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! 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 [2]. The incidence of epistaxis declines in adulthood, but approximately one-half of all adults with epistaxis had nosebleeds during childhood [3]. 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)

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 vWD, Autosomal recessive & Negative inheritance 30% of Hemophilia de novo Autosomal dominant: vWD, hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease) Autosomal recessive: rarer factor deficiencies VII, XI

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) PT PTT Level 1.5 vWP, TSH PFA-100 Fibrinogen (TT) Level II vWP 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 CBC: Psuedothrombocytopenia—examine peripheral smear The reptilase time (RT) is similar to the TT in measuring the conversion of fibrinogen to fibrin [27]. 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 TT Reptilase 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.

Coagulation Cascade Prothrombin 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.

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 However, clotting factor levels vary from one carrier to another due to lyonization [2], in which the expression of one of the two X chromosomes is randomly suppressed. Hemizygosity of X chromosome in Turner’s syndrome XO Homozygosity in a female VWD type 3 or 2 N Testicular feminization syndrome

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 However, clotting factor levels vary from one carrier to another due to lyonization [2], in which the expression of one of the two X chromosomes is randomly suppressed. Hemizygosity of X chromosome in Turner’s syndrome XO Homozygosity in a female VWD type 3 or 2 N Testicular feminization syndrome

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 FUTURE THERAPIES 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 (vWF) Platelet adhesion Binds and stabilizes FVIII Most common genetic bleeding disorder 1:10,000 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 Finland The 9th of 12 children ,4 died of bleed between 2- 4 y The same girl bled to death after her 4th M.P 23 members of her family were bleeders (16 women) He called the condition “Pseudo hemophilia”

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 vWD BS can be as predictive or superior to vWF 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 vWD: median BS: 7

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

von Willebrand Disease vWP testing –do the panel! Factor VIII vWAg Actual protein vWF (Ristocetin Cofactor /RCo) Effectiveness of the von Willebrand protein Look at ratio of vWF (RCo): vWAg > 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 vWF lowest first 1-3 days of menstrual cycle vWF 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 1-2x/year Depo shot, NuvaRing Levonorgestrel intrauterine system DDAVP (Stimate) Concentration 150mcg/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 vWF: RCo > 200 IU/dL, 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, vWF concentrate D&C is not usually effective in managing excessive uterine bleeding for women with vWD Labor & Delivery Plan with hematologist prior to pregnancy, high risk If vWF: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 vWD 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… -13mo: Hemophilia

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?