Congenital Fibrinogen Deficiency. Claude Negrier, MD, PhD Hôpital Louis Pradel Université Claude Bernard Lyon 1

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1 Congenital Fibrinogen Deficiency Claude Negrier, MD, PhD Hôpital Louis Pradel Université Claude Bernard Lyon 1 claude.negrier@chu-lyon.fr

2 Afibrinogenaemia Clinical presentation Phenotypic and genotypic features Peculiar complications Treatment modalities

3 Afibrinogenaemia Afibrinogenemiais a rare autosomal recessive bleeding disorder with an estimated prevalence of 1:1,000,000 Usual presentation of this disorder is spontaneous bleeding, bleeding after minor trauma and excessive bleeding during interventional procedures During pregnancy, women may be at greater risk of miscarriage and bleeding complications Paradoxically, few patients with afibrinogenaemiamay also suffer from severe thromboembolic complications The management of these patients is particularly challenging Caused by defects in genes coding for fibrinogen Aα-, Bβ-and Cγ-chains (FGA, FGB, and FGG, clustered on chromosome 4q32)

4 Clinicalbleedingsymptomsin 100 patients with afibrinogenemia A total of 517 bleeding episodes (322 spontaneous, 100 trauma-related, 79 surgery-related and 16 other or unspecified) were reported The mean annual incidence of bleeding episodes was 0.5 for patients on prophylactic replacement therapy (range 0 2.6) and 0.7 for patients on on-demand therapy (range ) Of the reported bleeding episodes, 40% were of mucosal type, 54% non-mucosal, and 6% unspecified Among the 72 patients with severe fibrinogen deficiency (< 10 mg dl-1), the most frequent hemorrhages were hemarthrosis(25%), muscle hematoma (17%), gastrointestinal (GI) bleeding (17%), epistaxis (10%) and menorrhagia(7%). Central nervoussystem (CNS) and intra-retroperitoneal bleeding were reported rarely (4% each) Peyvandi F et al, JTH 2006

5 Epidemiology of congenital fibrinogen deficiency: results from the European Network of Rare Bleeding Disorders (EN-RDB) Peyvandi F, Thrombosis Research, Volume 130, Supplement 2, 2012, S7 - S11

6 Distribution of clinical bleeding severity categories within the different rare bleeding disorders Peyvandi F, et al Journal of Thrombosis and Haemostasis 2012; 10:

7 Relative frequency of bleeding symptoms in 55 patients with abrinogenaemiacompared with 100 patients with severe haemophilia A (FVIII<1%) Lak M et al, BJH 1999; 107, 204-6

8 Afibrinogenaemia Clinical presentation Phenotypic and genotypic features Peculiar complications Treatment modalities

9 Diagnosisof afibrinogenaemia Afibrinogenaemia results in a profound quantitative deficiencyof fibrinogen(plasma concentration <0.1 g/l) Clear prolongation of all the coagulation assays (aptt, PT, TT, reptilase time) Diagnosis made by measuring fibrinogen activity and antigen

10 Laboratory diagnosis of congenital fibrinogen deficiencies Peyvandi F, Thrombosis Research, Volume 130, Supplement 2, 2012, S7 - S11

11 Linear regression analysis of the association between fibrinogen activity level and bleeding severity: results from the European Network of Rare Bleeding Disorders (EN- RDB) Peyvandi F, Thrombosis Research, Volume 130, Supplement 2, 2012, S7 - S11

12 Positions of 17 missense mutations in the fibrinogen beta C-terminal domain A. Casini et al, Thrombosis Research 2014, Volume 133, Issue 5, 2014,

13 Survival and bleeding of afibrinogenemic zebrafish (fga gene) Fish R J et al. Blood 2014;123: by American Society of Hematology

14 Afibrinogenaemia Clinical presentation Phenotypic and genotypic features Peculiar complications Treatment modalities

15 Afibrinogenaemiain women In adult life, women predominantly bear the burden of bleeding in afibrinogenemia, due to severemenorrhagiaand spontaneousfirst trimester abortion because of retroplacental bleeding Acuteintra-abdominal emergencies may recur during ovulation due to haemoperitoneum. Prevention of ovulation with oral contraceptives is in this case indicated

16 Available recommendations for treatment during pregnancy and delivery within the different rare bleeding disorders Peyvandi F et al, Fetal and Neonatal Medecine 2011

17 Bleeding manifestations in neonates Peyvandi F et al, Fetal and Neonatal Medecine 2011

18 Ischaemiclesion of the left first toe in a patient with afibrinogenaemia CastamanG et al, Haemophilia 2009

19 Afibrinogenaemia Clinical presentation Phenotypic and genotypic features Peculiar complications Treatment modalities

20 Therapeuticprinciples Treatment of afibrinogenaemiais aimed at replacing the missing fibrinogen to restore efficient haemostasis and to stop bleeding Three sources of fibrinogen are currently available: freshfrozenplasma, cryoprecipitate, and lyophilized fibrinogen concentrate Treatment modalities On-demandtreatment Prophylactictreatment

21 Therapeuticprinciples Fresh Frozen Plasma (FFP) FFP is probably inadequate therapy in severe fibrinogen deficiency as it contains insufficient concentrations of fibrinogen Cryoprecipitate no longer regarded as suitable for therapeutic use, on grounds of infectious risk Because of its fibrinogen content, cryoprecipitate continues to be the most common therapeutic material used in practice for fibrinogen replacement Reduction/eliminationof potentialblood-borne infectiousagents cannot be applied to retain clinically significant quantities of the final product. Methylene blue/uv light or psoralen/uv light treatment are effective pathogen-reduction methods applicable to the sourced FFP, but they cause significant loss of functional fibrinogen in the derived cryoprecipitate, rendering it unsuitable for therapeutic use The second major clinical problem in the use of cryoprecipitate for fibrinogen replacement is its uncertain content of fibrinogen

22 Fibrinogen concentration pre and post infusion of cryoprecipitate and fibrinogen concentrate A. Theodoulou et al, Transfusion and Apheresis Science 2012; 46, 2:

23 Therapeuticprinciples A purified fibrinogen concentrate is preferable to cryoprecipitate for the treatment of congenital fibrinogen deficiency on both practical and theoretical grounds Most importantly, fibrinogen concentrates undergo a validated virus inactivation/removal process and therefore represents a safer therapeutic option for the replacement of fibrinogen They have several other advantages over current therapy: Rapid preparation and administration Defined fibrinogen content Accurate dosing Fewer extraneous proteins Smaller infusion volume Optimal infusion practices for patients with inherited fibrinogen deficiency should be provided

24 Fibrinogen activity following a single infusion of 0.06gkg 1 T1/2= 82 +/-8h N= 5 patients Negrier et al, JTH 2008

25 Pharmacokinetic/ Pharmacodynamic relationship Negrier et al, JTH 2008

26 T1/2= 77,1 h N= 15 patients Dose 70 mg/kg bw Manco-Johnson M et al, JTH 2009

27 Suggested doses, schedules, and frequency of fibrinogen concentrate for the treatment of patients with afibrinogenemia Surgery in afibrinogenemiais often complicated by poor wound healing (or in the case of dental extraction, persisting open sockets ) with an increased risk of wound dehiscence and infection Perioperative fibrinogen replacement (and antifibrinolytictherapy) should therefore be extended until effective wound healing is observed Bevan DH, Thrombosis Research 124 Suppl. 2 (2009) S12 S16

28 Preoperative anteroposterior and lateral radiographs showing the severe arthropathic changes of the left elbow with advanced joint-space narrowing on the ulnar side, complete collapse on the radial side, as well as substantial elbow deformity Reidy K et al. J Bone Joint Surg Am 2010;92:

29 Is primary prophylaxis required in afibrinogenemia? Polack B et al, Transfusion 2010; 10:

30 Personal data

31 Conclusion A lot of knowledge has been gained in the last decades with regard to fibrinogen deficiency, particularly as a result of international cooperation Variable bleeding phenotype but commonly severe with some peculiarities shared with inherited FXIII deficiency Diagnosis based on common coagulation assays Fibrinogen concentrates represent the treatment of choice Surgery in afibrinogenemiais often complicated (poor wound healing, increased risk of wound dehiscence and infection, thrombotic complications) Prophylaxis of recurrent and/or life-threatening bleeds shoudbeproposedand individuallyadaptedto the bleedingphenotype. The question of the protective through fibrinogen levels still is a matter of debate