Transcript FERNE Template

Hemophilia and
Rare Bleeding Disorders
Edward P. Sloan, MD, MPH, FACEP
2007 EMA Advanced
Emergency & Acute Care
Medicine Conference
Atlantic City, NJ
September 24, 2007
Edward P. Sloan, MD, MPH, FACEP
Edward P. Sloan, MD, MPH
FACEP
Professor
Department of Emergency Medicine
University of Illinois College of Medicine
Chicago, IL
Edward P. Sloan, MD, MPH, FACEP
Attending Physician
Emergency Medicine
University of Illinois Hospital
Our Lady of the Resurrection Hospital
Chicago, IL
Edward P. Sloan, MD, MPH, FACEP
Disclosures
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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
Edward P. Sloan, MD, MPH, FACEP
www.ferne.org
Edward P. Sloan, MD, MPH, FACEP
Global Objectives
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Maximize patient outcome
Utilize health care resources well
Optimize evidence-based medicine
Enhance ED practice
Edward P. Sloan, MD, MPH, FACEP
Sessions Objectives
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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?
Edward P. Sloan, MD, MPH, FACEP
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?
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Edward P. Sloan, MD, MPH, FACEP
ED Bleeding Disorder Patients:
Key Concepts
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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
Edward P. Sloan, MD, MPH, FACEP
Background
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Rare disorder: Affects fewer than
200,000 Americans
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(NIH office of Rare Diseases)
Hemophilia
• Other bleeding disorders
• Rare Bleeding Disorders
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Edward P. Sloan, MD, MPH, FACEP
Disease States
Edward P. Sloan, MD, MPH, FACEP
Hemophilia
Hemophilia A
• Congenital deficiency of factor VIII
(FVIII)
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Hemophilia B: Christmas Disease
• Congenital deficiency of factor IX
(FIX)
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Edward P. Sloan, MD, MPH, FACEP
Hemophilia
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Insufficient generation of thrombin
by FVIIIa and FIXa complex
through the intrinsic pathway of
the coagulation cascade
Edward P. Sloan, MD, MPH, FACEP
Coagulation Cascade
Edward P. Sloan, MD, MPH, FACEP
Fibrin Clot Structure
Hemophilia A
Normal Clot Structure
Edward P. Sloan, MD, MPH, FACEP
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
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Edward P. Sloan, MD, MPH, FACEP
Other Inherited Bleeding Disorders
Congenital factor deficiencies
• von Willebrand’s Disease
• Other congenital platelet disorders
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Glanzmann’s Thrombasthenia
• Bernard Soulier Syndrome
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Edward P. Sloan, MD, MPH, FACEP
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
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Edward P. Sloan, MD, MPH, FACEP
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
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Edward P. Sloan, MD, MPH, FACEP
Acquired Bleeding Disorders
Vitamin K Deficiency
• Severe Liver Disease
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Factors II, VII, IX and X are decreased
• Platelets dysfunctional
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Renal Disease
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Platelet dysfunction
Edward P. Sloan, MD, MPH, FACEP
Acquired Bleeding Disorders
Oral Anticoagulant Therapy
• Prolonged Use of Antibiotics
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Develop anti-platelet antibodies
• Vitamin K deficiency
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Acquired Inhibitors (Antibodies)
Post malignancy
• Related to pregnancy
• Idiopathic
• Elderly
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Edward P. Sloan, MD, MPH, FACEP
Emergency Department
Evaluation
Edward P. Sloan, MD, MPH, FACEP
Patient Demographics
Hemophilia
• Present in childhood, esp with
greater disease severity
• All races
• X-linked, recessive  males
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Edward P. Sloan, MD, MPH, FACEP
Patient Presentations
Hemophilia
RBDs
90%
81%
80%
75%
70%
66%
75%
70%
65%
60%
50%
50%
40%
38%
30%
30%
20%
25%
25%
15%
16%
13% 13%
8%
10%
8%
0%
Epistaxis
Menorrhagia Hematuria
Mannucci et al. Blood
2004;104:1243-1252
GI
Joint
Muscle
CNS
Postpartum/postop
Mouth
Edward P. Sloan, MD, MPH, FACEP
History
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What is the Bleeding Disorder?
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vWD, Hemophilia A/B, other factor
deficiency or platelet disorder
Edward P. Sloan, MD, MPH, FACEP
History
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What is the severity of the factor
deficiency?
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Severe - < 1% factor present
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Moderate – 1-5 %
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Bleed spontaneously and often e.g. weekly
Can have spontaneous bleeding but less
frequent e.g. monthly
Mild - > 5 %
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Bleed only when hemostasis is challenged
e.g. trauma and surgery
Edward P. Sloan, MD, MPH, FACEP
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?
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Edward P. Sloan, MD, MPH, FACEP
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
Edward P. Sloan, MD, MPH, FACEP
Hemorrhage History
• GI - Hematemesis, melena, frank red
blood per rectum, and abdominal
pain
• Genitourinary - Hematuria, renal
colic, and postcircumcision bleeding
Edward P. Sloan, MD, MPH, FACEP
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
Edward P. Sloan, MD, MPH, FACEP
Physical Exam
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General hemorrhage signs
Organ-specific hemorrhage signs
Hepatitis signs
Infections signs
Medic Alert bracelet
Wallet
Edward P. Sloan, MD, MPH, FACEP
Physical Exam
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General hemorrhage signs
Organ-specific hemorrhage signs
Hepatitis signs
Infections signs
Medic Alert bracelet
Wallet (Hemophilia Treatment Center Card)
Edward P. Sloan, MD, MPH, FACEP
Laboratory Testing
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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?
Edward P. Sloan, MD, MPH, FACEP
Lab Results for Bleeding Disorders
Prolonged
PT
Inherited
Disorders
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Acquired
Disorders
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Prolonged
aPTT
FVII Deficiency
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FVII Inhibitor
• Vit K deficiency
• Liver disease
• Warfarin use
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Prolonged PT
and aPTT
vWF Type 2&3
• FII, fibrinogen, FV, X
• FVIII, FIX, FXI or or a combined factor
deficiency
FXII deficiency
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
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Edward P. Sloan, MD, MPH, FACEP
Laboratory Testing
• PT: Extrinsic, should be normal
unless FVII deficiency or acquired
• aPTT: Intrinsic, elevated in
moderate hemophilia disease
severity
Edward P. Sloan, MD, MPH, FACEP
Other ED Testing
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Extremity xrays
Head CT
Abdominal CT
Tests for increased compartment
pressures
• Nuclear bleeding studies
Edward P. Sloan, MD, MPH, FACEP
Emergency Department
Management
Edward P. Sloan, MD, MPH, FACEP
Initial Management
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Treat the patient
ABCs
Direct hemorrhage control
Hemodynamic support
Crystalloids
Blood products
Specifically assist hemostasis
Edward P. Sloan, MD, MPH, FACEP
The 3 Phases of Hemostasis
Primary hemostasis:
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Vasoconstriction
Platelet adhesion
Platelet aggregation and contraction
Secondary hemostasis:
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Activation of coagulation factors
Formation of fibrin
Fibrinolysis:
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Activation of fibrinolysis
Lysis of the plug
Edward P. Sloan, MD, MPH, FACEP
Blood Vessel & Endothelium
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Hemostasis requires and
involves various
physiological components:
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The blood vessel wall
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Endothelial cells
Subendothelial tissue
Smooth muscle cells
The components of blood
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Platelets
(thrombocytes)
Coagulation (clotting)
factors
Fibrinolytic/
anticoagulant proteins
Edward P. Sloan, MD, MPH, FACEP
Primary Hemostasis:
Vasoconstriction
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The first response
to endothelial
injury is the
constriction of the
damaged vessel
which reduces the
blood flow
at the site of
injury
Edward P. Sloan, MD, MPH, FACEP
Primary Hemostasis:
Formation of a Platelet Plug
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The exposure of
subendothelial
components such as
collagen promotes
platelet adhesion
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The adherence of
platelets to the subendothelium leads to
platelet activation and
the formation of platelet
aggregates (platelet
plug)
Edward P. Sloan, MD, MPH, FACEP
Secondary Hemostasis
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Adapted from Hoffman M et al., 2001.1
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 
Edward P. Sloan, MD, MPH, FACEP
How a Blood Clot Forms: Step 2
PTT
HMWK,PK
PT
XII
TF
XI
IX
VIIa/TF
VIIIa
X
VII
X
Va
IIa
(thrombin)
fibrinogen
(factor I)
II (prothrombin)
Fibrin
Clot
Edward P. Sloan, MD, MPH, FACEP
What is Broken?
• Platelets
• Clotting factors
• Coagulation cascade
Edward P. Sloan, MD, MPH, FACEP
What Can Be Provided?
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Vitamin K
FFP (Fresh frozen plasma)
PCC (prothrombin complex concentrate)
Platelets, packed RBCs, whole blood
Specific clotting factors
Anti-fibrinolytics, anti-hemophilics
Edward P. Sloan, MD, MPH, FACEP
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)
Edward P. Sloan, MD, MPH, FACEP
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
Edward P. Sloan, MD, MPH, FACEP
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%.
Edward P. Sloan, MD, MPH, FACEP
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
Edward P. Sloan, MD, MPH, FACEP
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
Edward P. Sloan, MD, MPH, FACEP
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)
Edward P. Sloan, MD, MPH, FACEP
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
Edward P. Sloan, MD, MPH, FACEP
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%.
Edward P. Sloan, MD, MPH, FACEP
Hemophilia B: Factor IX
• Factor IX complex concentrates
• Coagulation factor IX concentrates,
pooled plasma product (high purity)
Edward P. Sloan, MD, MPH, FACEP
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
Edward P. Sloan, MD, MPH, FACEP
vWDx: Platelet Activation
RESTING
ACTIVATED
50,000
 granules
Fibrinogen
> 500
P-selectin
GPIIb-IIIa
GPIIb-IIIa
GPIV
P-selectin
GPIV
GPIb/IX/V
GPIb/IX/V
ACTIVATION
25,000
- GPIb IX, V : internalized
- GPIIbIIIa : 1) membrane expression increased
2) complex occupied by fibrinogen, vonWillebrand Factor ...
Edward P. Sloan, MD, MPH, FACEP
- 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
Edward P. Sloan, MD, MPH, FACEP
von Willebrand’s Disease Rx
• Platelet transfusions if other Rx not
effective
• Cryoprecipitate, FFP contain
functional vWF, not used widely
Edward P. Sloan, MD, MPH, FACEP
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
Edward P. Sloan, MD, MPH, FACEP
Rare Bleeding Disorders: Rx
• Stabilize the patient.
• Call the hematology/oncology
consultant.
Edward P. Sloan, MD, MPH, FACEP
What Can Be Provided?
• Specific clotting factors
• PCC, other concentrates
• Anti-fibrinolytics, anti-hemophilics
• FFP (1 mL per Unit of clotting factor)
• Platelets
Edward P. Sloan, MD, MPH, FACEP
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
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Edward P. Sloan, MD, MPH, FACEP
Conclusions
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Complex medical problems
Lumpers and splitters
Treat the patient’s hemorrhage
Identify the disease
Treat the disease, as able
Consult liberally
Admit as indicated
Edward P. Sloan, MD, MPH, FACEP
Questions?
[email protected]
312 413 7490
sloan_ema_2007_hemophilia_rbd_092307_final
7/17/2015 12:32 AM
Edward P. Sloan, MD, MPH, FACEP