Bleeding Disorders PDF

Bleeding Disorders Integrated Hematology/Oncology Module – PHAR 5367 Emily Lee, PharmD Clinical Pharmacy Specialist – Leukemia [email protected] Slides provided by: Grace Park, PharmD, BCOP Clinical Pharmacy Specialist – Leukemia MD Anderson Cancer Center Objectives • Differentiate between h...

Bleeding Disorders Integrated Hematology/Oncology Module – PHAR 5367 Emily Lee, PharmD Clinical Pharmacy Specialist – Leukemia [email protected] Slides provided by: Grace Park, PharmD, BCOP Clinical Pharmacy Specialist – Leukemia MD Anderson Cancer Center Objectives • Differentiate between hemophilia A and hemophilia B • Develop a factor replacement plan or treatment plan for a patient with bleeding disorder • Describe treatment options for antiphospholipid syndrome Bleeding disorders Hemophilia A Von Willebrand Disease B Clotting disorders Antiphospholipid syndrome References • National Hemophilia Foundation (https://www.hemophilia.org/) • ASH ISTH NHF WFH 2021 guidelines on the management of von Willebrand disease (https://ashpublications.org/bloodadvances/article/5/1/301/4 74884/ASH-ISTH-NHF-WFH-2021-guidelines-on-themanagement) • EULAR recommendations for the management of antiphospholipid syndrome in adults (https://ard.bmj.com/content/78/10/1296) Coagulation Cascade Hemophilia • • • • Congenital deficiency in a plasma coagulation protein Due to recessive X-linked diseases Rare disease (~33,000 males in the US)1 Direct cost of care (2008)2 – Factor replacement products (>$140,000) – Comorbidities – HIV, hepatitis, inhibitors (59% increase in health care costs) – ER visits (33% of patients, 2.8 ED visits) – Hospitalizations (14% of patients, 1.4 admissions) • Indirect costs – Missed school/work – Decreased productivity ED = emergency department; ER = emergency room; HIV = human immunodeficiency virus. 1. Centers of Disease Control and Prevention (CDC). Accessed October 23, 2020. 2. Chen S. Am J Manag Care. 2016 Apr;22(5 Suppl):s126-133. Hemophilia Inheritance Pattern Hemophilia • Hemophilia A – Deficiency of factor VIII – 80-85% of all patients with hemophilia • Hemophilia B – Deficiency of factor IX – Hemophilia B Leyden Trinkman, et al. Chapter 119: Coagulation Disorders. ©2020 McGraw Classification of Hemophilia Normal FVIII or FIX 50 – 150% • Mild: 6- 49% circulating factor • Moderate: 1 – 5% circulating factor • Severe: <1% circulating factor – Spontaneous bleeding – Highest risk of intracranial bleeding – Highest risk for developing inhibitors – occur in up to 25% of hemophilia A vs. 2-3% hemophilia B Trinkman, et al. Chapter 119: Coagulation Disorders. ©2020 McGraw Signs and Symptoms • • • • • • • • • • Ecchymoses Hemarthroses Joint pain/swelling/erythema Muscle hemorrhage/pain Loss of range in motion Nerve compression Oral bleeding Hematuria Intracranial hemorrhage Excessive bleeding Trinkman, et al. Chapter 119: Coagulation Disorders. ©2020 McGraw Laboratory Testing • • • • • • Prolonged activated partial thromboplastin time (aPTT) Normal prothrombin time (PT) Normal platelet count Normal bleeding time Normal von Willebrand factor antigen and activity Decreased factor VIII or factor IX Trinkman, et al. Chapter 119: Coagulation Disorders. ©2020 McGraw Diagnosis • • • • • Considered in any male with unusual bleeding Family history of bleeding Brothers of patients with hemophilia should be screened Common factor VIII gene inversions Can be diagnosed prenatally in gestational weeks 9 to 14 Trinkman, et al. Chapter 119: Coagulation Disorders. ©2020 McGraw Hemophilia Goals of Care • Prophylaxis – Reduction in annualized bleeding rate (ABR) – Preservation of joints long term – Reduce frequency of infusion • Treatment of bleeds – Effective with minimal transfusion – Reduction of recurrent bleeds Trinkman, et al. Chapter 119: Coagulation Disorders. ©2020 McGraw Evolution of Therapies for Hemophilia 1900 1950 1960 1990 2014 2015 2017 2020 Gene therapy Trinkman, et al. Chapter 119: Coagulation Disorders. ©2020 McGraw Factor Concentrates Plasma Derived Recombinant Extended Half-Life (EHL) Factor VIII • Hemofil M • Koate DVI • Monoclate P Factor VIII + vWF • Alphanate • Humate P • Wilate Factor IX • AlphaNine • Mononine PCC • Bebulin • Kcentra • Profilnine aPCC • FEIBA Factor VIII • Advate • Afstyla • Helixate • Kogenate • Kovaltry • Obizur (PS) • Recombinate • Nuwiq • NovoEight (BDD) • Xyntha (BDD) Factor IX • BeneFIX • Ixinity • Rixubis Factor VII • NovoSeven vWF • Vonvendi Factor VIII • Adynovate (PEG) • Jivi (PEG) • Eloctate (Fc-IgG) Factor IX • Alprolix (Fc-IgG) • Idelvion (FP) • Rebinyn (PEG) Trinkman, et al. Chapter 119: Coagulation Disorders. ©2020 McGraw Adverse Events and Monitoring Parameters • Adverse Events • Patient Counseling • Arthralgia • Avoids NSAIDs and aspirin • Malaise • • Myalgia Avoid herbal products and vitamins • Headache • • Rash Regular exercise (avoid contact sports) • Line-associated thrombosis for infusions • Monitoring Parameters • Repeat factor level • Coagulation labs Trinkman, et al. Chapter 119: Coagulation Disorders. ©2020 McGraw Factor VIII Concentrate Replacement • 1 unit FVIII/kg = increase by 2 units/dL (2%) • Calculate expected increase in serum [FVIII] – Units/dL (% of normal) = [Total dose (units) / body weight (kg)] x 2 units/dL per units/kg • Calculate dose needed – Factor VIII (units) = Desired factor increase (units/dL or %) × 0.5 × Weight (kg) – Serious/life-threatening bleeding: 0.75 to 1units/mL (75%-100%) – Less severe bleeding: 0.3 to 0.5 units/mL (30%-50%) • Single dose vs. multiple doses • Subsequent doses reduce factor requirement by 20-50% Trinkman, et al. Chapter 119: Coagulation Disorders. ©2020 McGraw Factor IX Concentrate Replacement Trinkman, et al. Chapter 119: Coagulation Disorders. ©2020 McGraw Desmopressin tachyphylaxis Trinkman, et al. Chapter 119: Coagulation Disorders. ©2020 McGraw Non-Factor Replacement Therapies Emicizumab Fitusiran Concizumab Marstacimab Mechanism of Action FVIII mimetic Reduces Antithrombin Anti-TFPI Anti-TFPI Current Status Approved: • Nov 2017 (inhibitors) • Oct 2018 (without inhibitors) Phase 3 Approved in Canada Mar 2023 Phase 3 Indications or Target Population • Prophylaxis • Adults and children • Hemophilia A • Hemophilia A and B with and without inhibitors • Hemophilia A and B with inhibitors Dosing SQ every 1, 2, or 4 weeks SQ every 1 to 4 weeks SQ daily • Hemophilia A and B with and without inhib itors SQ daily Thrombosis ??? Safety Concerns Thrombosis Thrombosis TMA Do NOT use SQ = subcutaneously; TFPI = tissue factor pathway inhibitor; TMA = thrombotic microangiopathy. FEIBA US Food and Drug Administration (FDA). Accessed October 29, 2020. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-emicizumab-kxwh-hemophilia- or-withoutfactor-viii-inhibitors; https://www.fda.gov/media/124993/download Gene Therapy • A new treatment where new working genes are introduced to a person’s cells to fight the disease • Vector (e.g. AAV) is a virus that has been modified to change the DNA of the host • Eligible: male 18 yo or older with severe hemophilia A or B without a significant comorbities (e.g.HIV) • NOT considered as a cure https://www.hemophilia.org/events/gene-therapy-whats-new-whats-next-webinar Gene Therapy https://www.hemophilia.org/events/gene-therapy-whats-new-whats-next-webinar Gene Therapy • Roctavian approved June 2023 – Hemophilia A – Requires diagnostic test to detect pre-existing antibodies to adeno-associated virus (AAV) serotype 5 – Single IV dose gene therapy – ADR: LFT elevation, headache, nausea, vomiting, fatigue, abdominal pain, and infusion related reactions • Hemgenix approved November 2022 – Hemophilia B – Single IV dose gene therapy – ADR: LFT elevation, headache, infusion related reactions, flulike symptoms https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-adults-severe-hemophilia https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-treat-adults-hemophilia-b Knowledge Check Dr. Bob comes into your office and asks you to calculate factor VIII concentrate replacement for a patient with hemophilia coming to the hospital. What questions do you need to ask Dr. Bob prior to calculating the dose? Other Supportive Care • Immunizations – Hepatitis B – Hepatitis A – SQ injection preferred with severe hemophilia • Arthropathies – Increased need for orthopedic surgery • Pain management – 1st line: acetaminophen – 2nd line: selective COX2 inhibitors to reduce GI bleed • Delivery of infants with hemophilia – Vacuum extraction and forceps increase risk of cranial bleeding – Screening head ultrasound prior to discharge from nursery Trinkman, et al. Chapter 119: Coagulation Disorders. ©2020 McGraw Von Willebrand Disease (vWD) • 1924: Finnish physician Erik von Willebrand described the disease in a young female patient • Most common inherited bleeding disorder affecting 1% of the US population – Type 1 60-80% – Type 2 15-30% – Type 3 5-10% • Male = Female • Chromosome 12 Connell, et al. ASH ISTH NHF WFH 2021 guidelines on the diagnosis of von Willebrand disease. Blood Adv (2021) 5 (1): 301–325. https://doi.org/10.1182/bloodadvances.2020003264 vWD Pathophysiology • vWF – Platelet adhesion & aggregation (primary) – Chaperone for FVIII (secondary) – Angiogenesis – Bone metabolism NHLBI The Diagnosis, Evaluation, and Management of von Willebrand Disease . Types of vWD: Multimer Analysis • Type 1 is a partial quantitative deficiency of VWF • Type 2 is caused by qualitative abnormalities of VWF – – – – Type 2A: reduced or absent high-molecular-weight VWF Type 2B: gain of function in VWF that increases its affinity for platelets Type 2M: reduced VWF interactions with platelets or collagen Type 2N: reduced binding of VWF to FVIII • Type 3 is a virtual absence of the VWF protein with associated very low FVIII levels • Acquired vWD after a diagnosis of an autoimmune disease, such as lupus, or from heart disease or some types of cancer Connell, et al. ASH ISTH NHF WFH 2021 guidelines on the diagnosis of von Willebrand disease. Blood Adv (2021) 5 (1): 301–325. https://doi.org/10.1182/bloodadvances.2020003264 Laboratory Testing • von Willebrand Panel – vWF Antigen – vWF-Ristocetin Cofactor Activity (RCoF) • • • • Factor VIII:C (same assay as for hemophilia A) Ristocetin-Induced Platelet Aggregation Multimer analysis by starch gene electrophoresis PT, PTT, CBC Presentation • History of bleeding – – – – – – – – Excessive mucocutaneous bleeding Heavy menstrual bleeding Epistaxis Easy bruising Prolonged bleeding from minor wounds and the oral cavity Gastrointestinal bleeding Bleeding after dental work, childbirth, and surgery Musculoskeletal bleeding Connell, et al. ASH ISTH NHF WFH 2021 guidelines on the diagnosis of von Willebrand disease. Blood Adv (2021) 5 (1): 301–325. https://doi.org/10.1182/bloodadvances.2020003264 Von Willebrand Disease (vWD) Treatment Medication Constituents Dosing ADEs Humate-P Alphante Wilate FVIII-vWF Required IU = BW (kg) x 0.5 x vWF:Rco increase Hypotension, chest pain, phlebitis, parethesia, hemorrhage, anemia, increased inhibitors, arthralgia, and thrombosis 40-60 RCoF units/kg q12h for several days for major surgery 30-50 RCoF units/kg q24h or q48h for minor surgery 20-30 RCoF units/kg once for dental extraction VonVendi vonicog alfa rvWF LD 40—80 units/kg MD 40-60 units/kg q8-24h x 4872h Hypertension, tachycardia, EKG T wave inversion, paresthesia, antibody, thrombosis Connell, et al. ASH ISTH NHF WFH 2021 guidelines on the management of von Willebrand disease. Blood Adv (2021) 5 (1): 301–325. https://doi.org/10.1182/bloodadvances.2020003264 Other Considerations • Long-term prophylaxis vs. no prophylaxis? • Antiplatelet or anticoagulant therapy in patients with VWD and cardiovascular disease? • Surgeries? Major vs. Minor? VWF activity levels of ≥0.50 IU/mL for at least 3 days after surgery • Desmopressin? Connell, et al. ASH ISTH NHF WFH 2021 guidelines on the diagnosis of von Willebrand disease. Blood Adv (2021) 5 (1): 301–325. https://doi.org/10.1182/bloodadvances.2020003264 Desmopressin • 0.3 micrograms/kg IV or SQ given over 20 to 30 minutes – One or two whiffs in nostrils (intranasal) • For patients with vWD & history of severe and frequent bleeds • Contraindicated in patients with active cardiovascular disease, in patients with seizure disorders, and age <2 years • Caution in type 2B VWD due to risk of thrombosis • Used safely in women during pregnancy • Perform a challenge test to document response 60 minutes and 4 hour post levels • Adverse effects: flushing, hypotension, hyponatremia, tachyphylaxis Connell, et al. ASH ISTH NHF WFH 2021 guidelines on the management of von Willebrand disease. Blood Adv (2021) 5 (1): 301–325. https://doi.org/10.1182/bloodadvances.2020003264 Summary of the Guidelines on the Management of VWD • Routine treatment to prevent bleeds (prophylaxis) in patients with vWD with a history of severe and frequent bleeds • Desmopressin trial are recommended prior to treatment in vWF <30%. • In patients with VWD and cardiovascular disease, who need treatment with antiplatelet agents or anticoagulant therapy, the necessary medication should be given. Summary of the Guidelines on the Management of VWD • After major surgery, factor VIII (FVIII) and VWF activity levels should be >50% for >3 days. • For vWD and heavy menstrual bleeding, who do not wish to become pregnant, hormonal therapy or tranexamic acid should be given. • Pregnant people with vWD, tranexamic acid should be used after the delivery of a baby. Antifibrinolytics • Tranexamic acid (Lysteda) – IV or PO – 1000mg IV – 1300mg q8h PO • ε-aminocaproic acid (Amicar) – lysine analogue – – – – IV or PO 100 mg/kg up to 4g q6h for severe bleeding Lower doses q6h orally are usually sufficient May cause nausea Knowledge Check Von Willebrand Disease affects the _____ in primary hemostasis and ______ in secondary hemostasis it can result in ______ bleeding. A. B. C. D. Hemoglobin, platelets, severe Platelets, factor XIII, severe Platelets, factor VIII, severe Hemoglobin, factor VIII, severe Antiphospholipid Syndrome (aPL) • Heterogeneous antibodies against phospholipid-binding proteins (b2 GPI, prothrombin, others...) • Common in healthy populations • Even higher in the elderly, often transient - not useful in population screening Miyakis J Thromb Haem 2006 Diagnosis Clinical symptoms • Vascular thrombosis • Pregnancy morbidity + Laboratory findings • Clotting assays – Lupus anticoagulant • Solid assays – Anti-beta 2 glycoprotein antibodies – Anticardiolipin antibodies • Other tests – Mixing test – Confirmation test after 12 weeks Miyakis J Thromb Haem 2006 Clinical Manifestation • Asymptomatic aPL positivity • Venous, arterial, or small vessel thrombosis • Pregnancy loss during second or third trimester • Non-criteria manifestation of aPL (involvement of skin, cardiac valves, pulmonary, renal) • Microangiopathy/multi-organ failure Ruiz-Irastorza et al The Lancet 2010 Treatment • Long-term anticoagulation therapy for thrombosis – Warfarin “Standard of care” • INR goal 2 – 3 for venous event • INR goal 3 – 4 for arterial event • INR goal 2 – 3 with antiplatelet for arterial event – LMWH is an option if unable to tolerate warfarin • Anti Xa level >1 U/mL – DOACs may be used for typical VTE – Antiplatelet alone • Aspirin +/- LMWH or UFH for pregnancy morbidity (ACCP 2012 Guidelines) Cochrane Database Empson et al 2008 Terminated early Cohen et al Lancet Haematol 2016 Catastrophic Antiphospholipid Syndrome (CAPS) • If meeting all 4 criteria, definite CAPS – – – – Involvement of 3 or more organs, systems, tissues Simultaneous onset symptoms or within 1 week Small vessel occlusion (histologically confirmed) APL positive (LA or ACL) • Anticoagulation alone can be insufficient to control progressive thromboembolism, with any agent • Plasmapheresis daily • Immunosuppression with steroids, cyclophosphamide • Rituximab (can be given after daily plasmapheresis) Cervera et al (CAPS Registry Project Group) Ann Rheum Dis 2005 Knowledge Check What is a clinical manifestation of anti-phospholipid syndrome in a newly diagnosed patient? A. B. C. D. E. Transient ischemic stroke Blood in the urine Pregnancy loss in the first trimester Skin ulcerations Both A and D Take Home Points • Blood disorders may happen due to genetic deficiency of factors or overproduction of antibodies • There are treatment options available bleeding disorders including blood products and non-blood products as well as supportive care agents • Blood disorders may cause further complications which require acute management and prophylaxis • Pharmacists play a key role in managing blood disorders by providing treatment recommendations and managing drug interactions Bleeding Disorders Integrated Hematology/Oncology Module – PHAR 5367 Emily Lee, PharmD Clinical Pharmacy Specialist – Leukemia [email protected] Slides provided by: Grace Park, PharmD, BCOP Clinical Pharmacy Specialist – Leukemia MD Anderson Cancer Center