Bleeding Diathesis Recognition Evaluation Treatment of Hemophilia von

Bleeding Diathesis: Recognition, Evaluation & Treatment of Hemophilia & von Willebrand Disease Renee Marlette APRN, FNP-BC Hemophilia Treatment Center Hematology/Oncology Primary Children’s Medical Center

Bleeding Diathesis: Recognition, Evaluation & Treatment of Hemophilia & von Willebrand Disease • Identify red flags indicative of a bleeding diathesis in pediatric patients • Identify critical components of history, physical examination and laboratory studies • Pearls on recognition & management of Hemophilia • Pearls on recognition & management of von Willebrand Disease

Hemophilia Treatment Center Primary Children’s Medical Center Hematology/Oncology

Red 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!

WHO Bleeding Scale

Red Flags: Family History • X-linked recessive inheritance? • Male siblings and maternal uncles/grandfather • Hemophilia • Autosomal dominant inheritance? • Mother or father may transmit • Mucocutaneous symptoms • v. WD, • Autosomal recessive & Negative inheritance • 30% of Hemophilia de novo

Red Flags: Physical Exam • Is this bruising within normal limits? • Indurations • Placement • Petechiae • Wet purpura • Epistaxis • Hemarthrosis vs. soft tissue bleeds • Hyperflexibility of small joints and skin tissue laxity

Differentiation of Symptoms • Common to all • Differentiating “easy/prolonged” bleeding • Mucocutaneous Symptoms • Excessive bruising- indurations • Excessive initial bleeding • Petechiae • Oral, nasal mucosa • Genital tract (menorrhagia) • Hemarthrosis • Excessive bruising • Excessive continued bleeding • PAIN with compression • Differentiate from soft tissue bleeding

Coagulation screening in Children

Laboratory & Diagnostic Studies • Level I • CBC (Hgb/Hct/MCV/MCH/RBC/Plt) • PTT • Level 1. 5 • v. WP, TSH • PFA-100 • Fibrinogen (TT) • Level II • • • v. WP with multimers, ABO PT mixing study factor VII PTT mixing study factors IX, X (XI, others) PT & PTT prolonged factors II, V, X DRVVT /Lupus anticoagulants TT with RT

Coagulation Cascade

Hemophilia- Diagnosis • X-linked genetic disorder • Factor Deficiency • Prolonged PTT • CORRECTS with 1: 1 mixing study • Bleeding symptoms • Prevalence • 1 in 5, 000 male births • Estimated in US 20, 000

Hemophilia- Definitions • Factor Deficiency • Hemophilia A: FVIII • Hemophilia B: FIX • Hemophilia C: FXI • Severity • Mild > 5% - 50% • Moderate 1 – 5% • Severe < 1%

Hemophilia – Presentations • X-linked Family History • 30% new mutations • Symptoms • Bruising/bleeding • *Hemarthrosis (joint) – *Hallmark • Soft tissue/deep muscle • Nose/mouth, other bleeds

Hemophilia – Presentations • Severity of clinical bleeding symptoms • Genetics • Hemophilia A vs. Hemophilia B • Female: • Symptomatic carriers d/t Lionization • Expression of one of the X chromosomes is randomly suppressed

Hemophilia – Presentations • 5 major emergent bleeds: • Head • Eye • Neck/Throat • Abdominal/Stomach • Kidney/Bladder

Hemophilia- Tx with FACTOR • Factor Replacement • Percent correction • 50% correction • 100% correction • Products based on purity • Whole-molecule • Recombinant • Dosing • Factor VIII: 1 mg/kg 2% increase • Factor IX: 1 mg/kg 1% increase

Hemophilia- Treatment • Treatment Options • RICE – rest, ice, compression, elevation • Factor replacement • Prophylaxis • For Severe (<1% factor) patients • Prior to aggressive activities • DDAVP (Stimate) • Mild Hemophilia A • Topical Measures • Antifibrinolytics: Amicar, Lysteda

Hemophilia – Clinical Situations • Newborn Protocol • • Cord blood for PTT, factor level if +FHx Factor only if bleeding DELAY circumcision for 1 year Yes Vit K, Hep B SQ • Immunizations • SQ injections, pressure 10 min, ice (not direct) 10 min, call if swelling • Dental procedure • Ab coverage (ports) • +/- factor • +/- antifibrinolytic • Surgery /Trauma • IHTC consultation – notify early

Hemophilia • INHIBITORS • Development of autoimmune response with antibody development • 30% of Hemophilia A patients lifetime • Level • Low-level <5 BU • High/responder >5 BU • Treat with bypassing agent for bleeding • ITT – Immune Tolerance Therapy

Hemophilia • OUTCOMES • Improved morbidity and mortality when connected with IHTC • Role of PCP/specialty groups • FUTURE THERAPIES • Long-Acting Factors • Factor IX • Factor VIII • Gene Therapy • Europe, factor IX • Factor purity

von Willebrand Disease • Inherited bleeding disorder • Genetic mutation • Dysfunction of or deficiency of von Willebrand factor (v. WF) • Platelet adhesion • Binds and stabilizes FVIII • Most common genetic bleeding disorder • 1: 10, 000 or 1: 1000?

From The Diagnosis, Evaluation, and Management of von Willebrand Disease, US Dept of HHS 2007

Bleeding Score: Modified Vicenza Score

Bleeding Score: Modified Vicenza Score • Total all 3 columns • BS >3 in males or >5 in females was 98. 6% specific for v. WD • BS can be as predictive or superior to v. WF level if the bleeding is after tooth extraction or surgery • In pediatrics, a mean BS is 0. 5, normal range: 1. 5 to 2. 5 • Children with known v. WD: median BS: 7

From The Diagnosis, Evaluation, and Management of von Willebrand Disease, US Dept of HHS 2007

von Willebrand Disease • v. WP testing –do the panel! • Factor VIII • v. WAg • Actual protein • v. WF (Ristocetin Cofactor /RCo) • Effectiveness of the von Willebrand protein • Look at ratio of v. WF (RCo): v. WAg • > 0. 7 in Type 1 • Multimeric analysis

von Willebrand Disease • von Willebrand multimers help determine the subtype

von Willebrand Disease

von Willebrand Disease

von 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-bleeding • v. WF lowest first 1 -3 days of menstrual cycle • v. WF stress-reactant protein • may need to retest • other platelet disorder? • Can you test on OCPs?

von Willebrand Disease- Tx Options • Avoid NSAIDs and other platelet –inhibiting drugs • Hormonal Therapy –pair with OB • OCP – monophasic, active pills to allow menses 1 -2 x/year • Depo shot, Nuva. Ring • Levonorgestrel intrauterine system • DDAVP (Stimate) • Concentration 150 mcg/spray • Precautions: frequency, storage, dose, fluid restriction • Adjuvant Therapies: Antifibrinolytics • Aminocaproic acid (Amicar) • Tranexamic acid (Lysteda) • von Willebrand FACTOR • Humate P, Alphanate, Koate DVI

Fibrinolysis Cascade Aminocaproic Acid (Amicar) Tranexamic Acid (Lysteda)

von Willebrand Disease – Tx Pearls • Goal is cessation of bleeding (prophylaxis for surgical procedures) • no long-term prophylaxis • Immunization Hep A and B • Genetic counseling • Oral surgery: • Antifibrinolytics, DDAVP, topical agents (fibrin sealant, topical thrombin), surgical hemostatic measures • All major surgeries should be Tx in hospitals with monitoring and hematology • • Do not exceed v. WF: RCo > 200 IU/d. L, factor VIII >250% CALL FOR CONSULTATION - IHTC

Von Willebrand Disease • Menorrhagia • • Menorrhagia or abnormal vaginal bleeding- full gynecological eval before therapy (grade C, level IV) Adolescent or adult not desiring pregnancy • OCPs should be first choice • Levonorgestrel intrauterine system Desire pregnancy • DDAVP, antifibrinolytics, v. WF concentrate D&C is not usually effective in managing excessive uterine bleeding for women with v. WD • Labor & Delivery • • • Plan with hematologist prior to pregnancy, high risk If v. WF: RCo levels & FVIII >50 may consider regional anesthesia Delivery and post-partum support

Von Willebrand Disease • OUTCOMES • Depending on management • FUTURE THERAPIES • Long-Acting von Willebrand Factor • Gene therapy – potentially for v. WD type 3 • low prevalence, not likely to be high priority

Summary - Case Studies • 13 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…

Bleeding Diathesis: Recognition, Evaluation & Treatment of Hemophilia & von Willebrand Disease • Identify red flags indicative of a bleeding diathesis in pediatric patients • Identify critical components of history, physical examination and laboratory studies • Recognition & Management of Hemophilia • Recognition & Management of von Willebrand Disease THANK YOU!. . . Questions?