1Bleeding Diathesis: Recognition, Evaluation & Treatment of Hemophilia & von Willebrand Disease Renee Marlette APRN, FNP-BCHemophilia Treatment CenterHematology/OncologyPrimary Children’s Medical Center
2Bleeding Diathesis: Recognition, Evaluation & Treatment of Hemophilia & von Willebrand Disease Identify red flags indicative of a bleeding diathesis in pediatric patientsIdentify critical components of history, physical examination and laboratory studiesPearls on recognition & management of HemophiliaPearls on recognition & management of von Willebrand Disease
3Hemophilia Treatment Center Primary Children’s Medical Center Hematology/Oncology
4Red Flags: History* Ecchymosis? Soft tissue hematoma? Joint hemorrhages?Delayed bleeding?Bleeding from superficial skin abrasions?Bleeding from tooth extraction/T&A/surgery?Menorrhagia? (define)Male or Female?Medications? (NSAIDS, ASA, herbals)*Not all bleeding episodes suggest a bleeding disorder!Bleeding into the skin and mucous membranes is characteristic of disorders of platelets and blood vessels (purpuric disorders) and may be manifested as Petechiae and/or ecchymosis.Bleeding into soft tissue, muscle, and joints suggests the presence of hemophilia or other disorders of coagulation*EPISTAXIS: 1979 study found that 30 percent of children younger than five years and 56 percent of children aged 6 to 10 years had had at least one nosebleed . The incidence of epistaxis declines in adulthood, but approximately one-half of all adults with epistaxis had nosebleeds during childhood . Epistaxis is rare in children younger than two years (approximately 1 per 10,000) and should prompt consideration of trauma (intentional or unintentional) or serious illness (e.g., thrombocytopenia)
6Red Flags: Family History X-linked recessive inheritance?Male siblings and maternal uncles/grandfatherHemophiliaAutosomal dominant inheritance?Mother or father may transmitMucocutaneous symptomsvWD,Autosomal recessive & Negative inheritance30% of Hemophilia de novoAutosomal dominant: vWD, hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease)Autosomal recessive: rarer factor deficiencies VII, XI
7Red Flags: Physical Exam Is this bruising within normal limits?IndurationsPlacementPetechiaeWet purpuraEpistaxisHemarthrosis vs. soft tissue bleedsHyperflexibility of small joints and skin tissue laxity
8Differentiation of Symptoms Common to allDifferentiating “easy/prolonged” bleedingMucocutaneous SymptomsExcessive bruising- indurationsExcessive initial bleedingPetechiaeOral, nasal mucosaGenital tract (menorrhagia)HemarthrosisExcessive bruisingExcessive continued bleedingPAIN with compressionDifferentiate from soft tissue bleeding
10Laboratory & Diagnostic Studies Level ICBC (Hgb/Hct/MCV/MCH/RBC/Plt)PTPTTLevel 1.5vWP, TSHPFA-100Fibrinogen (TT)Level IIvWP with multimers, ABOPT mixing study factor VIIPTT mixing study factors IX, X (XI, others)PT & PTT prolonged factors II, V, XDRVVT /Lupus anticoagulantsTT with RTCBC: Psuedothrombocytopenia—examine peripheral smearThe reptilase time (RT) is similar to the TT in measuring the conversion of fibrinogen to fibrin . The reptilase time is useful for detecting abnormalities in fibrinogen (in which case the TT is also prolonged) and in detecting the presence of heparin (heparin will cause prolongation of the TT but not reptilase time). Thus, the RT is most useful for determining if heparin is the cause of a prolonged TTReptilase time:Reptilase is an enzyme similar to thrombin that is found in the venom of Bothrops snakes. However, it differs from thrombin by generating fibrinopeptide A but not fibrinopeptide B from fibrinogen and by resisting inhibition by heparin via antithrombin.
11Coagulation CascadeProthrombin time (PT) — The production of fibrin via the extrinsic pathway and the final common pathway requires tissue thromboplastin (tissue factor), factor VII, factors X, V, prothrombin (factor II), and fibrinogen. The functioning of these pathways is measured by the PT (figure 1). This test bypasses the intrinsic pathway and uses "complete" thromboplastins (ie, tissue factor) capable of activating the extrinsic pathway.Activated partial thromboplastin time (aPTT) The PT is sensitive to alterations in the vitamin K-dependent coagulation factors, especially factors II, VII, and X, and is used to monitor treatment with vitamin K antagonists.Activated partial thromboplastin time (aPTT) measures the intrinsic and common pathways of coagulation (figure 1). It is called "partial" because clotting is initiated in vitro with agents that are only partial thromboplastins (ie, they are incapable of activating the extrinsic pathway). This aPTT is routinely used to evaluate intrinsic coagulation and the degree of heparin anticoagulation. (See "Clinical use of coagulation tests", section on 'Activated partial thromboplastin time'.)The aPTT is sensitive to deficiencies of factors XII, XI, IX, and VIII and to inhibitors such as heparin (figure 1). It is less sensitive than the PT to deficiencies within the common pathway (eg, factors X, V, prothrombin, and fibrinogen) and is unaffected by alterations in factors VII and XIII.
15Hemophilia – Presentations X-linked Family History30% new mutationsSymptomsBruising/bleeding*Hemarthrosis (joint) – *HallmarkSoft tissue/deep muscleNose/mouth, other bleedsHowever, clotting factor levels vary from one carrier to another due to lyonization , in which theexpression of one of the two X chromosomes is randomly suppressed.Hemizygosity of X chromosome in Turner’s syndrome XOHomozygosity in a femaleVWD type 3 or 2 NTesticular feminization syndrome
16Hemophilia – Presentations Severity of clinical bleeding symptomsGeneticsHemophilia A vs. Hemophilia BFemale:Symptomatic carriers d/t LionizationExpression of one of the X chromosomes is randomly suppressedHowever, clotting factor levels vary from one carrier to another due to lyonization , in which theexpression of one of the two X chromosomes is randomly suppressed.Hemizygosity of X chromosome in Turner’s syndrome XOHomozygosity in a femaleVWD type 3 or 2 NTesticular feminization syndrome
17Hemophilia – Presentations 5 major emergent bleeds:HeadEyeNeck/ThroatAbdominal/StomachKidney/Bladder
18Hemophilia- Tx with FACTOR Factor ReplacementPercent correction50% correction100% correctionProducts based on purityWhole-moleculeRecombinantDosingFactor VIII: 1 mg/kg 2% increaseFactor IX: 1 mg/kg 1% increase
20Hemophilia – Clinical Situations Newborn ProtocolCord blood for PTT, factor level if +FHxFactor only if bleedingDELAY circumcision for 1 yearYes Vit K, Hep B SQImmunizationsSQ injections, pressure 10 min, ice (not direct) 10 min, call if swellingDental procedureAb coverage (ports)+/- factor+/- antifibrinolyticSurgery /TraumaIHTC consultation – notify early
21Hemophilia INHIBITORS Development of autoimmune response with antibody development30% of Hemophilia A patients lifetimeLevelLow-level <5 BUHigh/responder >5 BUTreat with bypassing agent for bleedingITT – Immune Tolerance Therapy
22Hemophilia OUTCOMES FUTURE THERAPIES Improved morbidity and mortality when connected with IHTCRole of PCP/specialty groupsFUTURE THERAPIESLong-Acting FactorsFactor IXFactor VIIIGene TherapyEurope, factor IXFactor purity
23von Willebrand Disease Inherited bleeding disorderGenetic mutationDysfunction of or deficiency of von Willebrand factor (vWF)Platelet adhesionBinds and stabilizes FVIIIMost common genetic bleeding disorder1:10,000 or 1:1000?1926. Erik VW , a dedicated physician, evaluated 4 year old girl in 1925 for bleeding lip , has H/O nose bleed and lived in a remote island off the shore of FinlandThe 9th of 12 children ,4 died of bleed between 2- 4 yThe same girl bled to death after her 4th M.P23 members of her family were bleeders (16 women)He called the condition “Pseudo hemophilia”
24From The Diagnosis, Evaluation, and Management of von Willebrand Disease, US Dept of HHS 2007
26Bleeding Score: Modified Vicenza Score Total all 3 columnsBS >3 in males or >5 in females was 98.6% specific for vWDBS can be as predictive or superior to vWF level if the bleeding is after tooth extraction or surgeryIn pediatrics, a mean BS is 0.5, normal range: 1.5 to 2.5Children with known vWD: median BS: 7
27From The Diagnosis, Evaluation, and Management of von Willebrand Disease, US Dept of HHS 2007
29von Willebrand Disease vWP testing –do the panel!Factor VIIIvWAgActual proteinvWF (Ristocetin Cofactor /RCo)Effectiveness of the von Willebrand proteinLook at ratio of vWF (RCo): vWAg> 0.7 in Type 1Multimeric analysis
30von Willebrand Disease von Willebrand multimers help determine the subtype
33von Willebrand Disease Pearls on testing…Do not treat until confirmed laboratory diagnosis of type and severity (unless emergency)DDAVP-responsiveness should be tested while non-bleedingvWF lowest first 1-3 days of menstrual cyclevWF stress-reactant proteinmay need to retestother platelet disorder?Can you test on OCPs?
34von Willebrand Disease- Tx Options Avoid NSAIDs and other platelet –inhibiting drugsHormonal Therapy –pair with OBOCP – monophasic, active pills to allow menses 1-2x/yearDepo shot, NuvaRingLevonorgestrel intrauterine systemDDAVP (Stimate)Concentration 150mcg/sprayPrecautions: frequency, storage, dose, fluid restrictionAdjuvant Therapies: AntifibrinolyticsAminocaproic acid (Amicar)Tranexamic acid (Lysteda)von Willebrand FACTORHumate P, Alphanate, Koate DVI
36von Willebrand Disease – Tx Pearls Goal is cessation of bleeding (prophylaxis for surgical procedures)no long-term prophylaxisImmunization Hep A and BGenetic counselingOral surgery:Antifibrinolytics, DDAVP, topical agents (fibrin sealant, topical thrombin), surgical hemostatic measuresAll major surgeries should be Tx in hospitals with monitoring and hematologyDo not exceed vWF: RCo > 200 IU/dL, factor VIII >250%CALL FOR CONSULTATION - IHTC
37Von Willebrand Disease MenorrhagiaMenorrhagia or abnormal vaginal bleeding- full gynecological eval before therapy (grade C, level IV)Adolescent or adult not desiring pregnancyOCPs should be first choiceLevonorgestrel intrauterine systemDesire pregnancyDDAVP, antifibrinolytics, vWF concentrateD&C is not usually effective in managing excessive uterine bleeding for women with vWDLabor & DeliveryPlan with hematologist prior to pregnancy, high riskIf vWF:RCo levels & FVIII >50 may consider regional anesthesiaDelivery and post-partum support
38Von Willebrand Disease OUTCOMESDepending on managementFUTURE THERAPIESLong-Acting von Willebrand FactorGene therapy – potentially for vWD type 3low prevalence, not likely to be high priority
39Summary - Case Studies13 month old male infant who is starting to walk and presents with a painful swollen joint after falling down one step…12 year-old girl with excessive menstrual bleeding from menarche, recurrent nosebleeds, and pallor…5 year-old girl child who is not clinically ill but presents with moderate Mucocutaneous purpura with a recent viral infection…-13mo: Hemophilia
40Bleeding Diathesis: Recognition, Evaluation & Treatment of Hemophilia & von Willebrand Disease Identify red flags indicative of a bleeding diathesis in pediatric patientsIdentify critical components of history, physical examination and laboratory studiesRecognition & Management of HemophiliaRecognition & Management of von Willebrand DiseaseTHANK YOU!...Questions?