Bleeding Problems in Asian Population. Ponlapat Rojnuckarin Chulalongkorn University

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1 Bleeding Problems in Asian Population Ponlapat Rojnuckarin Chulalongkorn University

2 ARE ASIANS MORE LIKELY TO BLEED?

3 Hemorrhagic stroke is more common in Asia Countries/Areas Ischemic: Hemorrhagic Stroke Ratio Japan : 1 Korea 2.4 : 1 China :1 Caucasians USA 5-10 : 1 UK 9 :1 Europe 5-10 : 1 Circulation 2008; 118: 2702

4 Low dose ASA Primary Prevention in Japanese Subjects with CV Risk Factors RCT N = , Follow-up for 6.5 years Hazard Ratio P values Major CV events/death 0.94 ( ) 0.54 Non-fatal MI 0.53 ( ) 0.02 TIA 0.57 ( ) 0.04 Major Extracranial bleed 1.85 ( ) JAMA 2014; 312: 2510

5 Bleeding in ASA Primary Prevention trials Western ( mg) ASA No ASA RR ( Pt-Yr) Intracranial Major Extracranial Japan (100 mg) ( Pt-Yr) Intracranial Major Extracranial Lancet 2009; 373: 1849, JAMA. 2014;312:2510

6 Bleeding on warfarin in warfarin vs. DOAC trials MAJOR BLEED INTRACRANIAL BLEED Int J Cardiol 2015; 180: 246

7 Bleeding on warfarin is not due to high INR Int J Cardiol 2015; 180: 246

8 EDOXABAN in VTE: ASIAN SUBGROUPS BASELINE DATA ARE DIFFERENT. JTH 2015; 13: 1606

9 EDOXABAN in VTE: ASIAN SUBGROUPS SIMILARLY EFFICACIOUS JTH 2015; 13: 1606

10 EDOXABAN in VTE: ASIAN SUBGROUPS INR <2 2-3 >3 Asian 23% 58% 12% Non-Asian 14% 66% 14.5% Asians are more sensitive to warfarin with similar INR? JTH 2015; 13: 1606

11 Warfarin overdose is unrelated to VKOR genotypes in Thais VKORC genotyping: AA require lower dose of warfarin Most Common: AA in Asians but GG in Caucasians AA AG GG Volunteers 61.1% 33.6% 5.3% Thrombosis Patients Warfarin Overdose 63.2% 31.1% 5.7% 59.1% 36.4% 4.5% N Engl J Med. 2005; 352: J Hematol Transfus Med 2010; 20: 113, J Hematol Transfus Med 2008; 4: 307

12 Thrombosis vs. Bleeding Balance in Asians Limitation: Baseline characteristics may be different Hemorrhagic stroke is more common in Asians. Asian patients are very susceptible to bleeding while on warfarin or aspirin. Antithrombotic therapy is always associated with bleeding. Risk-benefit ratios require clinical trails specific to Asian patients.

13 Variations in vwf levels among races in USA AA African, CA Caucasian, HA Hispanic, AsA Asian Americans ASH Educational Book 2016: 670

14 Von Willebrand Disease (vwd) Most common hereditary primary hemostatic defect Currently, vwf levels of IU/dL are considered low vwf. vwd should have vwf < 30 IU/dL Prevalence of vwf < 50 IU/dL is 3.5% and vwf < 35 IU/dL is 0.96% in Thai population (N = 311) However, vwd is rare: 20 times less common than hemophilia in Thai Hematology Clinics. Due to mild symptoms, vwd may be missed. Diagnosis requires repeated test and symptom correlations. Rojnuckarin & Akkawat, SEA J Trop Med Pub Health 2005; 36: 1292 Chuansumrit et al SEA J Trop Med Pub Health 2004; 35: 445

15 vwd in Thai population Check-up Population in Bangkok and nearby provinces (Saraburi, Samutprakan, Chachoengsao and Cholburi) Offices, Factories, Military camps and communities Study subjects Bleeding score evaluation vwf-cba and Blood group If CBA 50 IU/dL: vwf-ag and called for repeated tests

16 vwd in Thai population General Thai population (N = 5196) Baseline characteristics Age ± range yr Sex: Male 2129 (41%) Female 3067 (59%) Bl gr O 38.0%, B 33.5%, A 21.6% and AB 6.8%

17 Bleeding scores Abnormal: 4 Sensitivity 100% Specificity 87% For vwd (N 259) Semin Throm Hemost 2017; 43: 530 J Thromb Haemost 2008; 6: 2062

18 Condensed Bleeding Assessment Tools JTH 2011; 9: 1143

19 Condensed MCMDM-1 vwd in Thai population (N=5196) 95% of male +1 and 95% of female +3

20 vwf-cba in Thai population Total Bl Gr O (N 1975) Non-Bl Gr O (N 3220) Mean SD percentile No difference between sexes. Unpublished

21 vwf-cba vwf-cba is increasing with age r 2 = P < Pearson Correlation

22 vwf-cba vs. Bleeding in Thai population

23 vwd in general population vwf-cba: 178 (3.43%) 50IU/dL 29 (0.558%) 30IU/dL 25 (0.481%) < 30 IU/dL Subjects with CBA 50IU/dL: Bleeding score is not lower than CBA > 50 IU/dL and 2 had bleeding score 4 1. A 50y male with GI, dental and post surgical bleeding (6) CBA 23, vwf-ag 52, Repeat CBA 80, vwf-ag 76 IU/dL 2. A 56y male with wound, GI and CNS bleeding (7) CBA 28, vwf-ag 66 IU/dL, Repeat Not available Unpublished

24 vwd is rare in Thailand. No vwd (case with vwf 30IU/dL more than once or with bleeding symptoms consistent with vwd) among 5196 subjects. Estimated prevalence of low vwf (repeatedly) in Thailand 1.09% (95% Confidence interval %) Low vwf: >90% Bl Gr O and No increase in bleeding score This underscores the importance of repeat blood tests and bleeding symptom evaluation. Unpublished

25 Hemophilia in Thailand World prevalence of Hemophilia 1: 10,000 Estimated cases in Thailand 6,000 (Total 65 M) Currently 1,500 registered in UC system ~200 in social security system ~ 100? in government officer Probably under-diagnosis or short survival

26 Registered Hemophiliacs (N = 1519) in 48 centers Hemophilia A Hemophilia B Mild 306 (22.8%) 32 (18.0%) Moderate 468 (34.9%) 79 (44.4%) Severe 567 (42.3%) 67 (37.6%) Total 1341 (88.3%) 178 (11.7%) High percentage of moderate hemophilia? The 3 rd common hereditary coagulopathy: Factor VII deficiency National Health Security Office of Thailand Registry

27 Age group of PWH in Shorter survival in the past Currently, Hemophilia-related Deaths are rare Hemophilia A Hemophilia B

28 Treatment of Hemophilia in Thailand 1939: Whole Blood 1964: FFP/cryoprecipitate 1995: Heat-treated dried plasma/dried cryoprecipitate* (Only 10-20% of total demand) 2006: Home therapy: Virally inactivated plasmaderived factor concentrate Current trend: Recombinant product, Locally made plasma derived factor VIII concentrate *Not totally safe for Hepatitis C

29 Replacement for Hemophilia A depends on Resources Sites Level Days Joint CNS Major Surgery No Resource Constraint Pre-op Sites Level Days Joint CNS Major Surgery Resource Constraint Pre-op Thailand is in between. World Federation of Hemophilia Guideline 2012

30 Plasma Fractionation Plant Local Albumin, IVIG and factor VIII is now available.

31 Home Therapy in Thailand Patient registration to the nearest hemophilia center. Patients receive factor concentrates from the centers (q 1-3 months) and self-administer for early bleeding (Generally lower doses). Patients come to the centers only for severe bleeding or surgery.

32 Treatment program 2016 (NHSO) Fixed budget THB 300 M per year in 2016 Hemophilia A Mild Moderate Severe Age < 10 yr (250u) per m Age > 10 yr (500u) per m Hemophilia B Age < 10 yr (500u) per m Age > 10 yr (500u) per m THB 300,000 per admission and THB 150,000 per OPD (Including bypassing agents)

33 Bleeding disorders unique to Tropical countries 1. Dengue Hemorrhagic Fever 2. Snakebite-induced Coagulopathy 3. Acquired Platelet Dysfunction with Eosinophiilia (APDE)

34 Acquired Platelet Dysfunction with Eosinophilia (APDE) Prof. Chulee Mitrakul In 1975, 1 st description in Am J Clin Path as transient spontaneous bruising with prolonged bleeding time and normal platelet count Prof. Parttraporn Isarangkura In 1977, named the disease as APDE Prof. Vinai Suvatte In 1979, description of a series of 62 children With APDE

35 Acquired Platelet Dysfunction with Eosinophilia (APDE) Most reports are from Southeast Asia Few from South America and Western patients who travelled to Southeast Asia Mean age 6 yr; Male: Female ratio : 1 Eosinophils x 10 3 /L 50% Parasitic infestations Spontaneous resolution > 90% in 4-6 months Am J Clin Path 1975; 63: 81, SEA J Trop Med Hyg 1979; 10: 358, Platelet 2001; 12: 5

36 Acquired Platelet Dysfunction with Eosinophilia (APDE) 100% Ecchymoses 10-20% Mucosal bleeding 3-7% Petechiae SEA J Trop Med Hyg 1979; 10: 358, Platelet 2001; 12: 5 Normal platelet count Pale-stained platelets

37 APDE: Acquired Storage Pool Disease Normal Patients Normal Patients Platelet 2001; 12: 5

38 APDE hypothesis Environmental factors (? Parasites of others) Eosinophilia Platelet Activation and Release Exhaust platelets (Eosinophilia in adults is associated with thrombosis)

39 Summary Antithrombotic therapy in Asians may have higher bleeding rates. Clinical trials are needed. Prevalence of hereditary bleeding disorders in Asians appears to be similar to that of Caucasians. Clinical care for hemophilia needs to be customized among countries. Tropical bleeding disorders required further research