessive bleeding

Tranexamic acid

Epsilon amino caproic acid (EACA)

Aprotinin

Tranexamic acid and Epsilon-Amino caproic acid

Inhibits binding of plasmin to fibrin by interfering with the lysine binding

sites of the proenzyme plasminogen

Tranexamic acid is 10 times more active than EACA

Dose:

4 times daily 1 gram

In cardiac surgery: total dose 3-10 g; loading dose of 3-7 g, followed by

continuous infusion of 20-250 mg/hr

Mannucci, PM .NEJM 2007;356:2301

Fibrinolyis inhibitors and clinical events

Significant lower transfusion need for aprotinin and tranexamic acidMannucci, PM .NEJM 2007;356:2301

Fibrinolysis inhibitors do not increase the risk of thrombosis

Transfusie protocol massaal bloedverlies

Transfusie protocol massaal bloedverlies

Transfusie protocol massaal bloedverlies

Transfusie protocol massaal bloedverlies

Transfusie protocol massaal bloedverlies

Transfusiegids

New therapeutic indications for Novoseven

Recommendations concerning rFVIIa

Strict transfusion guidelines for each individual hospital (RBC, FFP and

platelet concentrates)

Based on laboratory control of APTT, PT, Fbg and platelets

Limit the use of rVIIa to indications and off-label use only in very

selected cases (diffuse oozing patient)

No rFVIIa in patients with severe hypothermia or acidosis

Last-ditch use is ineffective