Hemophilia and Rare Bleeding Disorders

2007 EMA Advanced Emergency & Acute Care Medicine Conference Atlantic City, NJ September 24, 2007

Edward P. Sloan, MD, MPH FACEP Professor Department of Emergency Medicine University of Illinois College of Medicine Chicago, IL 54 1 54

Attending Physician Emergency Medicine University of Illinois Hospital Our Lady of the Resurrection Hospital Chicago, IL 54 1 54

Disclosures Novo Nordisk grant to conference FERNE Chairman and President FERNE grants from Novo Nordisk No financial disclosures eMedicine source materials Slide materials from Novo Nordisk 54 2 54

www.ferne.org 54 1 54

Global Objectives Maximize patient outcome Utilize health care resources well Optimize evidence-based medicine Enhance ED practice 54 2 54

Sessions Objectives Learn about hemophilia and RBDs What are the diseases? How do patients present? What are management principles? What specific therapies? How to enhance pt outcomes? 54 2 54

Case Presentation 17 year old presents to ED Known hemophilia A Fell off of bicycle Abdominal trauma Hypotensive, tachycardic Abdominal tenderness What do you do?

ED Bleeding Disorder Patients: Key Concepts Identify the bleeding disorder Establish if bleeding is present Treat the bleeding Treat the bleeding disorder Establish endpoint for Rx success Disposition based on Dx, Rx, risk

Background Rare disorder: Affects fewer than 200,000 Americans (NIH office of Rare Diseases) Hemophilia Other bleeding disorders Rare Bleeding Disorders

Disease States

Hemophilia Hemophilia A Congenital deficiency of factor VIII (FVIII) Hemophilia B: Christmas Disease Congenital deficiency of factor IX (FIX)

Hemophilia Insufficient generation of thrombin by FVIIIa and FIXa complex through the intrinsic pathway of the coagulation cascade

Coagulation Cascade

Fibrin Clot Structure Hemophilia A Normal Clot Structure

Hemophilia Severity Based on procoagulant levels or bleeding severity Severe: <1% clotting factor present Moderately severe: 1-5% Mild: 5-40% Clinical bleeding severity may not match amount of deficiency

Other Inherited Bleeding Disorders Congenital factor deficiencies von Willebrand’s Disease Other congenital platelet disorders Glanzmann’s Thrombasthenia Bernard Soulier Syndrome

von Willebrand’s Disease Autosomally inherited bleeding disorder, mucocutaneous Deficiency or dysfunction of the protein termed von Willebrand factor (vWF) Primary hemostasis is impaired Defective interaction between platelets and the vessel wall

Factor VII Deficiency Fewer than 200 cases of true factor VII deficiency have been reported Gene mutations, protein dysfunction Factor VII coagulant activities measured in the laboratory are not well correlated with bleeding manifestations

Acquired Bleeding Disorders Vitamin K Deficiency Severe Liver Disease Factors II, VII, IX and X are decreased Platelets dysfunctional Renal Disease Platelet dysfunction

Acquired Bleeding Disorders Oral Anticoagulant Therapy Prolonged Use of Antibiotics Develop anti-platelet antibodies Vitamin K deficiency Acquired Inhibitors (Antibodies) Post malignancy Related to pregnancy Idiopathic Elderly

Emergency Department Evaluation

Patient Demographics Hemophilia Present in childhood, esp with greater disease severity All races X-linked, recessive  males

Patient Presentations Mannucci et al. Blood 2004;104:1243-1252

History What is the Bleeding Disorder? vWD, Hemophilia A/B, other factor deficiency or platelet disorder

History What is the severity of the factor deficiency? Severe - < 1% factor present Bleed spontaneously and often e.g. weekly Moderate – 1-5 % Can have spontaneous bleeding but less frequent e.g. monthly Mild - > 5 % Bleed only when hemostasis is challenged e.g. trauma and surgery

History Do they have a inhibitor (assoc with congenital factor def)? What is their HIV/Hepatitis Status? How is the bleeding disorder being treated? When was your most recent treatment or infusion? Are you taking other medications?

Hemorrhage History General - Weakness and orthostasis Musculoskeletal (joints) - Tingling, cracking, warmth, pain, stiffness, and refusal to use joint (children) CNS - Headache, stiff neck, vomiting, lethargy, irritability, and spinal cord syndromes

Hemorrhage History GI - Hematemesis, melena, frank red blood per rectum, and abdominal pain Genitourinary - Hematuria, renal colic, and postcircumcision bleeding

Hemorrhage History Other - Epistaxis, oral mucosal hemorrhage, hemoptysis, dyspnea (hematoma leading to airway obstruction), compartment syndrome symptoms, and contusions; excessive bleeding with routine dental procedures

Physical Exam General hemorrhage signs Organ-specific hemorrhage signs the astonishing results Physical Exam General hemorrhage signs Organ-specific hemorrhage signs Hepatitis signs Infections signs Medic Alert bracelet Wallet performance improvement

Physical Exam General hemorrhage signs Organ-specific hemorrhage signs the astonishing results Physical Exam General hemorrhage signs Organ-specific hemorrhage signs Hepatitis signs Infections signs Medic Alert bracelet Wallet (Hemophilia Treatment Center Card) performance improvement

Laboratory Testing CBC (Hb, platelets, WBC) PT, aPTT vWF:Ag (Von Willibrand factor antigen) Ristocetin Co-Factor Measures vWF activity to identify qualitative vWF disorder Factor coagulant activity e.g. VIII:C, IX:C in hemophilias Bleeding time?

Lab Results for Bleeding Disorders Prolonged PT Prolonged aPTT Prolonged PT and aPTT Inherited Disorders FVII Deficiency vWF Type 2&3 FVIII, FIX, FXI or FXII deficiency FII, fibrinogen, FV, X or a combined factor deficiency Acquired Disorders FVII Inhibitor Vit K deficiency Liver disease Warfarin use Inhibitor to FVIII, IX, XI, XII, vWF Heparin use Direct thrombin inhibitor Inhibitor to FII, fibrinogen or FV or X Liver disease, DIC, combined heparin and warfarin use

Laboratory Testing PT: Extrinsic, should be normal unless FVII deficiency or acquired aPTT: Intrinsic, elevated in moderate hemophilia disease severity

Other ED Testing Extremity xrays Head CT Abdominal CT Tests for increased compartment pressures Nuclear bleeding studies

Emergency Department Management

Initial Management Treat the patient ABCs Direct hemorrhage control Hemodynamic support Crystalloids Blood products Specifically assist hemostasis

The 3 Phases of Hemostasis Primary hemostasis: Vasoconstriction Platelet adhesion Platelet aggregation and contraction Secondary hemostasis: Activation of coagulation factors Formation of fibrin Fibrinolysis: Activation of fibrinolysis Lysis of the plug

Blood Vessel & Endothelium Hemostasis requires and involves various physiological components: The blood vessel wall Endothelial cells Subendothelial tissue Smooth muscle cells The components of blood Platelets (thrombocytes) Coagulation (clotting) factors Fibrinolytic/ anticoagulant proteins

Primary Hemostasis: Vasoconstriction The first response to endothelial injury is the constriction of the damaged vessel which reduces the blood flow at the site of injury Colman RW, et al. Overview of haemostasis. In: Colman RW, Hirsh J, Marder VJ, Clowes AW, George JN, eds. Haemostasis and Thrombosis: Basic Principles and Clinical Practice. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001: 3–16.

Primary Hemostasis: Formation of a Platelet Plug The exposure of subendothelial components such as collagen promotes platelet adhesion The adherence of platelets to the sub-endothelium leads to platelet activation and the formation of platelet aggregates (platelet plug) Colman RW, et al. Overview of haemostasis. In: Colman RW, Hirsh J, Marder VJ, Clowes AW, George JN, eds. Haemostasis and Thrombosis: Basic Principles and Clinical Practice. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001: 3–16. Monroe DM, Hoffman M. Arterioscler Thromb Vasc Biol 2006; 26(1): 41–48.

Secondary Hemostasis At the site of vascular injury binding of endogenous factor VII/VIIa to tissue factor (TF) leads to the generation of small amounts of thrombin  Thrombin activates platelets and additional coagulation factors which subsequently generate large amounts of thrombin  This “thrombin burst” induces the generation of a haemostatic plug that prevents further blood loss  Hoffman M, Monroe DM. Thromb Haemost 2001; 85(6): 958–965. Monroe DM, et al. Blood Coagul Fibrinolysis 1998; 9(Suppl 1): S15–20. Monroe DM, Hoffman M. Arterioscler Thromb Vasc Biol 2006; 26(1): 41–48. Adapted from Hoffman M et al., 2001.1

How a Blood Clot Forms: Step 2 PTT HMWK,PK PT XII XI TF IX VIIa/TF VII VIIIa X X Va IIa (thrombin) II (prothrombin) fibrinogen Fibrin Clot (factor I)

Platelets Clotting factors Coagulation cascade What is Broken? Platelets Clotting factors Coagulation cascade

What Can Be Provided? Vitamin K FFP (Fresh frozen plasma) PCC (prothrombin complex concentrate) Platelets, packed RBCs, whole blood Specific clotting factors Anti-fibrinolytics, anti-hemophilics

Hemophilia A: Factor VIII Recombinant factor VIII concentrate is the preferred source of factor VIII. The factor VIII activity level should be corrected to 100% of normal for potentially serious hemorrhage. Units factor VIII=(weight in kg)(50 mL plasma/kg)(1 U factor VIII/mL plasma)(desired factor VIII level minus the native factor VIII level)

Hemophilia A: Factor VIII As an example, an 80-kg individual diagnosed with hemophilia with known 1% factor VIII activity level presents to the ED with a severe upper GI bleed. Units factor VIII = (80 kg)(50 mL/kg)(1 U factor VIII/mL)(.99) = 3960

Hemophilia A: Factor VIII Next dose: 12 hours later, 1/2 initial dose. Minor hemorrhage: 1-3 doses factor VIII. Major hemorrhage: many doses, continued factor VIII activity monitoring. Goal: trough activity level at least 50%.

Hemophilia A: Other Rx FFP: administer 1 mL IV FFP/U factor VIII. Anti-fibrinolytics: Epsilon aminocaproic acid (Amicar) Oral mucosal bleeds, rich fibrinolytic activity 200 mg/kg PO/IV initial dose, 100 mg/kg q6h; not to exceed 5 g Alternatively, 10 g slow IV (over 2 h), followed by 1 g/h continuous infusion

Hemophilia A: Other Rx Anti-hemophilic agent: 1-deamino-8-D-arginine vasopressin (desmopressin acetate, DDAVP) Increase (up to 4-fold) in FVIII plasma levels 0.3 mcg/kg in 30-50 mL 0.9% isotonic saline IV over 15-20 min Not indicated in platelet type vWB

Hemophilia B: Factor IX Synthetic recombinant Factor IX Units factor IX =(weight in kg)(100 mL/kg)(1 U factor IX/mL)(desired factor IX level minus the native factor IX level)

Hemophilia B: Factor IX As an example, an 80-kg individual diagnosed with hemophilia with known 1% factor IX activity level presents to the ED with a severe CNS bleed. Units factor IX = (80 kg)(100 mL/kg) (1 U factor IX/mL)(.99) = 7920

Hemophilia B: Factor IX Next dose: 12 hours later, 1/2 initial dose. Minor hemorrhage: 1-3 doses factor IX. Major hemorrhage: many doses, continued factor IX activity monitoring. Goal: trough activity level at least 50%.

Hemophilia B: Factor IX Factor IX complex concentrates Coagulation factor IX concentrates, pooled plasma product (high purity)

Hemophilia B: Other Rx FFP: administer 1 mL IV FFP/U factor IX. Anti-fibrinolytics: Epsilon aminocaproic acid (Amicar) Oral mucosal bleeds, rich fibrinolytic activity 200 mg/kg PO/IV initial dose, 100 mg/kg q6h; not to exceed 5 g Alternatively, 10 g slow IV (over 2 h), followed by 1 g/h continuous infusion

vWDx: Platelet Activation RESTING ACTIVATED 50,000 > 500  Fibrinogen   granules P-selectin  GPIIb-IIIa  GPIIb-IIIa P-selectin GPIV GPIb/IX/V   GPIb/IX/V GPIV  ACTIVATION  25,000 - GPIb IX, V : internalized - GPIIbIIIa : 1) membrane expression increased 2) complex occupied by fibrinogen, vonWillebrand Factor ... - P-selectin : translocated to the membrane

von Willebrand’s Disease Rx Anti-hemophilic agent: Type 1 vWDx 1-deamino-8-D-arginine vasopressin (desmopressin acetate, DDAVP) Up to 3-6 fold increase in FVIII and 2-4 fold increase in vWF plasma levels 300 mcg intranasally produces levels comparable to IV infusion Useful for menorrhagia and epistaxis

von Willebrand’s Disease Rx Platelet transfusions if other Rx not effective Cryoprecipitate, FFP contain functional vWF, not used widely

Rare Bleeding Disorders Congenital factor deficiency of any of the following: VII XI X II V Combined V and VIII Fibrinogen XIII PAI-1 Congenital Platelet Disorders Glanzmann’s Thrombasthenia Bernard Soulier von Willibrands Disease – Types 2 & 3

Rare Bleeding Disorders: Rx Stabilize the patient. Call the hematology/oncology consultant.

What Can Be Provided? Specific clotting factors PCC, other concentrates Anti-fibrinolytics, anti-hemophilics FFP (1 mL per Unit of clotting factor) Platelets

Patient Outcome Low Hb, ruptured spleen IVF, cross-matched blood 10% Factor VIII levels prior Units factor VIII = (70 kg)(50 mL/kg) (1 U factor VIII/mL)(.90) = 3500 Stable to ICU with expectant management

Conclusions Complex medical problems Lumpers and splitters Treat the patient’s hemorrhage Identify the disease Treat the disease, as able Consult liberally Admit as indicated

Questions? edsloan@uic.edu 312 413 7490 sloan_ema_2007_hemophilia_rbd_092307_final 3/31/2017 9:51 PM