122 Hemophilia A and Hemophilia B

Question 1

Mode of inheritance of hemophilia

Answer 1

Sex-linked/X-linked

Question 2

TRUE O FALSE

In patients with hemophilia, clot formation is delayed because of the decreased thrombin generation.

Answer 2

TRUE

In patients with hemophilia, clot formation is delayed because of the decreased thrombin generation.

Question 3

Hemophilia A results when mutations occur in the F8 gene located on the

Answer 3

Long arm of the X-chromosome (X-q28)

Question 4

TRUE OR FALSE

All the sons of affected hemophilic males are hemophiliacs.

Answer 4

FALSE

All the sons of affected hemophilic males are normal.

• All the daughters are obligatory carriers of the F8 defect.
• Sons of carriers have a 50% chance of being affected
• Daughters of carriers have a 50% chance of being carriers themselves.

Question 5

One of the most common mutations, accounting for 40% to 50% of severe hemophilia A patients, is

Answer 5

“Combined gene inversion and crossing over”

The “inversion–crossing over” mutations result in severe hemophilia, and approximately 20% of these patients are susceptible to developing antibody inhibitors that neutralize factor VIII coagulant function.

In many cases of hemophilia, there is no family history of the disease, and at least 30% of the cases of hemophilia are a result of spontaneous (de novo) mutations.

Question 6

Patients with mild hemophilia A have a ____% lifetime risk of developing inhibitors and usually are diagnosed at an older age when compared with patients with severe hemophilia A.

Answer 6

5% to 10%

Question 7

The main risk factors for the antibody formation

Answer 7

Intensity of exposure to factor VIII and the type of genetic mutation

Question 8

TRUE OR FALSE

Hemophilia A in females is extremely rare

Answer 8

TRUE

Hemophilia A in females is extremely rare

Hemophilia A may occur in females with X chromosomal abnormalities such as Turner syndrome, X chromosomal mosaicism, and other X chromosomal defects.

Usually these manifestations are mild, but they may be serious during surgical procedures or after significant trauma.

Question 9

PRENATAL DIAGNOSIS AND CARRIER DETECTION

The current standard for identifying carrier status is through

Answer 9

Direct gene sequencing

Question 10

PRENATAL DIAGNOSIS AND CARRIER DETECTION

Carriers who harbor the intron 22 inversion or intron 1 inversion can be identified using

Answer 10

Southern blot technique and polymerase chain reaction

If these mutations are found to be absent, sequencing of the complete coding region is performed.

Prenatal diagnosis of hemophilia now can be performed almost routinely.

Question 11

Factor VIII level

Severe

Answer 11

≤1% of normal
(≤0.01 U/mL)

1. Spontaneous hemorrhage from early infancy
2. Frequent spontaneous hemarthroses and
   other hemorrhages, requiring clotting factor replacement

Question 12

Factor VIII level

Moderate

Answer 12

1%–5% of normal
(0.01–0.05 U/mL)

1. Hemorrhage secondary to trauma or surgery
2. Occasional spontaneous hemarthroses

Question 13

Factor VIII level

Mild

Answer 13

6%–40% of normal
(0.06–0.40 U/mL)

1. Hemorrhage secondary to trauma or surgery
2. Rare spontaneous hemorrhage

Question 14

TRUE OR FALSE

Measurement of factor VIII level is not recommended in all carriers.

Answer 14

FALSE

Measurement of factor VIII level is recommended in all carriers.

Carriers with factor VIII levels significantly less than 50%, as a result of imbalanced X chromosome inactivation, may experience excessive bleeding after trauma (eg, childbirth or surgery).

Question 15

Hemarthroses

The joints most frequently involved, in decreasing order of frequency

Answer 15

Ankles, knees, elbows, shoulders, wrists, and hips

Question 16

Hemarthroses

Type of joints more likely to be involved

Answer 16

Hinge joints

Question 17

Hemarthroses

A major factor in the pathogenesis of hemophilic arthropathy

Answer 17

Iron deposits from residual blood

Question 18

Hemarthroses

Radiologic stages of hemophilic arthropathy

Answer 18

• Stage 0: normal joint
• Stage 1: fluid in the joint
• Stage 2: some osteoporosis and epiphyseal overgrowth; Epiphysis is wide
• Stage 3: subchondral bone cysts, Joint spaces exhibit irregularities
• Stage 4: prominent bone cysts with marked narrowing of joint space
• Stage 5: Obliteration of jointspace with epiphyseal overgrowth

Question 19

Defined by the occurrence of three or more spontaneous bleeds within a 6-month period.

Answer 19

Target joint

The joints most often involved are the ankles, knees, and elbows, which become chronically swollen.

Question 20

Hemorrhages occur into muscle in the following order of frequency:

Answer 20

Calf, thigh, buttocks, and forearm

Question 21

Bleeding into fascia and muscle can result to a hemorrhage in a confined space compresses the arterial vasculature resulting in ischemic muscle injury

Answer 21

Compartment syndrome

Question 22

TRUE OR FALSE

Bleeding into the myocardium or erect penis is very unusual, perhaps explained by the high concentration of tissue factor in these tissues.

Answer 22

TRUE

Bleeding into the myocardium or erect penis is very unusual, perhaps explained by the high concentration of tissue factor in these tissues.

Question 23

Blood cysts that occur in soft tissues or bone

Answer 23

Pseudotumors

• Not associated with pain unless rapid growth or nerve compression occurs
• Tend to expand over several years and eventually become multiloculated

Question 24

Three types of pseudotumors

Answer 24

• Type 1- simple cyst that is confined by tendinous attachments within the fascial envelope of a muscle
• Type 2 - initially develops as a simple cyst in soft tissues such as a tendon, but it interferes with the vascular supply to the adjacent bone and periosteum, resulting in cyst formation and resorption of bone
• Type 3- is thought to result from subperiosteal bleeding that separates the periosteum from the bony cortex

Question 25

Pseudotumors often develop in what part of the body:

Answer 25

Lower half of the body
Usually in the thigh, buttock, or pelvis

But they can occur anywhere, including the temporal bone

Question 26

Imaging useful in the diagnosis of pseudotumor

Answer 26

CT or magnetic resonance imaging

Question 27

A reliable treatment of pseudotumor

Answer 27

Operative removal of the entire mass

Because the pseudotumor likely will reform if it is not completely removed

Needle biopsies of pseudotumors should be avoided because of the risk of infection and hemorrhage.

Embolization, percutaneous drainage, exeresis and filling of the dead cavity, and radiotherapy of a pseudotumor have been reported and may be of value in patients with inhibitors when surgery is not possible.

Question 28

Most genitourinary bleeding/hematuria arises from the

Answer 28

Renal pelvis

Usually from one kidney but occasionally from both

Question 29

TRUE OR FALSE

Antifibrinolytic agents, such as aminocaproic acid and tranexamic acid, should be avoided in individuals with hematuria because of the risk of forming clots and producing obstructing clots in the ureter and bladder

Answer 29

TRUE

Antifibrinolytic agents, such as aminocaproic acid and tranexamic acid, should be avoided in individuals with hematuria because of the risk of forming clots and producing obstructing clots in the ureter and bladder

Question 30

Recommended factor level before performing a lumbar puncture

Answer 30

50% of normal

Question 31

The most frequent surgical procedure performed on patients with hemophilia

Answer 31

Dental extraction

Appropriate factor VIII replacement therapy, sometimes supplemented by antifibrinolytic agents, can prevent intraoperative and postoperative hemorrhages

Patients with hemophilia are treated with clotting factor preoperatively and postoperatively to prevent bleeding.

Question 32

PT or aPTT

Patients with severe hemophilia A have a prolonged

Answer 32

Activated partial thromboplastin time (aPTT)

The prothrombin time (PT) and thrombin clotting time are normal.

Question 33

How to detect if the hemophilic plasma contains an anti–factor VIII inhibitor antibody

Answer 33

Mixing studies

Hemophilic plasma is mixed with an equal volume of normal plasma
The aPTT on a similar mixture is prolonged, but incubation of the mixture for one or two hours at 37  C is sometimes required to detect the prolongation.

Question 34

A definitive diagnosis of hemophilia A should be based on

Answer 34

Specific assay for factor VIII activity

• Functional factor VIII coagulant activity is measured by one-stage clotting assays based on the aPTT.
• Chromogenic assays for factor VIII activity also are used widely, but do not always agree with one-stage assays.
• Although infrequently measured in practice, factor VIII antigen is measured by immunologic assays, which detect normal and most abnormal factor VIII molecules.

Question 35

If the factor VIII antigen level is normal but the clotting activity is reduced, the patient has a

Answer 35

Dysfunctional factor VIII molecule

• Such patients have antigen-positive hemophilia, also referred to as cross-reacting material (CRM)-positive.
• Patients in whom both the factor VIII antigen level and activity are nearly undetectable are said to be CRM-negative.

Question 36

Differential Diagnosis

Acts as a carrier of factor VIII in vivo

Answer 36

Von Willebrand factor (vWF)

Although factor VIII is synthesized normally in patients with vWD, the half-life of factor VIII is markedly shortened because the vWF “carrier” molecule is decreased or absent.

Question 37

Differential Diagnosis

Other abnormalities in vWD that distinguish vWD from hemophilia A are decreased vWF antigen level, and decreased vWF activity, often measured using the

Answer 37

Ristocetin cofactor activity assay

Question 38

Differential Diagnosis

Type of vWD where factor VIII levels may be very low (<5% of normal), making it difficult to distinguish from classical hemophilia.

Answer 38

Type III vWD

The lack of a sex-linked pattern of inheritance in the family will help in the differential diagnosis.

Question 39

Differential Diagnosis

Variant of vWD in which vWF multimers are normal but plasma factor VIII levels are low.

Answer 39

vWD-Normandy

• Decreased binding of factor VIII to vWF –> shortening of the intravascular survival of factor VIII and thus reduced factor VIII activity
• The Normandy variant of vWD should be suspected in patients with mild hemophilia A who do not exhibit a sex-linked recessive inheritance pattern

Question 40

Differential Diagnosis

TRUE OR FALSE

Only deficiencies of factors VIII and IX cause chronic crippling hemarthroses, with a family history suggestive of an X-linked bleeding disorder.

Answer 40

TRUE

Only deficiencies of factors VIII and IX cause chronic crippling hemarthroses, with a family history suggestive of an X-linked bleeding disorder.

Hemophilia A must be distinguished from other hereditary blood clotting factor deficiencies that exhibit a prolonged aPTT, including deficiencies of factors IX, XI, and XII, prekallikrein, and high-molecular-weight kininogen.

Question 41

Differential Diagnosis

Factor deficiency that occurs in males and females and is a milder hemorrhagic disorder compared with severe hemophilia A or B.

Answer 41

Factor XI deficiency

Question 42

Differential Diagnosis

Factor deficiencies that are not associated with bleeding

Answer 42

Deficiencies of factor XII, prekallikrein, and high-molecular-weight kininogen

Question 43

Differential Diagnosis

Factor deficiencies that causes both the PT and aPTT to be moderately prolonged

Answer 43

Combined deficiency of factors V and VIII

Question 44

TRUE OR FALSE

Aspirin, nonsteroidal antiinflammatory drugs can be given safely to hemophilia patients

Answer 44

FALSE

Avoidance of aspirin, nonsteroidal antiinflammatory drugs, and other agents that interfere with platelet aggregation

Acetaminophen or relatively specific cyclooxygenase (COX)-2 inhibitors such as celecoxib have been recommended, but these drugs can be harmful when taken in excessive doses or for prolonged periods.

Question 45

TRUE OR FALSE

Prophylactic therapy is recommended in all severely affected patients, and it should be initiated before the onset of recurrent hemarthroses (primary prophylaxis) or as directed.

Answer 45

TRUE

Prophylactic therapy is recommended in all severely affected patients, and it should be initiated before the onset of recurrent hemarthroses (primary prophylaxis) or as directed.

Question 46

Blood products that contain factor VIII

Answer 46

Fresh-frozen plasma and cryoprecipitate

A disadvantage of plasma is that large volumes must be infused to achieve and maintain even minimal factor VIII levels.

The highest factor VIII level that can be achieved with plasma is approximately **20% **of normal, which is not always attainable or sufficient for hemostasis.

Question 47

Cryoprecipitate, containing approximately how many units of Factor VIII

Answer 47

80 U of factor VIII in 10 mL of solution

Individual bags of cryoprecipitate must be pooled, the factor VIII dose can only be estimated, and the product must be stored frozen

Question 48

Types of factor VIII concentrates

Answer 48

Plasma-derived factor VIII concentrate
Recombinant factor VIII concentrate

• standard half-life
• extended half-life

Question 49

Half-life of factor VIII

Answer 49

8 to 12 hours

Question 50

1U of factor VIII per kilogram of body weight raises the circulating factor VIII level by approximately ________ U/mL

Answer 50

0.02 U/mL

The site and severity of hemorrhage determine the frequency and dose of factor VIII to be infused.

Question 51

Dose of DDAVP

Answer 51

0.3 mcg per kilogram body weight

• Given intravenously or subcutaneously
• Factor VIII levels increase two- to threefold above baseline in most, but not all, mildly or moderately affected patients with hemophilia A
• *Patients with severe hemophilia A do not respond to DDAVP *
• A concentrated intranasal spray of DDAVP also can be used (150 mcg in each nostril for adults and 150 mcg in one nostril for children weighing <50 kg).

Question 52

The peak response to DDAVP

Answer 52

30–60 minutes after dosing

Question 53

Who can use DDAVP

Answer 53

Patients with mild or moderate hemophilia A and in carriers whose baseline factor VIII levels are less than 0.5 U/mL, DDAVP may be used in lieu of blood products

Question 54

Side efffect of DDAVP

Answer 54

Hyponatremia

DDAVP is a potent antidiuretic.

Repeated administration of DDAVP results in a diminished response to the agent (tachyphylaxis).

Question 55

Dose of antifibrinolytic agents

Answer 55

Tranexamic acid: 1 g four times per day
EACA: loading dose of 4 g to 5 g followed by 1 gram per hour by continuous IV infusion or 4 g every 4 to 6 hours orally for 2 to 8 days

Question 56

Antifibrinolytic therapy is contraindicated in the presence of

Answer 56

Hematuria

Clots resistant to lysis may obstruct the ureters

Question 57

Fibrin glue/fibrin tissue adhesive contains

Answer 57

Fibrinogen, thrombin, and factor XIII

Question 58

Considered as life-threatening hemorrhages

Answer 58

Retropharyngeal, retroperitoneal, and central nervous system bleeding, whether subdural, subarachnoid, or into the brain parenchym

• Retropharyngeal bleeding: factor VIII levels to normal (1.0 U/mL).
• For retroperitoneal hemorrhage, early treatment is required, and therapy should be continued for 7 to 10 days; otherwise, bleeding may recur upon resumption of activity.
• Even asymptomatic patients with a history of head trauma should receive at least one dose of factor VIII as a prophylactic measure, and this dose should be given before diagnostic procedures such as a CT scan.

Question 59

Replacement of Factor VIII for Surgical Procedures

Answer 59

Raised to normal levels before operation and maintained for** 7 to 10 days or until healing is complete**.

• Treatment can be started a few hours before surgery and continued intraoperatively using a continuous infusion or boluses every 8 to 12 hours.
• Postoperatively, factor VIII levels should be monitored at least one or two times per day to ensure that adequate levels are maintained.
• Because factor VIII may be “consumed” during surgery, factor VIII levels should be monitored intraoperatively and doses of factor VIII higher than normal may be required.

Question 60

Dosage of Prophylactic Therapy

Answer 60

Standard half-life factor VIII: 25 U to 40 U oper kilogram of body weight three times per week or every other day

Extended half-life factor VIII: 30 U to 50 U per kilogram twice weekly

Question 61

Bispecific, humanized IgG4 antibody mimics the cofactor activity of activated factor VIII by bridging factor IXa and factor X together for the formation of the prothrombinase complex

Answer 61

Emicizumab

Question 62

Initiation of primary prophylaxis

Answer 62

Before the age of 2 years or after the first joint bleed

Question 63

Initiation of secondary prophylaxis

Answer 63

After the onset of hemarthrosis

Can be used for short periods of time or to manage target joints.

Question 64

TRUE OR FALSE

The risk of inhibitor development is higher in patients with large deletions and nonsense mutations when compared with small deletions/insertions and missense mutations.

Answer 64

TRUE

The risk of inhibitor development is higher in patients with large deletions and nonsense mutations when compared with small deletions/insertions and missense mutations.

Some studies have reported that vWF is immunomodulatory, so that products containing vWF may be less likely to induce inhibitors compared with highly purified products.

Question 65

The presence of inhibitors arise among:

Answer 65

Severely affected patients, after treatment at an early age

Many have gross gene rearrangements or the intron 22 inversion abnormality of the factor VIII gene.

Question 66

Risk Factors for Development of Anti–Factor VIII Antibodies in Patients with Hemophilia A

Answer 66

• Disease severity: 80% of hemophilia A patients with inhibitors have <1% factor VIII activity
• Early exposure to factor VIII concentrates: majority of high-titer inhibitors develop after <90 days of exposure to factor VIII
• Genetic factors:
• 1. Family history of inhibitor development
     
     2. Ethnic background: blacks > Hispanics > whites
     3. Molecular defects: inversion and crossing over defect in intron 22, gene deletions, and nonsense point mutations resulting in patients without factor VIII antigen

Question 67

Factor VIII inhibitors are antibodies, most often of the immunoglobulin (Ig) ___ class and frequently restricted to the _____ subclass.

Answer 67

(Ig) G class

IgG4

Antibodies against the A2 and C domains of factor VIII are most common.

Question 68

TRUE OR FALSE

Factor VIII inhibitors are time and temperature independent in vitro.

Answer 68

FALSE

Factor VIII inhibitors are time and temperature dependent in vitro.

The aPTT of a 1:1 mixture of plasma from a patient with an inhibitor and normal plasma is significantly prolonged after incubation at 37  C for 1 to 2 hours

Question 69

A common assay used for inhibitor detection and quantification

Answer 69

Bethesda assay

The patient’s plasma is diluted such that, when the plasma is mixed with an equal volume of normal pooled human plasma and incubated for 2 hours at 37  C, the factor VIII activity in the mixture is decreased by 50%

Question 70

A modification of the Bethesda assay in which buffer is used instead of factor VIII–deficient plasma

Answer 70

Nijmegen assay

Question 71

High responders are defined as patients whose inhibitor titer is

Approximately 60% of patients who have inhibitors are high responders.

Answer 71

• Higher than 5 Bethesda units (BU) at baseline OR
• Initial inhibitor titer is less than 5 BU but rises to greater than 5 BU after administration of factor VIII

Question 72

High-Responder Patients

Dose of Factor VIII if to be used

Answer 72

Loading dose of 10,000 U to 15,000 U may be required, followed by up to 1000 U of factor VIII per hour, depending on the factor VIII level

When the initial titer is low, sufficient factor VIII can be administered in high doses to neutralize the inhibitor and attain adequate factor VIII levels for hemostasis.

One can expect an anamnestic response approximately five days after administration of factor VIII.

Question 73

High-Responder Patients

Dosing of Recombinant factor VIIa

Answer 73

90 mcg to 120 mcg per kilogram of body weight or higher every 2 to 3 hours

Question 74

High-Responder Patients

Dosing of Factor VIII inhibitor–bypassing activity (FEIBA)

Answer 74

50 U to 100 U per kilogram of body weight every 8 to 12 hours (not to exceed 200 U/kg/day)

Question 75

High-Responder Patients

If factor VIII inhibitor–bypassing agent are not available which agents can be considered

Answer 75

• Nonactivated prothrombin complex concentrates OR
• Plasma exchange with high-dose replacement factor VIII

Question 76

High-Responder Patients Treatment

• <5 BU, Minor Hemorrhage:
• > 5 BU, Minor Hemorrhage:
• <5 BU, Major Hemorrhage:
• > 5 BU, Major Hemorrhage:

Answer 76

• <5 BU, Minor Hemorrhage: Recombinant factor VIIa; FEIBA
• > 5 BU, Minor Hemorrhage: Recombinant factor VIIa; FEIBA
• <5 BU, Major Hemorrhage: Factor VIII?; recombinant factor VIIa; FEIBA
• > 5 BU, Major Hemorrhage: Recombinant factor VIIa; FEIBA; plasma exchange

Question 77

Low-responder patients are arbitrarily defined as patients

Answer 77

Inhibitor titer is less than 5 BU even after a challenge with factor VIII

Question 78

Low-Responder Patients Treatment

• Major bleeding episodes:
• Minor bleeding episodes:

Answer 78

• Major bleeding episodes: high doses of human factor VIII
• Minor bleeding episodes: recombinant factor VIIa or FEIBA#

Some “low” responders may convert to high responders when they are challenged repeatedly with factor VIII

Question 79

Adverse event associated with co-administration of FEIBA and emicizumab

Answer 79

Thrombosis

Question 80

The definitive goal of inhibitor management

Answer 80

Removal of the antibody

Question 81

Options for Immune Tolerance

Answer 81

• Plasmapheresis
• Administration of IV γ-globulin
• Immune tolerance regimens

The Malmö protocol uses nearly all of these approaches in combination, including extracorporeal adsorption of antibody to a Sepharose A column, administration of cyclophosphamide, daily administration of factor VIII, and IV γ-globulin.

Question 82

Immune Tolerance regimens more effective in patients with acquired hemophilia resulting from autoantibodies against factor VIII

Answer 82

Immunosuppressive drugs, like cyclosporine and rituximab

Question 83

The basis of immune tolerance regimens

Answer 83

Administration of frequent (daily or thrice weekly) doses of factor VIII until the inhibitor titer is undetectable

High-dose Regimen: 200 U/kg factor VIII per day
Low-dose Regimen: 50 U/kg factor VIII
three times per week

Question 84

Virus that can be transmitted with treatment modalities for hemophilia

Answer 84

Hepatitis A, B and C
HIV

All available factor VIII concentrates, both plasma-derived and recombinant products, are considered safe and effective with almost no risk of transmitting currently known viral diseases.

However, occasional exceptions have been observed. For example, *solvent-detergent treatment does not inactivate prions and viruses without lipid envelopes, including the hepatitis A virus and parvovirus. *

Question 85

More than 30% of factor IX mutations occur at

Answer 85

CpG dinucleotides

Question 86

Disorder is characterized by very low levels of factor IX antigen and activity at birth and during early childhood

The factor IX levels gradually rise to 60% of normal or greater after puberty, possibly caused by the age-related stability element/agerelated increase element-mediated genetic mechanism.

Answer 86

Hemophilia B Leyden phenotype

Question 87

TRUE OR FALSE

The hemophilia B population as a whole seems to have fewer and less severe complications than severely affected hemophilia A patients

Answer 87

TRUE

The hemophilia B population as a whole seems to have fewer and less severe complications than severely affected hemophilia A patients

Question 88

TRUE OR FALSE

The occurrence of factor IX inhibitor antibodies is more common in patients with hemophilia B than in patients with hemophilia A.

Answer 88

FALSE

The occurrence of factor IX inhibitor antibodies is much less common in patients with hemophilia B than in patients with hemophilia A and is very rare in nonsevere disease.

Question 89

The difference of dosing of Factor IX than VIII

Answer 89

Intravascular recovery of factor IX is only approximately 50%, and the recovery is even lower with the recombinant product.

Question 90

1 U of factor IX per kilogram body weight increases circulating factor IX by

Answer 90

1% of normal, or 0.01 U/mL

Factor IX half-life of 18 to 24 hours

Question 91

The prophylactic dose of standard half-life factor IX

Answer 91

25 to 40 U/kg of body weight two times per week

Question 92

The prophylactic dose of extended half-life factor IX

Answer 92

50 to 100 U/kg every 7 to 14 days

Question 93

Percentage of patients with severe hemophilia B who develop specific inhibitor antibodies

Answer 93

3%

Frequently restricted in immunoglobulin composition to the IgG4 subclass and κ light chains

Question 94

TRUE OR FALSE

In contrast to the inhibitors in hemophilia A patients, inhibitor antibodies against factor IX are not time and temperature dependent; thus, incubating the mixtures for 2 hours at 37  C usually is unnecessary.

Answer 94

TRUE

In contrast to the inhibitors in hemophilia A patients, inhibitor antibodies against factor IX are not time and temperature dependent; thus, incubating the mixtures for 2 hours at 37  C usually is unnecessary.

Question 95

TRUE OR FALSE

Acute DVT can be treated with heparin for 3 months as long as the patient receives factor replacement therapy.

Answer 95

FALSE

Acute DVT can be treated with heparin for 7 to 10 days as long as the patient receives factor replacement therapy.

Thereafter, anticoagulation is not recommended.

Question 96

For anticoagulation with heparin or vitamin K antagonists, factor trough levels recommended must be above

Answer 96

0.25 U/L