Samuel Merrill MD PhD Benign Hematology 101521 Medical Director WVU Hospitals HTC Director Benign Hematology Clinic Disclosures No relevant financial disclosures 10152021 2 Samuel Merrill MD PhD ID: 1045083
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1. Perinatal management of bleeding disordersSamuel Merrill MD PhD, Benign Hematology10/15/21Medical Director, WVU Hospitals HTCDirector, Benign Hematology Clinic
2. DisclosuresNo relevant financial disclosures10/15/20212Samuel Merrill, MD PhD
3. ObjectivesReview bleeding disorder diversityHighlight diagnostic considerations in obstetricsExplore that “carriers” may have a bleeding disorderDiscuss guideline recommendations for obstetric carePractical considerations and applicability of bleeding disorder management
4. Tales of bleeding disorders“She just wouldn’t stop bleeding in the OR during the C-section. Every thing we touched bled.”OB/GYN. Patient was a hemophilia ‘carrier.’“The absolute worst bleeding I ever saw.”OB/GYN. Child had hemophilia and circumcision.“My daughter had severe bleeding with surgery, that’s when they found that we had hemophilia in the family.”Patient with severe Hemophilia B (age >50 at diagnosis).“I went home after surgery and almost bled to death, twice. I’m afraid the surgeon isn’t taking my disorder seriously.”Patient with VWD.
5. Diversity of bleeding disordersCoagulation factor defectsHemophilia A: FVIIIHemophilia B: FIXvon Willebrand Disease: vWF (Type I, IIA/B/M/N, III)Many others: II, V, VII, X, XI, XIII, fibrinogenPlatelet function defectsTransmembrane receptors: Glanzmann, Bernard-Soulier…Granule deficiency: alpha and delta granules, Quebec platelet disorder…Signal transduction: Scott syndrome, PLC-β2…Cytoskeletal defects: Wiskott-Aldrich (XLT), MYH9 related disease…Connective tissue diseases (non-hematologic)Ehlers-Danlos syndromeOsteogenesis imperfecta1.Rao AK, Gabbeta J. Arterioscler Thromb Vasc Biol 2000;20:285-9.
6. Bleeding phenotypeSeverityHemophilia A,B, vWD: bleeding is generally a function of factor levelPlatelet function disorders: large variation within families (with same mutation)LocationHemophilia: typically joints (and surgical)vWD: typically mucosal (and surgical)TimingCongenital: most bleeding disorders are congenitalAcquired: acquired hemophilia A and acquired vWD are autoimmune disorders
7. Testing Pitfalls:“PT and PTT normal” or “the PTT is only a little abnormal”You only need 20-30% of a coagulation factor to have a normal PT or PTTPatients with hemophilia can have normal PT or PTT“Testing is normal”Many bleeding disorders have difficult to obtain tests, pre-analytic variables“What about the baby?”FIX is vitamin K dependent, may take months to become normalFVIII can be elevated at birth, mild hemophilia can be masked (retest 3-6mo later if normal)If baby is suspected of having a bleeding disorder, the mother is also likely affected“Patient has vWD”vWF is dependent on ABO blood type: 45-47% of the population is Type OType O has normal Rco and vWF levels 30-40%OCP and pregnancy increase FVIII and vWF levels
8. Bleeding disorders have interventions“Factor”Replacement of FVIII, FIX, or vWF depending on the bleeding disorderIV medications with variable doses and frequenciesPatients can self-infuse with IV medications at home (more common in severe or moderate Hemophilia A or B)Many hospitals do not carry: cost can be >$5,000-15,000 a doseDDAVPDesmopression: IV or nasal formulation for transient increase of vWF or FVIII for some patientsLimited by disease (mild/moderate and vWF type), duration (not longer than 3 days)AntifibrinolyticsAminocaproic acidTranexamic acid
9. “Carriers” can have hemophiliaFVIII and FIX are on the X chromosomeOther factors besides X inactivation also influence level1Lyonization: random X inactivationEarly in embryonic developmentFVIII can range from <1% to >150% in carriersFVIII also influenced by: ABO, weight, age, OCP, liver disease1.Orstavik KH, Scheibel E, Ingerslev J, Schwartz M. Thromb Haemost 2000;83:433-7.
10. “Carriers” can have hemophilia1.Plug I. Blood. 2006;108(1):52-56.
11. “Carriers” can have hemophilia1. Paroskie A, Gailani D, DeBaun MR, Sidonio RF, Jr. A cross-sectional study of bleeding phenotype in haemophilia A carriers. Br J Haematol 2015;170:223-8.
12. “Carriers” can have hemophilia1. Paroskie A, Gailani D, DeBaun MR, Sidonio RF, Jr. A cross-sectional study of bleeding phenotype in haemophilia A carriers. Br J Haematol 2015;170:223-8.
13. Perinatal considerationsCounseling, accurate diagnosisBefore pregnancy, due to hormonal effects on testingDelivery planningFactor use and management plan (hematology)Mode of delivery discussion, option of planned C/s (obstetrics)Delivery considerationsFactor prophylaxis, factor monitoring, antifibrinolytic useAvoidance of forceps or vacuumPost-partum careFactor prophylaxis, factor monitoring, antifibrinolytic useExtended hospitalization
14. Perinatal Guidelines (NHF)Women who may be carriers should be evaluated before pregnancy. Normal levels do not exclude carrier status.Preconception consultation should be offered to women with bleeding disorders and possible carriersPregnancy should be managed by a multidisciplinary team (OB, hematology, anesthesia) knowledgeable in bleeding disordersAny early pregnancy procedures should be performed where hemorrhage can be managed (evacuation, abortion)Prophylaxis is indicated before uterine evacuation, CVS, cerclage, etcNHF MASAC Guideline #265.https://www.hemophilia.org/healthcare-professionals/guidelines-on-care/masac-documents
15. Perinatal Guidelines (NHF)A plan for management of birth should be in place before deliveryWomen should deliver in a facility with: bleeding disorder specialist, neonatology, lab, pharmacy, transfusion supportClotting factors must be available on siteFactor levels should be assessed in the 3rd trimester to plan for needs during deliveryCarriers and vWD patients should receive factor replacement at delivery if their levels are <50%. Women with levels >50% should be given the option of neuraxial anesthesia (attained 50% for at least 6hrs after removal)NHF MASAC Guideline #265https://www.hemophilia.org/healthcare-professionals/guidelines-on-care/masac-documents
16. Perinatal Guidelines (NHF)Decisions about anesthesia and delivery should be made with discussion in advance: anesthesia, hematology, OB, and patientDDAVP must be used with caution (if used), electrolytes and urine output must be monitored closely for 24hrsDelivery: mode of delivery and ICHInstrumentation is associated with high risk of bleedingObstetricians should discuss maternal and fetal risks of vaginal delivery vs planned caesarian, option of planned C/s should be considered for potentially affected infantsForceps, vacuum, scalp electrodes should be avoidedNHF MASAC Guideline #265https://www.hemophilia.org/healthcare-professionals/guidelines-on-care/masac-documents
17. Prevention is the goal1. Kader et al. 2017. Dicle Medical Journal 44 (3): 293-298.
18. Prevention is the goalSingleton TC, Keane M. Ochsner J 2012;12:249-53.Loomans JI, Eckhardt CL, Reitter-Pfoertner SE, et al.J Thromb Haemost 2017;15:1115-22.
19. Perinatal Guidelines (NHF)Umbilical cord blood should be obtained to avoid venipuncture of the infant: ensure proper test and early testingActive management of 3rd stage of laborTranexamic acid is advised for women with low vWF and vWDFactor levels may drop precipitously postpartum and should be monitoredFor women needing factor replacement, use for at least 5 days or longer (target closer to 150% than 50%)NHF MASAC Guideline #265https://www.hemophilia.org/healthcare-professionals/guidelines-on-care/masac-documents
20. Hemophilia Treatment CentersCAMCWVU-RubyW. PaHopkinsGeorgetownChildren’s NationalAkronClevelandColumbus
21. Guidelines (WFH)All potential carriers should have FVIII/IX levels measured before procedures, surgery, pregnancyFor carriers and at-risk women: factor levels, genetic counseling, and genetic testing be offeredFor pregnant carriers: prenatal diagnostic testing be offered if carrying male fetus (with genetic counseling and discussion of risks of testing)Delivery should occur in a hospital with access to specialized hemophilia careFor pregnant carriers, WHF recommends against instrumental delivery1. Srivastava A, Santagostino E, Dougall A, et al. WFH Guidelines for the Management of Hemophilia, 3rd edition. Haemophilia 2020;26 Suppl 6:1-158.
22. Guidelines (WFH)Carriers should be monitored for postpartum hemorrhage, and treated with appropriate hemostatic measuresBabies born to carriers should have cord blood testing of factor levelsCircumcision should be done electively by an experienced surgeon and hematology team at a HTC, with factor supportInhibitor testing if intractable bleedingVaccinations: route should be subcutaneous (rather than intramuscular)1. Srivastava A, Santagostino E, Dougall A, et al. WFH Guidelines for the Management of Hemophilia, 3rd edition. Haemophilia 2020;26 Suppl 6:1-158.
23. Perinatal Data: Carriers90 Pregnancies in carriers of Hemophilia A or BFactor levels: FVIII 121% and FIX 48% at delivery8% of A carriers needed factor50% of B carriers needed factorMode of delivery53% vaginal47% C/s (10 elective, 12 emergency)1.Chi C, Lee CA, Shiltagh N, Khan A, Pollard D, Kadir RA. Pregnancy in carriers of haemophilia. Haemophilia 2008;14:56-64.
24. Perinatal Data: CarriersMaternal bleeding complications: Post termination or miscarriage: 2Secondary post partum hemorrhage: 1 (day 2-3)Primary postpartum hemorrhage: 9 (19%)7 associated with C/s (2 elective, 6 emergency)2 vaginal from retained placentaNeonatal bleeding complications: 4 (3 were unknown carrier)Heel prick bleedingExtensive bruising and anemia from scalp bleeding after forceps/vacuumExtensive bleeding after surgery for pyloric stenosisEmergency C/s for failure to progress, cephalhematoma (no IVH, known carrier)1.Chi C, Lee CA, Shiltagh N, Khan A, Pollard D, Kadir RA. Pregnancy in carriers of haemophilia. Haemophilia 2008;14:56-64.
25. Perinatal data: delivery1. Andersson NG, Chalmers EA, Kenet G, et al. Haematologica 2019;104:2100-6.
26. Perinatal data: delivery1. Andersson NG, Chalmers EA, Kenet G, et al. Haematologica 2019;104:2100-6.
27. Perinatal data: deliveryVaginal instrumentation is a risk for bleeding compared to: C/s before labor: ICH RR 6.4, major bleeding RR 4.8Vaginal delivery: ICH RR 6.9, major bleeding RR 7.4C/s in labor is a risk for major bleeding compared to:Vaginal delivery (no instrumentation) RR 3.42Non-significant increase in ICH (p=0.37)No family history of hemophilia was known: 445/906 casesOne neonatal death from ICH after C/s, at day 6 (unknown affected)1. Andersson NG, Chalmers EA, Kenet G, et al. Haematologica 2019;104:2100-6.
28. Major Perinatal Concern:Hemophilia may not be knownNo family history of hemophilia was known: 445/906 cases1In 49% of infants with hemophilia it was unexpectedHemophilia was familial in ~70% of cases2That means in 30% of affected people it was sporadic In sporadic cases, 88% of mothers had mutation, and of 19% maternal grandmothersAndersson NG, Chalmers EA, Kenet G, et al. Haematologica 2019;104:2100-6.Kasper CK, Lin JC. Haemophilia 2007;13:90-2.
29. Perinatal data: delivery counselingPlanned vaginal delivery (n=703)Vaginal delivery: 77%Instrumental vaginal delivery: 9.7%C/s in labor: 9.9%Planned C/s (n=134)C/s before labor: 93.2%C/s in labor: 6.8%Known history of hemophilia led to more C/s (36% vs 28%)No difference in bleeds (known vs unknown family history)1. Andersson NG, Chalmers EA, Kenet G, et al. Haematologica 2019;104:2100-6.
30. Sample Delivery Management Plan
31. Vitamin K for newbornsOral Vitamin K:1mg PO x1 is a viable alternative if hemophilia suspected1. Puckett RM, Offringa M. Cochrane Database Syst Rev 2000:CD002776.
32. Practical Considerations for ProvidersDo (for possibly affected mothers or children)Refer to hematology early to develop a management planMultidisciplinary discussion (OB, Hematology, Anesthesia, etc)Counselling on mode of delivery (OB)Consider mother as having a possible bleeding disorder if a ‘carrier’Best to avoid (for mother or child)Instrumented vaginal delivery, emergent C/sHeel sticks in suspected affected childIM injections in suspected affected childCircumcision, surgery, or procedures: they will need factor coverage to prevent bleeding
33. ResourcesMASAC (NHF): https://www.hemophilia.org/healthcare-professionals/guidelines-on-care/masac-documentsWFH: https://elearning.wfh.org/resource/treatment-guidelines/
34. Hematologic question break