122 Hemophilia A and Hemophilia B Flashcards
Mode of inheritance of hemophilia
Sex-linked/X-linked
TRUE O FALSE
In patients with hemophilia, clot formation is delayed because of the decreased thrombin generation.
TRUE
In patients with hemophilia, clot formation is delayed because of the decreased thrombin generation.
Hemophilia A results when mutations occur in the F8 gene located on the
Long arm of the X-chromosome (X-q28)
TRUE OR FALSE
All the sons of affected hemophilic males are hemophiliacs.
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.
One of the most common mutations, accounting for 40% to 50% of severe hemophilia A patients, is
“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.
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.
5% to 10%
The main risk factors for the antibody formation
Intensity of exposure to factor VIII and the type of genetic mutation
TRUE OR FALSE
Hemophilia A in females is extremely rare
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.
PRENATAL DIAGNOSIS AND CARRIER DETECTION
The current standard for identifying carrier status is through
Direct gene sequencing
PRENATAL DIAGNOSIS AND CARRIER DETECTION
Carriers who harbor the intron 22 inversion or intron 1 inversion can be identified using
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.
Factor VIII level
Severe
≤1% of normal
(≤0.01 U/mL)
- Spontaneous hemorrhage from early infancy
- Frequent spontaneous hemarthroses and
other hemorrhages, requiring clotting factor replacement
Factor VIII level
Moderate
1%–5% of normal
(0.01–0.05 U/mL)
- Hemorrhage secondary to trauma or surgery
- Occasional spontaneous hemarthroses
Factor VIII level
Mild
6%–40% of normal
(0.06–0.40 U/mL)
- Hemorrhage secondary to trauma or surgery
- Rare spontaneous hemorrhage
TRUE OR FALSE
Measurement of factor VIII level is not recommended in all carriers.
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).
Hemarthroses
The joints most frequently involved, in decreasing order of frequency
Ankles, knees, elbows, shoulders, wrists, and hips
Hemarthroses
Type of joints more likely to be involved
Hinge joints
Hemarthroses
A major factor in the pathogenesis of hemophilic arthropathy
Iron deposits from residual blood
Hemarthroses
Radiologic stages of hemophilic arthropathy
- 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
Defined by the occurrence of three or more spontaneous bleeds within a 6-month period.
Target joint
The joints most often involved are the ankles, knees, and elbows, which become chronically swollen.
Hemorrhages occur into muscle in the following order of frequency:
Calf, thigh, buttocks, and forearm
pataas!
Bleeding into fascia and muscle can result to a hemorrhage in a confined space compresses the arterial vasculature resulting in ischemic muscle injury
Compartment syndrome
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.
TRUE
Bleeding into the myocardium or erect penis is very unusual, perhaps explained by the high concentration of tissue factor in these tissues.
Blood cysts that occur in soft tissues or bone
Pseudotumors
- Not associated with pain unless rapid growth or nerve compression occurs
- Tend to expand over several years and eventually become multiloculated
Three types of pseudotumors
- 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
Pseudotumors often develop in what part of the body:
Lower half of the body
Usually in the thigh, buttock, or pelvis
But they can occur anywhere, including the temporal bone
Imaging useful in the diagnosis of pseudotumor
CT or magnetic resonance imaging
A reliable treatment of pseudotumor
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.
Most genitourinary bleeding/hematuria arises from the
Renal pelvis
Usually from one kidney but occasionally from both
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
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
Recommended factor level before performing a lumbar puncture
50% of normal
The most frequent surgical procedure performed on patients with hemophilia
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.
PT or aPTT
Patients with severe hemophilia A have a prolonged
Activated partial thromboplastin time (aPTT)
The prothrombin time (PT) and thrombin clotting time are normal.
How to detect if the hemophilic plasma contains an anti–factor VIII inhibitor antibody
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.
A definitive diagnosis of hemophilia A should be based on
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.
If the factor VIII antigen level is normal but the clotting activity is reduced, the patient has a
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.
Differential Diagnosis
Acts as a carrier of factor VIII in vivo
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.
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
Ristocetin cofactor activity assay
Differential Diagnosis
Type of vWD where factor VIII levels may be very low (<5% of normal), making it difficult to distinguish from classical hemophilia.
Type III vWD
AR to unlike majority VWD
The lack of a sex-linked pattern of inheritance in the family will help in the differential diagnosis.
Differential Diagnosis
Variant of vWD in which vWF multimers are normal but plasma factor VIII levels are low.
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
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.
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.
Differential Diagnosis
Factor deficiency that occurs in males and females and is a milder hemorrhagic disorder compared with severe hemophilia A or B.
Factor XI deficiency
Differential Diagnosis
Factor deficiencies that are not associated with bleeding
Deficiencies of factor XII, prekallikrein, and high-molecular-weight kininogen
Differential Diagnosis
Factor deficiencies that causes both the PT and aPTT to be moderately prolonged
Combined deficiency of factors V and VIII
TRUE OR FALSE
Aspirin, nonsteroidal antiinflammatory drugs can be given safely to hemophilia patients
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.
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.
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.
Blood products that contain factor VIII
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.
Cryoprecipitate, containing approximately how many units of Factor VIII
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
Types of factor VIII concentrates
Plasma-derived factor VIII concentrate
Recombinant factor VIII concentrate
- standard half-life
- extended half-life
Half-life of factor VIII
8 to 12 hours
1U of factor VIII per kilogram of body weight raises the circulating factor VIII level by approximately ________ U/mL
0.02 U/mL
The site and severity of hemorrhage determine the frequency and dose of factor VIII to be infused.
Dose of DDAVP
0.3 mcg per kilogram body weight
note effective sa severe!
- 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).
The peak response to DDAVP
30–60 minutes after dosing
Who can use DDAVP
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
Side efffect of DDAVP
Hyponatremia
DDAVP is a potent antidiuretic.
Repeated administration of DDAVP results in a diminished response to the agent (tachyphylaxis).
Dose of antifibrinolytic agents
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
Antifibrinolytic therapy is contraindicated in the presence of
Hematuria
Clots resistant to lysis may obstruct the ureters
Fibrin glue/fibrin tissue adhesive contains
Fibrinogen, thrombin, and factor XIII
Recommended factor VIII levels for secondary prophylaxis in target joints
> 50% of normal for 6 to 8 weeks
Considered as life-threatening hemorrhages
Retropharyngeal, retroperitoneal, and central nervous system bleeding, whether subdural, subarachnoid, or into the brain parenchyma
- 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.
Treatment of a known intracranial hemorrhage should be maintained for a minimum of ______________, and the circulating factor VIII level should be kept above _______% throughout this period.
20 to 30 days
50%
Replacement of Factor VIII for Surgical Procedures
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.
Dosage of Prophylactic Therapy
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
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
Emicizumab
ONLY FOR PROPHYLAXIS NOT FOR BLEEDING!
Initiation of primary prophylaxis
Before the age of 2 years or after the first joint bleed
Initiation of secondary prophylaxis
After the onset of hemarthrosis
Can be used for short periods of time or to manage target joints.
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.
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.
The presence of inhibitors arise among:
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.
Risk Factors for Development of Anti–Factor VIII Antibodies in Patients with Hemophilia A
- 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
Factor VIII inhibitors are antibodies, most often of the immunoglobulin (Ig) ___ class and frequently restricted to the _____ subclass.
(Ig) G class
IgG4
Antibodies against the A2 and C domains of factor VIII are most common.
TRUE OR FALSE
Factor VIII inhibitors are time and temperature independent in vitro.
TRUE
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
A common assay used for inhibitor detection and quantification
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%
A modification of the Bethesda assay in which buffer is used instead of factor VIII–deficient plasma
Nijmegen assay
High responders are defined as patients whose inhibitor titer is
Approximately 60% of patients who have inhibitors are high responders.
- 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
High-Responder Patients
Dose of Factor VIII if to be used
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.
High-Responder Patients
Dosing of Recombinant factor VIIa
90 mcg to 120 mcg per kilogram of body weight or higher every 2 to 3 hours
High-Responder Patients
Dosing of Factor VIII inhibitor–bypassing activity (FEIBA)
50 U to 100 U per kilogram of body weight every 8 to 12 hours (not to exceed 200 U/kg/day)
High-Responder Patients
If factor VIII inhibitor–bypassing agent are not available which agents can be considered
- Nonactivated prothrombin complex concentrates OR
- Plasma exchange with high-dose replacement factor VIII
High-Responder Patients Treatment
- <5 BU, Minor Hemorrhage:
- > 5 BU, Minor Hemorrhage:
- <5 BU, Major Hemorrhage:
- > 5 BU, Major Hemorrhage:
- <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
Low-responder patients are arbitrarily defined as patients
Inhibitor titer is less than 5 BU even after a challenge with factor VIII
Low-Responder Patients Treatment
- Major bleeding episodes:
- Minor bleeding episodes:
- Major bleeding episodes: high doses of human factor VIII, recombinant factor VIIa or FEIBA
- Minor bleeding episodes: recombinant factor VIIa or FEIBA
Some “low” responders may convert to high responders when they are challenged repeatedly with factor VIII
Adverse event associated with co-administration of FEIBA and emicizumab
Thrombosis
The definitive goal of inhibitor management
Removal of the antibody
Options for Immune Tolerance
- 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.
Immune Tolerance regimens more effective in patients with acquired hemophilia resulting from autoantibodies against factor VIII
Immunosuppressive drugs, like cyclosporine and rituximab
Cause inhibitors in hemophilia are ALLOANTIBODIES
The basis of immune tolerance regimens
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
Predictors of success of immune tolerance regimens
- Young age at detection of inhibitor
- Inhibitor titer less than 10 BU before starting immune tolerance induction (ITI)
- Peak titer less than 200 BU after starting ITI
- Historical peak titer less than 200 BU
- Age less than 5 years old between diagnosis and start of ITI and
- Genotype (small deletions and insertions, and missense mutations)
Virus that can be transmitted with treatment modalities for hemophilia
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.
More than 30% of factor IX mutations occur at
CpG dinucleotides
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.
Hemophilia B Leyden phenotype
TRUE OR FALSE
The hemophilia B population as a whole seems to have fewer and less severe complications than severely affected hemophilia A patients
TRUE
The hemophilia B population as a whole seems to have fewer and less severe complications than severely affected hemophilia A patients
TRUE OR FALSE
The occurrence of factor IX inhibitor antibodies is more common in patients with hemophilia B than in patients with hemophilia A.
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.
The difference of dosing of Factor IX than VIII
Intravascular recovery of factor IX is only approximately 50%, and the recovery is even lower with the recombinant product
1 U of factor IX per kilogram body weight increases circulating factor IX by
1% of normal, or 0.01 U/mL
Di na dinidivide by 2
Factor IX half-life of 18 to 24 hours
The prophylactic dose of standard half-life factor IX
25 to 40 U/kg of body weight two times per week
The prophylactic dose of extended half-life factor IX
50 to 100 U/kg every 7 to 14 days
Percentage of patients with severe hemophilia B who develop specific inhibitor antibodies
3%
Frequently restricted in immunoglobulin composition to the IgG4 subclass and κ light chains
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.
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.
TRUE OR FALSE
Acute DVT can be treated with heparin for 3 months as long as the patient receives factor replacement therapy.
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.
For anticoagulation with heparin or vitamin K antagonists, factor trough levels recommended must be above
0.25 U/L
