1. Hemophilia and Rare Bleeding Disorders

2. 2007 EMA Advanced Emergency & Acute Care Medicine Conference Atlantic City, NJ September 24, 2007

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

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

5. 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

6. 54 1 54

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

8. 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

9. 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?

10. 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

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

12. Disease States

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

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

15. Coagulation Cascade

16. Fibrin Clot Structure
Hemophilia A
Normal Clot Structure

17. 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

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

19. 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

20. 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

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

22. 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

23. Emergency Department Evaluation

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

25. Patient Presentations
Mannucci et al. Blood 2004;104:

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

27. 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

28. 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?

29. 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

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

31. 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

32. 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

33. 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

34. 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?

35. 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

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

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

38. Emergency Department Management

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

40. 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

41. 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

42. 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.

43. 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.

44. 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.,

45. 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)

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

47. 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

48. 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)

49. 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

50. 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%.

51. 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

52. 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 mL 0.9% isotonic saline IV over min
Not indicated in platelet type vWB

53. 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)

54. 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

55. 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%.

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

57. 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

58. 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

59. 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

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

61. 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

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

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

64. 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

65. 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

66. Questions? edsloan@uic.edu 312 413 7490
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