Edward P. Sloan, MD, MPH, FACEP Hemophilia and Rare Bleeding Disorders.

Edward P. Sloan, MD, MPH, FACEP

Hemophilia and Hemophilia and Rare Bleeding DisordersRare Bleeding Disorders

2007 EMA Advanced Emergency & Acute Care

Medicine Conference

Atlantic City, NJAtlantic City, NJSeptember 24, 2007September 24, 2007

Edward P. Sloan, MD, MPH FACEP

Professor

Department of Emergency MedicineUniversity of Illinois College of Medicine

Chicago, IL

Attending PhysicianEmergency Medicine

University of Illinois HospitalOur Lady of the Resurrection Hospital

Chicago, IL

DisclosuresDisclosures• Novo Nordisk grant to conferenceNovo Nordisk grant to conference• FERNE Chairman and PresidentFERNE Chairman and President• FERNE grants from Novo NordiskFERNE grants from Novo Nordisk• No financial disclosuresNo financial disclosures

• eMedicine source materialseMedicine source materials• Slide materials from Novo NordiskSlide materials from Novo Nordisk

www.ferne.orgwww.ferne.org

Global ObjectivesGlobal Objectives

• Maximize patient outcomeMaximize patient outcome• Utilize health care resources wellUtilize health care resources well

• Optimize evidence-based medicineOptimize evidence-based medicine• Enhance ED practiceEnhance ED practice

Sessions ObjectivesSessions Objectives

• Learn about hemophilia and RBDsLearn about hemophilia and RBDs• What are the diseases?What are the diseases?• How do patients present?How do patients present?• What are management principles?What are management principles?• What specific therapies?What specific therapies?• How to enhance pt outcomes?How to enhance pt outcomes?

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: ED Bleeding Disorder Patients: Key ConceptsKey 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 StatesDisease States

Hemophilia

• Hemophilia A • Congenital deficiency of factor VIII

(FVIII)

• Hemophilia B: Christmas Disease• Congenital deficiency of factor IX

Hemophilia

• Insufficient generation of thrombin by FVIIIa and FIXa complex

through the intrinsic pathway of the coagulation cascade

Coagulation CascadeCoagulation Cascade

Fibrin Clot StructureFibrin Clot Structure

Hemophilia A Normal Clot Structure

Hemophilia Severity

• Based on procoagulant levels or bleeding severity

• Severe: <1% clotting factor present Severe: <1% clotting factor present • Moderately severe: 1-5%Moderately severe: 1-5%• Mild: 5-40%Mild: 5-40%• Clinical bleeding severity may not Clinical bleeding severity may not

match amount of deficiency match amount of deficiency

Other Inherited Bleeding Disorders

• Congenital factor deficienciesCongenital factor deficiencies • von Willebrand’s Diseasevon Willebrand’s Disease• Other congenital platelet disorders Other congenital platelet disorders

• Glanzmann’s ThrombastheniaGlanzmann’s Thrombasthenia• Bernard Soulier SyndromeBernard Soulier Syndrome

von Willebrand’s Diseasevon 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 Fewer than 200 cases of true factor VII deficiency have been factor VII deficiency have been reportedreported• Gene mutations, protein dysfunctionGene mutations, protein dysfunction• Factor VII coagulant activities Factor VII coagulant activities measured in the laboratory are measured in the laboratory are not not well correlated with bleeding well correlated with bleeding manifestationsmanifestations

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 Emergency Department EvaluationEvaluation

Patient Demographics

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

Patient PresentationsPatient Presentations

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

75%70%

66% 65%

Epistaxis Menorrhagia Hematuria GI Joint Muscle CNS Post-partum/ post-

Hemophilia RBDs

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 HistoryHemorrhage 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

• GI - Hematemesis, melena, frank red blood per rectum, and abdominal pain

• Genitourinary - Hematuria, renal colic, and postcircumcision bleeding

• 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

• Hepatitis signs

• Infections signs

• Medic Alert bracelet

• Wallet

Physical Exam

• General hemorrhage signs

• Organ-specific hemorrhage signs

• Hepatitis signs

• Infections signs

• Medic Alert bracelet• Wallet (Hemophilia Treatment Center Card)Hemophilia Treatment Center Card)

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 DisordersLab Results for Bleeding Disorders Prolonged Prolonged PTPT

Prolonged Prolonged aPTTaPTT

Prolonged PT Prolonged PT and aPTTand aPTT

Inherited Inherited DisordersDisorders

• FVII DeficiencyFVII Deficiency • vWF Type 2&3 vWF Type 2&3 • FVIII, FIX, FXI or FVIII, FIX, FXI or FXII deficiencyFXII deficiency

• FII, fibrinogen, FV, X FII, fibrinogen, FV, X or a combined factor or a combined factor deficiencydeficiency

AcquiredAcquired

DisordersDisorders

• FVII InhibitorFVII Inhibitor• Vit K deficiencyVit K deficiency• Liver diseaseLiver disease• Warfarin useWarfarin use

• Inhibitor to FVIII, Inhibitor to FVIII, IX, XI, XII, vWF IX, XI, XII, vWF • Heparin useHeparin use

• Direct thrombin Direct thrombin inhibitor inhibitor • Inhibitor to FII, Inhibitor to FII, fibrinogen or FV or Xfibrinogen or FV or X• Liver disease, DIC, Liver disease, DIC, combined heparin and combined heparin and warfarin usewarfarin 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 Emergency Department ManagementManagement

Initial Management

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

Primary hemostasis:Primary hemostasis:• Vasoconstriction Vasoconstriction • Platelet adhesion Platelet adhesion • Platelet aggregation and contraction Platelet aggregation and contraction

Secondary hemostasis:Secondary hemostasis:• Activation of coagulation factors Activation of coagulation factors • Formation of fibrinFormation of fibrin

Fibrinolysis:Fibrinolysis:• Activation of fibrinolysis Activation of fibrinolysis • Lysis of the plugLysis of the plug

The 3 Phases of Hemostasis The 3 Phases of Hemostasis

Blood Vessel & EndotheliumBlood Vessel & Endothelium• Hemostasis requires and Hemostasis requires and

involves various physiological involves various physiological components:components:

• The blood vessel wallThe blood vessel wall

• Endothelial cellsEndothelial cells• Subendothelial tissueSubendothelial tissue• Smooth muscle cellsSmooth muscle cells

• The components of bloodThe components of blood

• Platelets (thrombocytes)Platelets (thrombocytes)• Coagulation (clotting) Coagulation (clotting)

factorsfactors• Fibrinolytic/ anticoagulant Fibrinolytic/ anticoagulant

proteinsproteins

Primary Hemostasis: Primary Hemostasis: VasoconstrictionVasoconstriction

• The first response The first response to endothelial to endothelial injury is the injury is the constriction of the constriction of the damaged vessel damaged vessel which reduces the which reduces the blood flow blood flow at the site of at the site of injuryinjury

Primary Hemostasis: Primary Hemostasis: Formation of a Platelet PlugFormation of a Platelet Plug

• The exposure of The exposure of subendothelial subendothelial components such as components such as collagen promotes collagen promotes platelet adhesionplatelet adhesion

• The adherence of The adherence of platelets to the sub-platelets to the sub-endothelium leads to endothelium leads to platelet activation and platelet activation and the formation of platelet the formation of platelet aggregates (platelet aggregates (platelet plug)plug)

• At the site of vascular injury At the site of vascular injury binding of endogenous factor binding of endogenous factor VII/VIIa to tissue factor (TF) VII/VIIa to tissue factor (TF) leads to the generation of small leads to the generation of small amounts of thrombin amounts of thrombin

• Thrombin activates platelets Thrombin activates platelets and additional coagulation and additional coagulation factors which subsequently factors which subsequently generate large amounts of generate large amounts of thrombin thrombin

• This “thrombin burst” induces This “thrombin burst” induces the generationthe generationof a haemostatic plugof a haemostatic plugthat prevents furtherthat prevents furtherblood loss blood loss

Secondary HemostasisSecondary Hemostasis

Adapted from Hoffman M et al., 2001.1

IXVIIIa

IIa (thrombin)

II (prothrombin)

fibrinogen FibrinClot

FibrinClot

VIIVIIa/TF

HMWK,PK

(factor I)

PTTPTT How a Blood Clot Forms: Step 2

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)

• 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

• 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 1-deamino-8-D-arginine vasopressin (desmopressin acetate, DDAVP)(desmopressin acetate, DDAVP)

• Increase (up to 4-fold) in FVIII plasma levelsIncrease (up to 4-fold) in FVIII plasma levels

• 0.3 mcg/kg in 30-50 mL 0.9% isotonic saline 0.3 mcg/kg in 30-50 mL 0.9% isotonic saline IV over 15-20 minIV over 15-20 min

• Not indicated in platelet type vWBNot 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)

• 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

• 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%.

• 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 ActivationvWDx: Platelet Activation

- GPIb IX, V : internalized- GPIIbIIIa : 1) membrane expression increased

2) complex occupied by fibrinogen, vonWillebrand Factor ...- P-selectin : translocated to the membrane

RESTING ACTIVATED

ACTIVATION

granules

P-selectin

GPIIb-IIIa

GPIb/IX/V

P-selectinGPIIb-IIIa

GPIV GPIb/IX/V

Fibrinogen

50,000

25,000

von Willebrand’s Disease Rxvon Willebrand’s Disease Rx

• Anti-hemophilic agent:• Type 1 vWDx • 1-deamino-8-D-arginine vasopressin 1-deamino-8-D-arginine vasopressin (desmopressin acetate, DDAVP)(desmopressin acetate, DDAVP)• Up to 3-6 fold increase in FVIII and 2-4 fold Up to 3-6 fold increase in FVIII and 2-4 fold

increase in vWF plasma levelsincrease in vWF plasma levels• 300 mcg intranasally produces levels 300 mcg intranasally produces levels comparable to IV infusioncomparable to IV infusion • Useful for menorrhagia and epistaxisUseful for menorrhagia and epistaxis

von Willebrand’s Disease Rxvon Willebrand’s Disease Rx

• Platelet transfusions if other Rx not effective

• Cryoprecipitate, FFP contain functional vWF, not used widely, not used widely

Rare Bleeding DisordersRare 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: RxRare 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

ConclusionsConclusions

• 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?Questions?

edsloan@uic.edu312 413 7490

sloan_ema_2007_hemophilia_rbd_092307_final04/10/23 22:55

Edward P. Sloan, MD, MPH, FACEP Hemophilia and Rare Bleeding Disorders.

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