1. Rare Bleeding Disorders Factor XI deficiency FX deficiency Fibrinogen deficiency Dr Niamh O’Connell The National Centre for Hereditary Coagulation Disorders, St. James’s Hospital, Dublin

2. doi: 10.1111/bjh.13058 British Journal of Haematology, 2014, 167, 304–326 http://www.ukhcdo.org/ukhcdoguidelines.htm

3. GRADE recommendations Strength of Recommendation Strong (grade 1): Certainty of effect Weak (grade 2): Benefits and risks finely balanced or uncertainty Quality of Evidence (A)High (B)Moderate (C)Low (D) Very Low

4. Factor XI deficiency Third commonest bleeding disorder in the UK Caused by variations in the F11 gene – higher prevalence in defined populations Bleeding associated with surgery, trauma, menorrhagia and PPH in women Severe bleeding more likely with FXI:C <0.1 iu/ml (EN-RBD registry Peyvandi J Thromb Haemost 2012) Bleeding variable in non-severe FXI deficiency

5. Which patient with Factor XI deficiency is at risk of bleeding...with surgery or delivery?

6. Recommendation 1 Cases with F11D should be identified as at a higher risk of bleeding if any of the following: the FXI activity is <0.1 iu/ml there is another coagulopathy there is a personal history of bleeding surgery is a dental extraction or involves the oropharyngeal or GU mucosa (2C)

7. Are Factor XI deficient patients likely to develop inhibitors?

8. Increased risk if very low levels FXI AND exposure to plasma or concentrate DOI: http://dx.doi.org/10.1182/blood-2002-09-2794

9. Recommendation 2 Cases with FXI activity <0.1 iu/ml should be screened for FXI inhibitors before surgery or childbirth, if they have had previous FXI replacement therapy (2B).

10. What haemostatic treatment should be used for minor procedures?

11. Antifibrinolytics Increased bleeding rates in tissues with high fibrinolytic activity Tranexamic acid Used extensively No bleeding in 41 dental extractions in 19 severely deficient patients with a positive bleeding history Berliner et al, 1992

12. Recommendation 3 For minor bleeds or minor surgery in higher bleeding risk cases, and for all bleeds or surgery in low bleeding risk cases, consider tranexamic acid 15–20 mg/kg or 1 g four times daily for 5–7 d (2C).

13. In a patient with a higher bleeding risk, should concentrate or plasma be used for surgery or trauma related bleeding?

14. FXI concentrate and thrombosis Case reports prior to early/mid 1990s Changes in concentrate manufacture – Addition of anticoagulants Changes in clinical prescribing – Reduction in target FXI:C and dose – Caveat in patients with RF for thrombosis

16. 242 Rx12 AEs8 Bleeding 4 Non- bleeding 1 thrombotic

17. FXI concentrate current approach Haemostatic FXI:C likely 0.3-0.4 iu/ml – achieved by 10-15u/kg FXI concentrate or 15- 25mls SD plasma Avoid FXI concentrate in patients with increased risk of thrombosis (if possible) No Tranexamic acid with FXI concentrate AEs are uncommon but bleeding is most likely AE!

18. Recommendation 4 For severe bleeds or major surgery in high bleeding risk cases, consider an initial dose of FXI concentrate 10–15 iu/kg, without additional tranexamic acid. A combination of SD-FFP 15–25 ml/kg and tranexamic acid 15–20 mg/kg or 1 g four times daily is an alternative to FXI concentrate (2C).

19. Does a FXI deficient woman need haemostatic cover for delivery?

20. 27 studies, all observational 18% of 498 deliveries associated with PPH In 6 studies, prophylactic treatment was given to 21% of women No firm conclusion can be drawn from the available literature on optimum treatment or patient stratification

21. Recommendation 5 For delivery in all women with factor XI activity <0.15 iu/ml in the third trimester, consider FXI concentrate 10–15 iu/kg or SD- FFP 15–25 ml/kg and tranexamic acid 15–20 mg/kg at established labour or before caesarean section (2C).

22. Recommendation 6 For delivery in women with FXI activity 0.15– 0.7 iu/ml in the third trimester and a history of bleeding or no previous haemostatic challenges, consider tranexamic acid 15 mg/kg or 1 g four times a day continued for at least 3 d (2C).

23. Recommendation 7 For delivery in women with FXI activity 0.15– 0.7 iu/ml in the third trimester and no bleeding despite haemostatic challenges, only consider FXI concentrate or anti- fibrinolytics if abnormal bleeding occurs (2C).

25. What patients with FX deficiency need haemostatic treatment?

26. Bleeding phenotype in FX def Bleeding is more likely with FX <0.1 iu/ml and ICH, GI and joint bleeding if FX < 0.02 iu/ml Neonates may present with ICH and umbilical bleeding Surgery Obstetrics

27. Treatment options in FX def PCC 20-30 iu/kg SD plasma 15-25 mls/kg High purity FX concentrate Prospective, open-label, multicenter, non-randomized phase III study in 16 patients with severe/moderate factor X deficiency 98% of bleeds were controlled with 1 or 2 infusions 5 pts underwent 7 surgeries (4 major/3 minor) with excellent haemostasis No SAEs related to the product

28. Factor X deficiency

29. Fibrinogen deficiency Hypofibrinogenaemia Afibrinogenaemia Dysfibrinogenaemia – Haemorrhagic – Thrombotic

30. What patients with fibrinogen deficiency need treatment? Surgery – Levels and bleeding or thrombotic history. – Not all patients need Fibrinogen concentrate pre- operatively. “Watch and wait” Prophylaxis Afibrinogenaemia, Pregnancy Thromboprophylaxis

31. Fibrinogen deficiency

32. Thank You