Dr Simon Mcrae Director Haemophilia Treatment Centre Royal Adelaide - PowerPoint PPT Presentation

Dr Simon Mcrae Director Haemophilia Treatment Centre Royal Adelaide Hospital SA Pathology, South Australia

Collection of coagulation factor deficiency states Factor I, II, V, VII, X, XI, XIII, (FV + FVIII)  Comprise 3 to 5% of inherited bleeding disorders  Incidence - 1:500 000 (FVII) to 1 in 2 million (FII,FXIII)  Typically autosomal recessive pattern inheritance  Variable association of factor level with phenotype

WFH global survey 2010

% pts Country Number pts RBDs RBD+HA+HB Australia 228 10% China 24 0.2% India 203 1.5% Iran 1109 18% Japan 215 3.8% Malaysia 135 10% Singapore 73 26% Vietnam 40 2.1% WFH Global Survey 2010

 Variable association with coagulation factor level  Most associated with post-surgical and mucosal bleeding  ICH restricted to FXIII, afibrinogenemia, FVII, FX  Joint bleeding rare FV, FV + FVIII, FXI deficiency  Obstetric bleeding rare – can be seen FVII deficincy

• Circulates as a Homo-dimer • Each sub unit contains 4 apple domains and a catalytic domain

Intrinsic Pathway Extrinsic Pathway XII XIIa TF / FVIIa XI XIa IX IXa X Xa Common Pathway II IIa Fibrinogen Fibrin

Elmsley BLOOD 2010 115: 2569-2577

 All activation pathways result in cleavage at Arg 369 – Ile 370  Results in exposure of factor IX binding site on apple domain 3  Intermediate form with activation of only one monomer exists

Clot formation

Von der Borne et al J. Clin. Invest. 1997. 99:2323 – 2327

Described in 1953 by Rosenthal  2 sisters and an uncle with post surgical bleeding Diagnostic assay developed in 1961  Autosomal pattern of inheritance - Homozygous deficiency state levels < 15% - Heterozygous deficiency with levels 20-60% Rosenthal Blood 1955;10:120-131. Leiba Br J Haematol. 1965;11:654-665.

Incidence Heterozygous Homozygous Ashkenazi Jews 1 in 11 1 in 450 Iraqi Jews 1 in 30 1 in 360  Basque, UK Caucasian, Western France Sporadic in other populations ~ 1 in 100,000  Australia 170 pts – 0.7 / 100 000  China 20/1300 pts with bleeding disorders Zhang et al Haemophilia. 2003 Nov;9(6):696-702

Australian Bleeding Disorder Registry 2012  170 pts with factor XI deficiency  35% pts with rare bleeding disorders  Next commonest FVII deficiency – 53 pts

Factor XI gene  Located on chrom 4, 23 kb length, 15 exons Mutations in factor XI deficiency Database of mutations at www.factorxi.org 220 mutations described as of sept 2009 Known recurring mutations - type II Glu117Stop exon 5, type III Phe283Leu exon 9 - Cys128stop in the UK, Cys38Arg Basques

60 50 40 30 20 10 0 Deletion Insertion Missense Nonsense Polymorphism Promoter Splice site

CRM – mutations Category 1  Reduction in synthesis of FXI – Glu 117 stop  Levels 0% homozygotes, ~50% heterozygotes Category 2  Impairment of dimerisation – Phe283Leu  Levels ~10% homozygotes, ~60% heterozygotes Category 3  Impairment of secretion of dimers – Ser225Phe  Levels of ~ 25% in heterozygotes

CRM + mutations A. Impairs FXI activation  Impairs HK binding - Gly155Glu  Effects activation loop cleavage - Val371Ile  Reduction of affinity for platelets - Ser248Asn B. Impairs FIX activation  Hampers substrate engagement - Arg184Gly, Ser576Arg  Influences catalytic activity - Ala375Val, Pro521Leu

Bowyer et atl Int. Jnl. Lab. Hem. 2011, 33, 154 – 158

100 90 80 70 60 APTT secs 50 40 30 20 10 0 0 10 20 30 40 50 60 70 Factor XI level iu/dL

 Spontaneous bleeds uncommon except menorrhagia - ICH, muscle, and joint bleeds rare  Post-injury or post-surgical bleeding common - May occur hrs to days following procedure - More common at sites with fibrinolytic activity Oral mucosa, nose, urogenital tract  Post-partum haemorrhage described in 20% cases

2.6-fold  risk [95% CI 0.8 – 9.0] % pts with bleeding 10 – 50% 13-fold  risk [95% CI 3.8 – 45]

Levels of other coagulation factors Underlying genetic defect  Within Jewish population type II defect > bleeding risk than type III mutation  Otherwise no clear genotype – phenotype association

Dargaud Haemophilia (2010), 16 , 771 – 777

1pM tissue factor Nov 2012

Salomon et al Haemophilia (2006), 12, 490 – 493

Levels of other coagulation factors Guegen et al BJH 2010 156, 245 – 251 Underlying genetic defect  Within Jewish population type II defect > bleeding risk than type III mutation  Otherwise no clear genotype – phenotype association

High levels of FXI predispose to thrombosis  2.2 fold increase in VTE risk if FXI level in top 10 % N Engl J Med 2000;342:696 – 701.  High levels predispose to risk of recurrent thrombosis Blood 2004;103:3773 – 6. Low levels FXI protect against thrombosis  0/219 pts with severe deficiency had VTE Thromb Haemost 2011;105:269 – 73.  Reduced incidence of stroke (1/115 pts vs 9/115 population) Blood 2008;111:4113 – 7.

 Poor correlation between levels and bleeding risk  Increasing diagnosis asymptomatic pts

Issues to be taken into account  Severity of deficiency  Personal history of bleeding with prior challenge  Site of surgery planned  Presence of cardiovascular disease / risk factors  Inhibitor +/- Therapeutic options  Observation alone  Anti-fibrinolytic therapy  FFP or FXI concentrate  rFVIIa

Fresh Frozen Plasma  10 – 15 ml / kg required to raise level to 20-30%  Issues with viral safety  Problems with volume overload Factor XI concentrates  Available since the mid- 1990’s  Early preparations problems with thrombogenicity, DIC  Currently 2 concentrates available globally BPL, Hemoleven  1 unit / kg = 2.4 iu/ml rise in FXI  Aim peak ~70 iu/ml – dose should not exceed 30 u/kg.

Major surgery in pts with severe deficiency  Maintain levels at > 45 iu/dl for 5 to 7 days  Care with Factor XI concentrate if vascular risk factors  Concurrent use of tranexamic acid Major surgery in pts with mild deficiency  Expectant management if non-fibrinolytic site  Factor XI replacement if fibrinolytic site  Care to avoid excessive levels Minor surgery  Anti-fibrinolytic therapy only

Patients with severe deficiency Major surgery at fibrinolytic site  Maintain levels at > 45 iu/dl for 5 to 7 days  Care with Factor XI concentrate if vascular risk factors Major surgery at non-fibrinolytic site  Consider Tx acid alone (orthopaedic surgery, caesarian)  Replacement if strong history of bleeding with surgery Minor surgery – dental extraction, skin biopsy  Anti-fibrinolytic therapy only  Extractions safe with Tx acid only 0/19 pts significant bleed

Patients with mild deficiency Major surgery at fibrinolytic site  Consider Tx acid alone if no strong bleeding history  Factor XI replacement if bleeding history – aim level ~70%  Care with Factor XI concentrate if vascular risk factors Major surgery in pts with mild deficiency  Tranexamic acid alone Minor surgery  Anti-fibrinolytic therapy only at most

Pts with null/stop mutations are at risk of inhibitor development  33% of patients homozygous for Glu117stop Saloman BLOOD 2003  Inhibitors can occur after immunoglobulin exposure, anti-D At risk pts (levels<1%, known  risk mutation) should be screened Treatment with rVIIa  Demonstrated to be safe for major procedures  Low doses 15-30 ug/kg are effective, thrombosis with higher  May only need single dose with anti-fibrinolytic therapy Schulman Haemophilia (2006), 12, 223 –227, O’Connell Haemophilia (2008), 14, 775 – 781, Kenet Haemophilia (2009), 15, 1065 – 1073

Approximately 30% pts with FXI <1% have inhibitors  particularly in pts with type II Glu117stop mutation Salomon Blood. 2003;101: 4783-4788 Proportion of pts will be unable to use FFP / FXI conc  Unavailability, or concerns re plasma products  Issues with volume overload if only FFP available In both scenarios low-dose rFVIIa has been effective  Doses of 15-30 ug/kg used with effect  Thrombotic complications with higher doses Riddell et al Thromb Haemost 2011; 106: 521 – 527, Kenet et al Haemophilia (2009), 15 , 1065 – 1073

Srtucture factor VIIa Persson et al Thrombosis Research 125 (2010) 483 – 489

 FVII gene long arm chrom 13, 9 exons, 12 kb  More than 180 mutations reported - Sporadic in nature - Predominantly missense mutations or splicesite - Deletions rare  Significant bleeding limited to homozygote state

Highly variable - from severe to minimal  Most often mucosal  Severe bleeds can involve TF rich organs - CNS / GI  More common bleeding in females  Variable relationship to FVII levels

Schved et al. Thromb Haemost 2005; 94: 901 – 6

Major surgery with history of bleeding  Cover with FVII or rVIIa replacement Major surgery with no history of bleeding  ? Cover for limited time period or single dose Minor surgery  Manage expectantly or cover with single dose and anti-fibrinolytic Haemophilia (2012), 18 , e60 – e87