Management of HMB in women with haematological disease and other medical disorders. Rezan A Kadir The Royal Free Foundation Trust IfWH, UCL

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1 Management of HMB in women with haematological disease and other medical disorders Rezan A Kadir The Royal Free Foundation Trust IfWH, UCL

2 HMB - Systemic causes FIGO Classification - PALM-COEIN COEIN- Non Structural Coagulopathy Ovulatory Dysfunction Endometrial Iatrogenic Not yet classified Systemic conditions Inherited bleeding disorders VWD Carriers of haemophilia Inherited Platelet abnormalities Rare coagulation factor defects Acquired Bleeding disorders Immune thrombocytopenia Anticoagulant therapy Other medical disorders Endocrine abnormalities Chronic disorders

3 HMB - Other medical disorders Chronic conditions Possible mechanisms Renal failure Liver failure Diabetes Thyroid abnormalities Adrenal abnormalities Blood malignancies Coagulopathy Impaired Clotting factor production Thrombocytopenia, impaired platelet function Anticaogulant therapy HPO axis - direct effect or secondary to medications Oestrogen metabolism Chemotherapy, steroids, other medications

4 Von Willebrand Disease - VWD

VWF mediated platelet aggregation Fibrin formation Vasoconstriction Tissue regeneration Hemostasis in menstruation INADEQUATE and/or OVER- INDUCTION COMPENSATION Platelet adhesion

5 VWF mediated platelet aggregation Fibrin formation Vasoconstriction Tissue regeneration Hemostasis in menstruation INADEQUATE and/or OVER- INDUCTION COMPENSATION Platelet adhesion Platelet aggregation PG induced platelet inhibition Fibrinolysis Vasodilatation platelets platelets GP 1b Endothelial cells VWF platelets Increased menstrual blood loss HMB Subendothelium Collagen

6 PBAC score - higher in affected women p = Excessive bleeding at Menarche

7 Breakthrough bleeding IMB and PCB Iron deficiency anaemia Early hysterectomy

8 HMB and Bleeding Disorders VWD in women with HMB Overall = 13% (C.I %) 131/998 European studies Edlund 1996 Kadir 1998 Woo 2001 Krause 2000 Total 18% N. American studies Kouides 2000 Hambleton 2000 G-Gruen 2001 Dilley 2001 Philip 2003 Total 10% Other studies Baindur 2000 Ekiaby Shanker et al 2004

9 HMB and Bleeding Disorders Platelet function defect 50% 45% 40% 35% 30% 25% 20% 15% 10% Platelet aggregation and/or release defect Agonists Platelet agg./rel. defect to multiple agonists Platelet agg./rel. defect to ristocetin at 1 ng/ml Platelet agg./rel. defect with one non-risotcetin 5% 0% VWD others Platelet dysfunction Miller CH et al 2007

10 102 women with HMB

13 Pictorial blood assessment chart (PBAC)

14 Condensed MCMDM-1 VWD Bleeding Questionnaire Epistaxis -- No or trivial ( 5 per year) > 5 per year or more than 10 Consultation only Packing or cauterization or antifibrinolytic Blood transfusion or replacement therapy or desmopressin Cutaneous -- No or trivial ( 1 cm) > 1 cm and no trauma Consultation only Bleeding from minor wounds -- No or trivial ( 5 per year) > 5 per year or more than 5 Consultation only Surgical hemostasis Blood transfusion or replacement therapy or desmopressin Oral cavity -- No Referred, no consultation Consultation only Surgical hemostasis or antifibrinolytic Blood transfusion or replacement therapy or desmopressin Gastrointestinal bleeding -- No Associated with ulcer, portal hypertension, hemorrhoids, angiodysplasia Spontaneous Surgical hemostasis, blood transfusion, replacement therapy, desmopressin, antifibrinolytic -- Tooth extraction No bleeding in at least 2 extractions None done or no bleeding in 1 extraction Reported, no consultation Consultation only Resuturing or packing Blood transfusion or replacement therapy or desmopressin Surgery No bleeding in at least 2 surgeries None done or no bleeding in 1 surgery Reported, no consultation Consultation only Surgical hemostasis or antifibrinolytic Blood transfusion or replacement therapy or desmopressin Menorrhagia -- No Consultation only Antifibrinolytics, oral contraceptive pill use Dilation & curettage, iron therapy, ablation Blood transfusion or replacement therapy or desmopressin or hysterectomy Postpartum hemorrhage No bleeding in at least 2 deliveries None done or no bleeding in 1 delivery Consultation only Dilation & curettage, iron therapy, antifibrinolytics Blood transfusion or replacement therapy or desmopressin Hysterectomy Muscle hematomas -- Never Post trauma, no therapy Spontaneous, no therapy Spontaneous or traumatic, requiring desmopressin or replacement therapy Hemarthrosis -- Never Post trauma, no therapy Spontaneous, no therapy Spontaneous or traumatic, requiring desmopressin or replacement therapy Spontaneous or traumatic, requiring surgical intervention or blood transfusion Spontaneous or traumatic, requiring surgical intervention or blood transfusion Central nervous system bleeding -- Never Subdural, any intervention Intracerebral, any intervention

16 HMB - Haemostatic assessment Heavy menstrual bleeding since menarche Recurrent ovulation bleeding Not responding to medical treatment Or HMB + One of the following bleeding Significant or recurrent postpartum haemorrhage Surgery-related bleeding Bleeding associated with dental work Two or more of the following conditions: Bruising, epistaxis, gum bleeding Family history of bleeding disorder Or BS 5

17 HMB - Haemostatic assessment Diagnostic approach FBC and Ferritin level PT, APTT FVIII, VWF:Ag, VWF:Ricof, VWF:CB Platelet function tests Further testing - If high suspicion for Bleeding disorder - or FH of specific BD

HMB - Haemostatic assessment Diagnostic approach VWF FVIII variation Physical activity, stress Effect of female hormones Collaboration Haemotology team Hormonal therapy?

18 HMB - Haemostatic assessment Diagnostic approach VWF FVIII variation Physical activity, stress Effect of female hormones Collaboration Haemotology team Hormonal therapy? mask Dx Day of the cycle, use of OC pill, HRT noted Borderline levels repeat test Day 1-5 of the cycle Variation Mandalaki et al 1980, Blomback et al 1992, Kadir et al 1999, Miller et al 2002

HMB - Haemostatic assessment FBC and Ferritin assessment Iron deficiency (ID) /Low Ferritin predicts Clinical severity of HMB Low ferritin - predict 60% of MBL>80ml Underlying bleeding disorders HMB

19 HMB - Haemostatic assessment FBC and Ferritin assessment Iron deficiency (ID) /Low Ferritin predicts Clinical severity of HMB Low ferritin - predict 60% of MBL>80ml Underlying bleeding disorders HMB and ID odd ratio 3.3 Jayasinghe et al 2005, Warner et al 2004 Medical management of ID/IDA Improve PF - May reduce MBL Reduce the need for BT in HMB Reduce peri-operative BT 370 women prior Hysterectomy Iron therapy - BT reduced 22.7% to 1% Akay et al 2007, Sheth&Das 2002

20 HMB - Therapeutic options Options - haemostatic, hormonal and surgical Choice - age, fertility wishes, underlying cause, severity and type of bleeding disorder, side effect profile and availability of the treatment Women with bleeding disorders - often require combination therapy

21 LNG-IUS (Mirena IUS) Most effective treatment for HMB Most effective reversible contraceptive 5 years Other Possible Health Benefits Menstrual pain &PMS Endometrial hyperplasia Endometriosis, adenomyosis, fibroid Suitable for women with Bleeding disorders Thrombotic disorders

22 LNG-IUS (Mirena IUS) HMB in women with bleeding disorders Follow up - 3 years 45% - amenorrhea Improved QoL Kingman et al 2004, Chi et al 2007

23 Other hormonal contraceptives Combined Hormonal Contraception (Oral, Transdermal, vaginal rings) Effective Contraception Good cycle control Control menstrual pain and PMS Inhibit ovulation - prevent ovulation bleeding Extended use - reduce menstrual episodes with no complications Progesterone only contraceptives Progesterone only contraceptives pill (POP) - Desogestrel Amenorrhoea in up to 20% - can be used when OCP is contraindicated Depot medroxyprogesterone acetate (DMPA) - amenorrhoea 50% But significant irregular bleeding in women with bleeding disorders

24 Other hormonal therapies Cyclical progestagens 63% and 78% reduction in MBL during 1 st and 3 rd cycle Discontinuation - 78% - hormonal SE GnRH analogue with/without add-back therapy Amenorrhea - but menopausal symptoms Long-term - significant SE - Osteoporosis Last option in severe BD - with add-back therapy - GT and BSS

25 Haemostatic agent (Tranexamic acid - DDAVP) 116 women TA and DDAVP Improved HRQOL Combination of TA+DDAVP Improve efficacy Shorter duration and smaller dose DDAVP Reduce adverse effects Discontinuation TA 4, DDAVP 6 (1 hyponatremia) Edlund et al 2003, Kouides et al 2009

26 Haemostatic agent - Factor Replacement Menstrual related bleeding Factor Replacement 10% Chi et al 2010

27 HMB - Surgical Management Hysterectomy - Pelvic pathology, unresponsive to other therapies Appropriate haemostatic assessment and haemostaic cover No VWD n=1,357,588 VWD n=545 P value Thrombosis 0.20% Infection 0.38% 0.73% Transfusion 2.13% 7.34% <0.001 Bleeding 0.86% 2.75% <0.001 Wound compl. 0.15% 0.37% Length of stay 3.49 days Cost $13,225 $19,584 <0.001 Died 0.13% 0.18% James et al 2009, data from the NIS

28 HMB - Endometrial Ablation Women with coagulopathy not responding to medical treatments Uterus 10/52, fibroids < 3 cm PBAC Scores Pre Ablation Post Ablation P value Mean Median <0.01 Increased Hb, Ferritin Improved QOL El-Nashar et al 2007 Huq et al 2013

29 HMB - Oral anticoagulant Vitamin K antagonists 90 menstruating women - after starting VKA 71% reported HMB - 30% required treatment Sjalander et al % - PBAC score >100 VKA therapy - 53 women - 70% reported change - 50% increase MBL - 30% - referral to gynaecologist None - major bleeding Yaq et al 2011

Thrombin Prothrombin Direct Factor IIa inhibition Dabigatran etexilate Clot formation

30 Direct Oral Anti-Coagulants (DOACs) Initiation TF VIIa VII X IX Propagation Direct Factor Xa inhibition Rivaroxaban Apixaban Edoxaban Betrixaban Darexaban Xa IIa IXa II Thrombin Prothrombin Direct Factor IIa inhibition Dabigatran etexilate Clot formation Fibrinogen Fibrin Adapted from Spyropoulos AC. Expert Opin Investig Drugs 2007;16:

31 HMB - Direct Oral Anti-Coagulant Meta-analysis of 8 RCTs on DOACs for VTE patients Difference between men and women No difference in the primary efficacy outcome of recurrent VTE Men had less major bleeding compared to women [RR 0.79, 95% CI , p=0.03] Alotaibi et al DOACs women 57 women reported - 72 vaginal bleeding HMB - 6 (8%) Major bleed - 4 in Rivaroxaban Jan Beyer-Westendorf et al 2016

32 Menstrual bleeding - DOACs Study Cases Major findings Ferreira; Br J Haematol 2016 De Crem; Thromb Res 2015 Bryk; Vascul Pharmacol Kline; Patient Prefer Adherence Godin; Vascul Pharmacol Women rivaroxaban 52 women rivaroxaban vs 52 women VKA 76 women rivaroxaban vs. 45 women VKA 113 women with rivaroxaban therapy 139 women (96 rivaroxaban vs. 43 apixaban) HMB in 26 (20%); mean age 38,7 years Increase in MB duration more frequent with rivaroxaban vs. VKA; also interventions more frequent Increase of MB intensity more frequent with rivaroxaban vs. VKA (41% vs 18%); also interventions more frequent high rate of menorrhagia after starting rivaroxaban (15% of women); hysterectomy in one patient 24 (25%) HMB with rivaroxaban (9 women discontinued rivaroxaban) 4 (9.3%) HMB with apixaban (1 woman discontinued apixaban)

33 HMB - Women on anticoagulant therapy Prior assessment and counselling Menstrual history Use of other medication that may exacerbate HMB Check for ID/IDA Advice - report any change in menstrual loss Those affected with heavy bleeding on on treatment Assess severity of bleeding Exclude pelvic pathology Dresden series - 18% had anatomical abnormality (fibroid, polyp), with worse bleeding in such women Jan Beyer-Westendorf et al 2016

34 Management of HMB - Anticoagulant therapy Anticoagulant management Reduce / split does or omit during heavy menstrual days or change type Alternative anticoagulant therapy Hormonal therapy Mirena IUS - thrombotic risk? - benefit outweigh the risk 17 women- Reduction MBL reported in 59% and amenorrhea in 23% CHC - Controversial WHO 2015 guideline - CHC - confers an unacceptable health risk ISTH SSC- CHC or HRT until they discontinue anticoagulant therapy ENJM 2010

No increase of VTE recurrence risk from COC during OAC 1888 women aged < 60 years included in EINSTEIN DVT/PE Cox regression models with hormonal therapy (on vs.

35 No increase of VTE recurrence risk from COC during OAC 1888 women aged < 60 years included in EINSTEIN DVT/PE Cox regression models with hormonal therapy (on vs. off) as a timedependent variable to VTE incidence densities on and off hormonal therapy were 3.7%/year and 4.7%/year (adjusted HR, 0.56; 95% CI ), respectively VTE incidence densities 3.7%/year for estrogen-containing and 3.8%/year for progestin-only therapy Blood 2016;127(11):

36 Management of HMB - Anticoagulant therapy Cyclical Progesterone - therapeutic dose WHO collaborative study - odd ratio for VTE 5.92 GPRD women - odd ratio 5.3 GPRD nested case control study of 134 women with a VTE event and HMB - adjusted OR Norethisterone Vs medroxyprogesterone acetate Sundstrom et al 2009

37 Management of HMB - Anticoagulant therapy Non Hormonal therapies Tranexamic acid - No increase in thrombotic risk Mefanamic acid (NSAIDs) Improve menstrual symptoms But increased bleeding risk GPRD - increased VTE risk - OR 5.54 ( ) Sundstrom et al 2009

38 Management of HMB - Anticoagulant therapy Surgical treatment Endometrial ablation - women require long-term anticoagulant therapy and completed their family Cohen et al 2017 El-Nashar et al 2007

39 Conclusions HMB is a common gynaecological problem has a significant health impact and adversely affect women QOL Women with bleeding disorders and those on anticoagulant therapy are at a higher risk of HMB Close collaboration between Gynaecology and haematology teams is essential for provision of quality care There are several therapeutic options - an individualised approach is important to provide the women the best option Further research is required especially in better understanding the local factors within the endometrium for development of future therapeutic options and for precision medicine approach for management

41 Thank you

43 n= 105 patients Referred for HMB 62% diagnosed with BD - 36% had Platelet Storage Pool Deficiency Vo K et al. Haemophilia (2012)

44 100 women with AUB 30% abnormal thyroid function Hypothyroid - HMB and prolonged menses Hyperthyroid - oligomenorrhea 50 women with AUB - 44% Thyroid dysfunction

45 VWD - bleeding symptoms in women

46 VWD - bleeding symptoms in women HMB in girls/women with mild/moderate VWD Initial bleeding symptom 53% of women The only bleeding symptom for a long time Kadir et al haemophilia 1999 Ragni et al haemophilia 1999

47 Immune thrombocytopenia - ITP

Controversies in the Diagnosis of Type 1 VWD. Paula James MD, FRCPC ISLH Honolulu, Hawaii Friday, May 5, 2017

Controversies in the Diagnosis of Type 1 VWD Paula James MD, FRCPC ISLH Honolulu, Hawaii Friday, May 5, 2017 Disclosures for Paula James Research Support/P.I. Employee Consultant Major Stockholder Speakers