February 22, 2019 Sioux Falls, SD

Please complete the preassessment

located in your handout

before the program begins.

Sponsorship and Support

This educational activity is jointly provided by

The American College of Emergency Physicians

and Spire Learning.

This activity is supported by an educational grant from Genentech, Inc.

2

Accreditation and Designation Statements

ACCREDITATION STATEMENTThis activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of the American College of Emergency Physicians, Spire Learning, and the Illinois College of Emergency Medicine. The American College of Emergency Physicians is accredited by the ACCME to provide continuing medical education for physicians.

DESIGNATION STATEMENTThe American College of Emergency Physicians designates this live activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)TM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

ACEP Category I Credit StatementApproved by the American College of Emergency Physicians for 1.0 hour(s) of ACEP

Category I credit.

3

Instructions to Receive Credit

To receive credit for your participation in this educational activity:

• Read the objectives and other introductory CME information

• Complete the preassessment located in your handout materials

at the start of the activity

• Participate in the hemophilia A presentation

• Complete the postassessment/evaluation located in your handout

materials at the conclusion of the activity

4

Faculty and Disclosures (Cont’d)

Activity Co-Chair/Faculty Presenter:

Colin G. Kaide, MD, FACEP, FAAEM

Associate Professor of Emergency Medicine

Specialist in Hyperbaric Medicine

Department of Emergency Medicine

Wexner Medical Center at The Ohio State University

Columbus, OH

Dr Kaide has disclosed the following relationships:

Consulting Fees: Portola Pharmaceuticals, Inc

Ownership (stocks, stock options, or other ownership interest excluding

diversified mutual funds): Callibra, Inc

5

Faculty and Disclosures

Activity Co-Chair/Faculty Presenter:

Joanna A. Davis, MD

Associate Professor of Clinical Pediatrics

Medical Director, Comprehensive Pediatric Hemophilia Treatment Center

Associate Director, Pediatric Hematology-Oncology Fellowship Program

University of Miami Miller School of Medicine

Miami, FL

Dr Davis has disclosed the following relationships:

Consulting Fees: Bayer Pharmaceuticals; CSL Behring; Genentech, Inc; Shire

Fees for Non-CME Services: Bioverativ; Genentech, Inc; Shire

6

Off-Label Statement and Disclaimer

This educational activity will contain discussion of published and/or investigational uses of agents that are not indicated by the FDA, specifically the use of emicizumab for the treatment of hemophilia A without inhibitors. Faculty have been asked to indicate such discussion at the time of their mention. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of the planners. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

7

Learning Objectives

Upon completion of this activity, learners should be better able to:

• Recognize signs of hemophilia A bleeding episodes in the ED and initiate

appropriate therapy in a timely manner

• Identify hemophilia A patients who have likely developed inhibitors to FVIII

treatment and select the appropriate screening tests

• Identify patients who do not have hemophilia A, but who may have

developed an acquired inhibitor to FVIII

• Select effective and safe treatment for patients with hemophilia and those

with inhibitors to FVIII who present to the ED

• Collaborate with hematologists and HTCs to optimize treatment of

hemophilia A and congenital or acquired inhibitors in the ED

8ED, Emergency Department; FVIII, Factor VIII; HTCs, hemophilia treatment centers.

Case Study 1

An 18-year-old male with a history of hemophilia A presents after a bicycle

accident. He was riding his bike when he accidentally rear-ended a parked

car. He was not wearing a helmet and struck his head on the back

windshield of the vehicle. He denies loss of consciousness. He complains of

significant discomfort in his left upper quadrant and in both knees.

9

Case Study 1 (Cont’d)

Physical examination:

Alert and oriented x 3. He has a scalp hematoma on the top of his head. No

CTLS spine tenderness. Clear lungs bilaterally. Heart sounds are normal.

He has significant swelling to his knees bilaterally and exquisite tenderness

to palpation in the left upper quadrant. Neurologic exam is normal.

Previous medical history: Hemophilia A and previous episodes of

hemarthrosis. He does not recall when he last infused FVIII concentrate.

Lab results: CBC is remarkable only for a Hb of 9.5 g/dL (his baseline is 13

g/dL measured at an outpatient appointment 2 weeks ago).

10CBC, complete blood count; CTLS, cervical, thoracic, lumbar, sacral; Hb, hemoglobin.

Questions

• What imaging should be ordered immediately for this

patient?

• What should occur prior to the performance of the imaging?

• What additional information would be helpful in planning

therapy

for this patient?

11

Hemostasis and Hemophilia

Hemostasis

• The body’s effort to regulate coagulation through three distinct but

sequential processes1:

‒ Vessel constriction

‒ Platelet aggregation (Primary hemostasis)

‒ Activation of clotting cascade to form fibrin (Secondary hemostasis)

• Dependent upon the equilibrium between procoagulant and

anticoagulant factors2

• Primary and secondary hemostasis are intimately intertwined, yet function

independently and have their own set of diseases and malfunctions

‒ Bleeding patterns are different

‒ They are identified with different tests

13

1. Colman RW, Marder VJ, Clowes AW, George MD, and Goldhaber SZ. Hemostasis and Thrombosis: Basic Principles and Clinical Practice.

5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005.

2. Blanchette VS, Breakey VR, and Revel-Vilk. SickKids Handbook of Pediatric Thrombosis and Hemostasis. Basel, Switzerland: Karger; 2013.

von Willebrands Factor attaches...

Platelets adhere via vWF to endothelium...

Injury causes exposure of subendothelium...

Primary Hemostasis

14

Thromboxane A2Platelet Activating Factor

SerotoninADP

Fairy Dust

Exposed

Collagen

15

Secondary Hemostasis: Coagulation

• The coagulation cascade is initiated

‒ Contact Activation Pathway (Intrinsic Pathway)

‒ Tissue Factor Pathway (Extrinsic Pathway)

• Tissue Factor (on fibroblasts and leuks)

• Inhibitors of the pathway are generated to control the

reaction

16

Tissue Factor

Pathway (Extrinsic)

Contact Activation

Pathway (Intrinsic)

The Pathways

17

Collagen

10a

7

TF

9

8

II

12

Hemophilias

Common

Pathway

The Final Product

18

It’s all about fibrinogen (Fx I)… to fibrin

Xa V

19

Cross-linking of fibrin and

plateletsstrengthens

the clot

Exposed

Collagen

Bleeding Patterns

Platelet disorders/vWD (Primary hemostasis)

• Cutaneous, mucosal

‒ GI and menstrual bleeding

‒ epistaxis

‒ Intracranial hemorrhage is possible

• All are capillary bleeding

Coagulopathy (Secondary hemostasis)

• Bleeding occurs in the muscles, joints, soft tissues,

genitourinary system, and CNS

• Trauma – delayed bleeding 8-72 hours may be seen

21CNS, central nervous system; vWD, von Willebrand disease.

Some Clinical Pearls…

22

Gingival or

Mucosal Bleeding

vWD or

platelet abnormalities

Hemarthrosis or

Lumpy Hematomas

Coagulopathy

(hemophilia A or B)

thin

k

thin

k

Hemophilia

23

An X-linked, recessive hereditary

disorder in which clotting protein VIII or

IX is missing or present in low levels

Factor VIII deficiency (hemophilia A)

affects 1 in every 5000 to 7000 males1

Factor IX deficiency (hemophilia B)

affects 1 in every 25,000 to 30,000

males1

Levels of SeverityNormal clotting factor in blood is 50% to 150%2

Levels of SeverityNormal clotting factor in blood is 50% to 150%2

MODERATE

1% to 5%

SEVERE

<1%

MILD

5% to 50%

1. Roberts HR, et al. In: Kaushansky K, et al, eds. Williams Hematology. 8th ed. New York, NY: McGraw-Hill Companies, Inc; 2010:2009-2029.

2. Butler RB. Basic Concepts of Hemophilia: a Self-Study and Planning Workbook for Families With a New Diagnosis of Hemophilia. Atlanta, GA:

CDC; 2007.

Severe disease accounts for 60% of cases

Genetics of Hemophilia

The hemophilia gene is on the X chromosome

• Females have two X chromosomes

• Males have one X chromosome and one Y chromosome

• Females with an affected X chromosome are carriers

• Males with an affected X chromosome have the disease

24

Butler RB. Basic Concepts of Hemophilia: a Self-Study and Planning Workbook for Families With a New Diagnosis of Hemophilia.

Atlanta, GA: CDC; 2007.

Inheritance Based on Who Has What!

25

X-linked recessive inheritance

When a Person With Hemophilia and a Female Carrier Mate

26

Clinical Features of Hemophilia

27

Severity of bleeding tendency depends on the factor level

Moderate (1%-5%)

• Bleed after

injury, surgery

• May have

occasional

spontaneous

bleeding

Severe (<1%)

• Frequent

spontaneous

bleeding

• Diagnosis

made in early

childhood

Mild (>5%)

• Bleed only

after severe

injury, trauma,

or surgery

• May not be

diagnosed until

adulthood

World Federation of Hemophilia. Severity of Hemophilia. Updated May 2012. https://www.wfh.org/en/page.aspx?pid=643. Accessed August 23, 2018.

Bleeding Classifications

• Minor

‒ Early hemarthrosis

‒ Mild soft tissue

‒ Mild muscular

• Moderate

‒ Definite hemarthrosis

‒ Moderate muscular

‒ Hematuria

‒ Dental

‒ Epistaxis (rare)

• Severe

‒ CNS

‒ Retroperitoneum

‒ Retropharynx

‒ Surgery

‒ GI

28GI, gastrointestinal.

Hemarthrosis

29

Ankle

Elbow

Knee

Hip

Shoulder

Most frequently affected joints:

knees, elbows, & ankles

TARGET JOINT:

Repeated bleeding in the same joint

Hemophilic Arthropathy

Persistent intra-articular blood

results in progressive

degeneration of the joint

cartilage and bone

World Federation of Hemophilia. Hemophilia in Pictures: Educator’s Guide. Published 2008. http://www1.wfh.org/publication/files/pdf-1318.pdf.

Accessed August 23, 2018.

Signs and Symptoms of Hemarthrosis

• Tingling or bubbling sensation

• Pain, stiffness

• Swelling

• Impaired range of motion

• Heat

• Inability to bear weight or use the limb

30Christine Lee, Erik E. Berntorp, W. Keith Hoots, eds. Hemophilia. 2nd ed. Hoboken, NJ: Wiley-Blackwell; 2010.

Hemarthrosis

• Hemarthrosis, primarily involving the ankles, knees,

and elbows, has been the most common complication

of hemophilia

‒ 45% experience a joint bleed within the first year of life

‒ 90% have at least one joint bleed by 4 years of age

• 90% of those with severe hemophilia have chronic

degenerative changes due to recurrent hemarthrosis in

at least one joint by age 25

‒ 40% report restricted physical activities due to arthropathy

31

Lafeber FP, et al. Haemophilia. 2008;14(Suppl 4):3-9.

Valentino LA, et al. Semin Hematol. 2008;45(2 Suppl 1):S50-S57.

How Many Bleeds Does It Take to Damage a Joint?

• “…there are currently no standard criteria for determining

unacceptable bleeds”1

• “…there are no established criteria for determining how

many joint bleeds can be tolerated before irreversible

damage occurs.”2

• “It is unclear how many joint bleeds are needed to cause

arthropathy in patients with haemophilia; this may be

subject to inter-individual variation.”3

• “Structural joint damage may occur after just a few (or no)

hemarthroses or may develop after numerous joint

bleeding episodes in those who appear to be protected

from the adverse effects of blood.”4

32

1. Petrini P, et al. Haemophilia. 2007;13 Suppl 2:16-22.

2. Santagostino E, et al. Haemophilia. 2008;14 Suppl 6:16-19.

3. Richards M, et al. Br J Haematol. 2010;149(4):498-507.

4. Valentino L. J Thromb Haemost. 2010;8(9):1895-1902.

Spontaneous Retroperitoneal Bleed

33

• 52-year-old with severe

hemophilia B

• Spontaneous bleed

Is It Really Hemophilia?

Is It Abuse or a Bleeding Disorder?

35

Is It Abuse or a Bleeding Disorder?

36

Is It Abuse or a Bleeding Disorder?

• Children who present with bleeding/bruising suggestive of abuse require

careful evaluation for an underlying bleeding disorder

‒ The presence of a bleeding disorder DOES NOT rule out abuse

‒ The presence of trauma (accidental or nonaccidental) DOES NOT rule out a bleeding

disorder

• Any bruising in a nonmobile child is highly suspicious for abuse

• BUT: bleeding disorders can present with bruising/petechiae in sites of

normal pressure or handling

• Consultation with a hematologist is recommended:

‒ Specific, expanded testing is necessary

‒ Preliminary testing, along with history and clinical evaluation, suggests the possibility

of a coagulopathy

37Anderst JD, et al. Pediatrics. 2013;131(4):e1314-e1322.

When Is Bruising Just Easy Bruising?

38

• Occurs mainly on the lower extremities

• No petechiae, purpura, mucosal hemorrhage, telangiectasias

• Negative family history/social/drug history

• Normal physical examination

• Normal baseline laboratory panel

Bleeding Disorders in Women

WOMEN DO HAVE

BLEEDING DISORDERS!

BY THE WAY:

4040

The National Hemophilia Foundation estimates that one million women and girls in the US have a bleeding disorder but only 20,000 know about it

41

Menorrhagia – Heavy Menstrual Bleeding

• Who is affected?

‒ ~ 90% of women with an underlying inherited bleeding disorder (platelet dysfunction,

deficiency of fibrinogen, factors V, VII, VIII, IX, XI, XIII, and other rare disorders)

‒ ~ 70% of women taking an anticoagulant

• Consequences of HMB

‒ Iron-deficiency anemia

‒ Hysterectomy during reproductive years

‒ High healthcare costs

‒ Poor quality of life

• 50% of hysterectomies performed in the 1990s can be attributed to an

undiagnosed bleeding disorder

42

HMB, heavy menstrual bleeding.

Nichols WL, et al. Haemophilia. 2008;14(2):171-232.

von Willebrand Disease (vWD)

• Most common inherited bleeding disorder

• Estimated to occur in 1%-3% of the population

• Affects all racial groups

• Men and women equally affected

• Affects up to 2.5 million American women

• Fewer than 15,000 are diagnosed

• Variable clinical manifestations

43

Ewenstein B. Annu Rev Med. 1997;48:525-542.

Hambleton J. Curr Opin Hematol. 2001;8:306-311.

Murray E, et al. Transfus Med Rev. 1996;10:93-110.

Werner EJ, et al. J Pediatr. 1993;123:893-898.

von Willebrand Factor

• Carries FVIII in the blood

and protects it from

degradation

• Allows platelets to adhere

to the injured endothelium

• Defects/deficiencies can

manifest as a platelet

disorder or coagulopathy

44

Platelet

disorder horn Coagulopathy

horn

von Wildebeest!

Bleeding in vWD

• The type of vWD is primarily based on the structure and function of the

building blocks, or “multimers” of the vW antigen (this cannot be

evaluated in the ED).

• Manifestations may be intermittent and inconsistent throughout a lifetime

• Laboratory analyses, especially the aPTT, may be normal, or only mildly

normal

45aPTT, activated partial thromboplastin time; PTT, partial thromboplastin time; vW, von Willebrand.

Bleeding in vWD

• There is a spectrum of severity with much overlap between categories

‒ Type I (80%-90%): structurally/functionally normal protein; decreased quantity

• Epistaxis, heavy menstrual bleeding, petechiae/bruising

• Occasionally can have more severe bleeding

‒ Type II (10%-15%): usually normal quantity of vW antigen; structurally/functionally

abnormal

• GI bleeding not uncommon with one subvariant

• +/- prolonged PTT

• +/- hemophilia-type bleeding (ie, muscular, joint, or other internal bleeding)

‒ Type III (1%-5%): the most severe form; absence of vW antigen AND FVIII

• Prolonged PTT (coagulopathy)

• Mucosal bleeding

• Hemophilia-type bleeding

46aPTT, activated partial thromboplastin time; PTT, partial thromboplastin time; vW, von Willebrand.

Did you know that the incidence of vWD is high in Doberman pinschers?

Why Haven’t I Heard Much About vWD?

1. Incorrectly thought to be rare

2. Physicians and nurses are not familiar with vWD

3. Lack of public awareness

4. Can be hard to diagnose

5. Bleeding disorders are often considered to affect only males

6. Many people with this disorder have very mild symptoms

7. Many people with vWD are undiagnosed unless a family member is

identified or when pre-surgical lab tests are done

47

Female Carriers of Hemophilia

X – gene for normal production of FVIII

or factor IX

Xh – gene for hemophilia (absent or

deficient production of FVIII or factor IX)

48

X

Xh

FVIII and Factor IX Expression Levels in Carriers

• Clotting factor levels

‒ Vary from one carrier to another

‒ FVIII levels are variable over time

‒ Data on factor IX level are conflicting

• Most carriers have no symptoms (there is enough clotting

FVIII or factor IX to control bleeding)

• Female carriers with lower than normal levels are

considered mild hemophiliacs

‒ If they have trauma or surgery, they may bleed longer than normal

and need to be treated as a hemophilia patient

• It is recommended that carriers know what their levels are

so that appropriate treatment decisions can be made

49

Carrier State – Asymptomatic Carrier

• Most cells will make a normal

amount of FVIII or factor IX

• This woman will have a normal

coagulation profile and will not

bleed excessively

50

X

Xh

X

Xh

X

Xh

X

Xh

X

Xh

X

Xh

X X X

XhXX

X normal gene

Xh

hemophilia gene

Carrier State – Asymptomatic Carrier?

• Most cells will not make very

much or any FVIII or factor IX

• This woman will have an

abnormal coagulation profile

and will have symptoms of a

bleeding disorder

51

X normal gene

Xh

hemophilia gene

X

Xh

X

Xh

X

Xh

X

Xh

X

Xh

X

Xh

Xh Xh Xh

XXhXh

Case Study 2

A 20-year-old Caucasian woman presents to the ED with profuse vaginal

bleeding associated with her period. Her periods are “always heavy,”

typically lasting 9 days. She needs to change double overnight pads every

2 hours on 5 of those days. In addition, she passes quarter-sized clots and

floods her clothing. She is not sexually active and does not take any

medications. She has been treated for iron deficiency intermittently since

menarche at age 13. She has no other bleeding symptoms.

52

Case Study 2 (Cont’d)

Family history:

Brother and 2 sisters are well with no bleeding manifestations. Mother has never experienced menorrhagia or postpartum hemorrhage. Mother has an identical twin sister who has a 5-year-old boy with severe hemophilia A.

Lab results:

Hb 8.2 g/dL; MCV 62 fl; platelet count 345,000 per mcL; PT 12 s; aPTT 35 s (ULN 34 s)

53

• Could this young woman have mild hemophilia A?

• If so, how could that be possible?

• Could this young woman have vWD?

MCV, mean corpuscle volume; ULN, upper limit of normal.

If a Woman…

• Has a 20% FVIII or factor IX level

• Has normal von Willebrand antigen/ristocetin cofactor and multimers, and

• Requires factor concentrates, desmopressin acetate (hemophilia A only),

tranexamic acid or birth control pills to manage bleeding due to trauma,

surgery or menstruation…

She has hemophilia A

54

Diagnostic Challenges: Women With Hemophilia A or Type I vWD

• PT/PTT and FVIII levels may NOT be diagnostic

• FVIII is paired with the large von Willebrand protein

• This complex is stored in endothelial cells – the cells that line the blood vessel walls

• Situations that cause a stress response, or “adrenaline rush” will release this FVIII/vWF into the bloodstream and can temporarily raise the circulating level of FVIII or vWF to normal levels (the PTT will also be normal)

• This false correction of the PTT and FVIII can occur if the woman:‒ Is worried/anxious/scared/nervous

‒ Has a fever or infectious problem

‒ Has hyperthyroidism

‒ Is pregnant

‒ Is taking estrogen-based contraceptive pills/patches/implants

55vWF, von Willebrand factor.

Acquired Hemophilia:Spontaneous Inhibitors

Case Study 3

A previously healthy 58-year-old Hispanic man presents to your ED with the

sudden onset of profuse bright red rectal bleeding. He neither smokes nor

drinks and underwent an elective colonoscopy 6 months ago which did not

reveal any lesions. He takes neither prescription nor over-the-counter

medications. He denies recent fever, URI, or gastroenteritis. He denies

foreign travel, exposure to pets or pesticides.

57URI, upper respiratory infection.

Case Study 3 (Cont’d)

Physical examination:

Multiple large ecchymoses over his torso and extremities; oozing from his

gums and nares, as well as from venipuncture sites

Previous medical history: No history of joint pain/arthritis; has undergone

dental extractions and hernia repair without complications

Lab results: CBC is remarkable only for an Hb of 6.4 g/dL with normal RBC

indices, WBC, platelet count; PT/INR 12 s/1.0; aPTT > 120 s

58

• What lab test should be ordered ASAP?

• Could your patient be a previously undiagnosed

congenital hemophiliac?

INR, international normalized ratio; PT, prothrombin time; RBC, red blood cell; WBC, white blood cell.

Mixing Study in a Patient With Prolonged PT and/or PTT

• Mix equal volumes of patient and normal plasma

• Factor deficiency: mixture will correct PT or PTT

• Inhibitor: the target protein will be inactivated in the

normal plasma and the PT +/- PTT will remain prolonged

59

Normal SampleTest Sample

PT or PTT

Normalized

PT or PTT

Factor

Deficiency

PT or PTT

Inhibitor

Acquired Hemophilia: What Is It?

• Rare autoimmune disorder

• Overall incidence is ~ 1.5 per million/year

• Caused by an autoantibody (inhibitor) to FVIII – IgG

• Interferes with coagulant function of FVIII

• Predisposes affected individuals to severe, potentially

life-threatening bleeding

60

IgG, immunoglobulin G.

Janbain M, et al. J Blood Med. 2015;6:143-150.

Acquired Hemophilia: Epidemiology

• 0.045/million (45/billion) annually in children <16 years of age

• 14.7/million annually in persons >85 years of age

• Incidence increases with age

‒ ~10% of acquired hemophilia patients are women of childbearing age, diagnosed

during or after a pregnancy

‒ >80% of patients are men and women over the age of 65 years

• 50% of patients have an underlying medical condition; treatment of

underlying condition eliminates the inhibitor and resolves the bleeding

‒ Another autoimmune disorder

‒ Undiagnosed malignancy

‒ Drug/allergic reaction

61Janbain M, et al. J Blood Med. 2015;6:143-150.

Manifestations of Acquired Hemophilia

• Spontaneous or provoked bleeding

‒ Spontaneous subcutaneous hematomas

‒ Extensive bruising

‒ Muscle/renal/GI/intracranial/head and neck bleeding

• Unexplained, prolonged aPTT in a person with a negative personal or

family history of a coagulopathy

‒ 50% of patients in a large European study had no symptoms but the prolonged aPTT

was an incidental laboratory finding

63Janbain M, et al. J Blood Med. 2015;6:143-150.

Manifestations of Acquired Hemophilia (Cont’d)

• Hemarthrosis—the hallmark of severe congenital hemophilia A—is rare

• Severe, life-threatening bleeds occur in 70%-90% of patients

• Fatal bleeding occurs in 5%-10% of patients

• Overall mortality has been reported up to 42% in some studies, usually within

the first 4-6 weeks after presentation

• Severity of bleeding, morbidity, and mortality is affected by various factors:‒ Diagnostic delay (inadequate recognition of an acquired inhibitor as a cause of bleeding)

‒ Inadequate/inappropriate management of bleeding – FFP/cryoprecipitate/FVIII infusions

will not help

‒ Bleeding complications during invasive procedures

‒ Inadequate recognition of underlying condition and delay in initiating therapy

‒ Secondary effects of interventions for underlying condition

64FFP, fresh frozen plasma.

Franchini M, et al. Hematology. 2017;22(9):514-520.

Congenital Hemophilia With Inhibitor Development

Inhibitor Development in Persons With Hemophilia

• The most serious complication of hemophilia today

• Inhibitors are IgG antibodies

‒ Most develop within the first 10-20 exposures

• More common in individuals with severe gene defects (eg, gene deletion,

inversion, nonsense, or frameshift mutations)

• Twice as common in African American patients compared to Caucasian patients

• Frequency‒ Severe hemophilia A: 20%-30%

‒ Mild and moderate hemophilia A: 3%-13%

‒ Severe hemophilia B: 5%

• Factor replacement is often ineffective

• Increased morbidity and mortality

• Increased surgical challenges

66Viel KR, et al. N Engl J Med. 2009;360(16):1618-1627.

FVIII Inhibitors

• Previously thought that almost all inhibitors in those with severe

hemophilia A developed after only a few exposures, early in life

• Current evidence shows that inhibitors arise throughout life, with a

bimodal risk

67Hay CRM, et al. Blood. 2011;117(23):6367-6370.

Persons With Inhibitors Have More Hospital

Admissions and Higher Healthcare Expenditures

68Armstrong EP, et al. J Med Econ. 2014;17(11):798-802.

Percentage of persons with at least one

hospitalization within 5 years by inhibitor status

Median aggregate overall healthcare costs

per year by inhibitor status

0

10

20

30

40

50

60

70

80

90

100

Persons withhemophilia A and

inhibitors

Persons withhemophilia A without

inhibitors

Persons withhemophilia B without

inhibitors

Pe

rso

ns w

ith

≥1

ho

sp

itali

za

tio

n (

%)

(n=7)

(n=155) (n=52)

$0

$50,000

$100,000

$150,000

$200,000

$250,000

$300,000

$350,000

Persons withhemophilia A and

inhibitors

Persons withhemophilia A without

inhibitors

Persons withhemophilia B without

inhibitors

Pe

rso

ns w

ith

≥1

ho

sp

itali

za

tio

n (

%)

(n=7)

(n=155)

(n=52)

Clinical Features of Hemophilia With Inhibitors

69

Clinical Features of Hemophilia With Inhibitors (Case Example)

• 26-year-old with severe hemophilia A

and FVIII inhibitor

• Recurrent traumatic and spontaneous

knee bleeds

• Left side surgically replaced

• Note severe muscular atrophy

• Following right TKA he became fully

ambulatory (again)

70TKA, total knee arthroplasty.

Hemophilia Treatment Paradigm

Hemophilia Treatment Paradigm

• The WFH primary aim of hemophilia care is to

“prevent and treat bleeding by replacing deficient

clotting factor”1

• Factor replacement is administered

intravenously2:

‒ On-demand

‒ Prophylaxis

• Early and appropriate treatment of each bleeding

episode is critical to minimize complications1

72

Remember: Treat first, diagnose later.

WFH, World Federation of Hemophilia.

World Federation of Hemophilia. Published 2012. Guidelines for the Management of Hemophilia. https://www1.wfh.org/publication/files/pdf-1472.pdf .

Accessed August 23, 2018.

Makris M. Blood Transfus. 2012;10(2):165-168.

Treatment of Bleeding Episodes

Early and appropriate treatment of each bleeding episode is

critical to minimize complications

73

Remember: Treat first, diagnose later.

REPLACEMENT OF DEFICIENT CLOTTING FACTOR IS

THE SINGLE MOST IMPORTANT STEP

IN ANY INTERVENTION

Kitchens CS, Alving BM, and Kessler CM. Consultative Hemostasis and Thrombosis. 3rd ed. Philadelphia, PA: Saunders Elsevier; 2002.

Factor Dosing

Factor dosing is dependent on type, location, and severity of bleeding episode*

• rFVIII: 1 IU/kg raises factor level 2%

‒ Minor: 15-20 units/kg

‒ Major: 20-50 units/kg

‒ Life-threatening: 40-50 units/kg

‒ Half-life: 8-12 hours

• rFIX: 1.2-1.4 IU/kg raises factor level 1%

‒ Minor: 20-40 units/kg

‒ Major: 40-80 units/kg

‒ Life-threatening: 80-100 units/kg

‒ Half-life: 24-48 hours

74

rFVIII, recombinant factor VIII; rFIX, recombinant factor IX.

*Refer to package insert for full dosing information.

Simon TL, McCullough J, Snyder EL, Solheim BG, and Strauss GS. Rossi’s Principles of Transfusion Medicine. Hoboken, NJ: John Wiley & Sons, Ltd; 2016.

Remember: Treat first, diagnose later.

Simplified Factor Dosing*

Bleeding TypeTarget Percent

Correction

Dose of Factor VIII

(IU/dL)

Dose of Factor IX

(IU/dL)

Minor 25% 12.5 units/kg 25 units/kg

Moderate 50% 25 units/kg 50 units/kg

Severe 100% 50 units/kg 100 units/kg

• Minor‒ Early hemarthrosis

‒ Mild soft tissue

‒ Mild muscular

• Moderate‒ Definite hemarthrosis

‒ Moderate muscular

‒ Hematuria

‒ Dental

‒ Epistaxis (rare)

• Severe‒ CNS

‒ Retroperitoneum

‒ Retropharynx

‒ Surgery

‒ GI

*Calculations based on factor dosing recommendations. Refer to package insert for full dosing information.

Factor VIII Dosing Calculator. https://mprcalc2.usbmis.com/24535.html. Accessed October 18, 2018.

Factor IX Dosage Calculator. https://www.empr.com/medical-calculators/factor-ix-dosage-calculator/article/170191/. Accessed October 18, 2018.

Treatment of Bleeding in Patients With Inhibitors

Bypassing agents:

• Recombinant factor VIIa (rFVIIa, NovoSeven ®)

• Activated prothrombin complex concentrates (aPCC, FEIBA®)*

76*Not effective for hemophilia B.

FEIBA, Factor VIII inhibitor bypassing activity; rFVIIa, recombinant factor VIIa.

FEIBA aka aPCC

• Factor Eight Inhibitor Bypassing Activity

• Activated PCC

‒ A mix of factors 2, 7, 9 and 10 with some activated forms.

‒ Activated factor 7 occurs in the highest quantity.

• Bypasses the need for factor 8 to be present in order to activate

coagulation.

77

Bypassing Therapy for Treatment of Bleeds: rFVIIa

• Pros

‒ Small volume

‒ Recombinant

• Cons

‒ Half-life 2/4 hours

‒ 2-4 hour dosing for major bleeds

‒ Daily for prophylaxis

‒ Thrombotic

‒ Cost

78

Bypassing Therapy for Treatment of Bleeds: aPCCs

• Pros

‒ Half-life 8-12 hours

‒ 1-2 x per week for prophylaxis

• Cons

‒ Large volume

‒ Plasma product

‒ Thrombotic

79

Two Bypassing Agents: Which Is Better?

• 80% efficacy for bleeding events

• FEIBA NovoSeven Comparative Study

‒ Prospective randomized crossover study of aPCC compared to rFVIIa to treat

joint bleeds

‒ Primary endpoint control of bleeding at 6 hours

‒ Results showed similar efficacy

‒ More discordance than anticipated indicating individual variability in response to

bypassing agents

80Astermark J, et al. Blood. 2007;109(2):546-551.

Change the Focus: Thrombin Generation, Not Factor Replacement: Novel Therapies

81

AT, antithrombin deficiency; TF, tissue factor; TFPI, tissue factor pathway inhibitor.

Dargaud Y, et al. Thromb Haemost. 2005;93(3):475-480.

Emicizumab-kxwh Bispecific Antibody (Hemlibra®)

• A bispecific IgG antibody that binds FIXa and FX, mimicking the function of FVIII cofactor,

activating FX and promoting thrombin generation1,2

• Commercially available since November 2017 for inhibitor patients3

• Approved for non-inhibitor patients in October 20184

• Indicated as prophylaxis in patients with hemophilia A (with or without inhibitors to FVIII)3,4

• Dosed by subcutaneous injection: weekly, biweekly, monthly4

82

FIXa, activated factor IX; FX, factor X.

1. Kitazawa T, et al. Nat Med. 2012;18:1570-1574.

2. Shima M, et al. Presented at: 2014 ASH annual meeting. Abstract #691; December 14, 2014; San Francisco, CA.

3. US FDA. CDER. Emicizumab BLA 761083. Label 11/16/2017.

4. US FDA. CDER. Emicizumab BLA 761083. Label 10/04/2018.

Emicizumab-kxwh Bispecific Antibody (Hemlibra®)

• IS NOT used alone in patients with bleeding episodes

• Must be combined with bypassing agents such as rVIIa

or FEIBA (with caution)

83

Hemlibra® Boxed Warning: Thrombotic Microangiopathy and Thromboembolism

• Cases of thrombotic microangiopathy and thrombotic events were reported

when on average a cumulative amount of > 100 U/kg/24 hours of aPCC

was administered for 24 hours or more to patients receiving Hemlibra®

prophylaxis.

• Monitor for the development of thrombotic microangiopathy and thrombotic

events if aPCC is administered.

• Discontinue aPCC and suspend dosing of Hemblibra® if symptoms occur.

84US FDA. CDER. Emicizumab BLA 761083. Label 10/04/2018.

MASAC Guidelines for Emergency Department Management of Individuals With Hemophilia and Other Bleeding Disorders

TRIAGE

• Individuals with known bleeding disorders should be triaged urgently

because delays in administering factor concentrate can significantly impact

morbidity and mortality

• Consultation with the patient’s hematologist or a regional HTC professional

is strongly advised, although this should not delay giving clotting factor

concentrate replacement to the patient

85

The CDC (www.CDC.gov) provides a list of all federally funded

HTCs in the US and their contact information.

MASAC, Medical and Scientific Advisory Council of the National Hemophilia Federation.

National Hemophilia Foundation. MASAC Report No. 252. September 17, 2017.

MASAC Guidelines for Emergency Department Management of Individuals With Hemophilia and Other Bleeding Disorders (Cont’d)

ASSESSMENT

• Treatment for a suspected bleeding disorder is based on clinical history

• Physical findings may be NORMAL in the early phases of most hemophilic bleeds

• Spontaneous bleeding is common in individuals with severe disease (<1% factor level)

• WHEN IN DOUBT, ADMINISTER CLOTTING FACTOR REPLACEMENT IMMEDIATELY

– DO NOT DELAY FOR IMAGING STUDIES, LAB RESULTS, OR CONSULTATIONS

• Treatment decisions should be based on the SUSPICION of a bleeding-related problem

• If the patient or parent of a patient suspects that occult bleeding is occurring, administer

clotting factor replacement

• Established patients often bring home supply of factor and dosing guidelines to the ED

86National Hemophilia Foundation. MASAC Report No. 252. September 17, 2017.

MASAC Guidelines for Emergency Department Management of Individuals With Hemophilia and Other Bleeding Disorders (Cont’d)

DIAGNOSTIC STUDIES

• Clotting factor should be given before any diagnostic studies are performed, especially

in case of head trauma, abdominal trauma or suspected ICH

• Routine joint bleeds do NOT require imaging

• For the established patient, routine surveillance labs (PT, PTT, factor levels) are NOT

indicated unless requested by the patient’s hematologist

• If an invasive procedure is required (ie, lumbar puncture, ABG, lung/joint tap) OR if

surgery is indicated, clotting factor to raise the patient’s level to 100% must be

administered in the ED prior to the procedure

87ABG, arterial blood gases; ICH, intracranial hemorrhage.

National Hemophilia Foundation. MASAC Report No. 252. September 17, 2017.

Every Patient Represents a Unique Challenge

88

A single, severity-based, therapeutic model does not represent the

optimal treatment strategy for all patients with hemophilia1

Individualization of hemophilia care is recommended

Patient’s bleeding patternLevel and timing of

physical activityCondition of the patient’s

musculoskeletal system

Individual

pharmacokinetic profile

Central venous access Presence of target jointPatient likelihood of

good adherencePsychosocial factors

Factors to consider for individualized treatment1-4

1. Sorenson B, et al. Blood Coagul Fibrinolysis. 2003;14(5):469-477.

2. Collins PW. Haemophilia. 2012;18(Suppl 4):131-135.

3. Oldenburg J. Blood. 2015;125(13):2038-2044.

4. Valentino LA. Haemophilia. 2014;20(5):607-615.

Patient-Centered Care Is Beneficial

• Better recovery from patients’ discomfort and concern1

• Better emotional health1

• Fewer diagnostic tests and referrals1

• Better adherence2

• Overall better outcomes3

89

1. Stewart M, et al. J Fam Pract. 2000;49(9):796-804.

2. Zolnierek KB, et al. Med Care. 2009;47(8):826-834.

3. Street RL, et al. Diabetes Care. 1993;16(5):714-721.

Patients and their families like to know about treatment

options and want to be involved in decision making.

Essential Steps of Shared Decision Making

90

The SHARE Approach:

Seek patient’s participation

Help patient explore and compare treatment options

Assess patient’s values and preferences

Reach a decision with patient

Evaluate patient’s decision

S

H

A

R

E

AHRQ. The Share Approach – Essential Steps of Shared Decision Making.

https://www.ahrq.gov/professionals/education/curriculum-tools/shareddecisionmaking/tools/tool-1/index.html. Accessed August 23, 2018.

Comprehensive Care

91

Nurse Coordinator

Psychologist

Primary Care Physician

Dentist

Orthopedist

Radiologist

Geneticist

Hematologist

Social Worker

Physical Therapist

Soucie JM, et al. Blood. 2000;96(2):437-442.

Does Comprehensive Care Work?

92Soucie JM, et al. Haemophilia. 2001;7(2):198-206.

Patients receiving hemophilia care outside an HTC

have a 67% higher mortality rate and a 40% higher

hospitalization rate for bleeding complications

Take-Home Messages

• Beware of delayed bleeding in individuals with hemophilia who have trauma

• Consider the development of an acquired inhibitor to FVIII in the differential

diagnosis of the previously well adult patient with sudden onset profuse bleeding

• Consider a possible undiagnosed bleeding disorder in a woman who presents

with profuse vaginal bleeding/syncope/severe anemia

• Recognize that a joint bleed in a hemophilia patient IS an emergency

• Patients with established hemophilia who present with bleeding should be

infused with factor concentrate prior to imaging/consultative services

• Utilize the nearest HTC if a local hematologist is unavailable/unfamiliar with

bleeding disorder management

93

Questions

Thank YouPlease complete the postassessment and

evaluation located in your meeting handout.