Inherited Bleeding Disordrs Flashcards
Prophylaxis dosing for Hemophilia A?
- Factor VIII 25-40 IU/kg/dose 3x per week OR QOD
- some centres start with weekly dosing and escalate with bleeds
Prophylaxis dosing for Hemophilia B?
- Factor IX 50-100IU/kg/dose 2x per week
- Some centres start with weekly dosing and escalate
What is a target joint?
-Multiple bleeds in the same joint: 3 bleeds in 6 months or 4 in a year
Options for management of chronic arthropathy in hemophilia?
- Medical: Initiation of secondary prophylaxis
- Surgical: Synovcectomy (open, arthroscopic, radioisotopic)
- Other: Pain management, physiotherapy, casting, bracing, orthotics, walking/mobility aids
Management of intracranial bleeding in hemophilia with factor replacement?
- 100% correction for at least 2 weeeks
- Continue treatment with prophylaxis dosing indefinitely
Management of retroperitoneal bleeding in hemophilia with factor replacement?
- 80% correction for at least a few days
- Follow-up with short-term prophylaxis (weeks)
Management of muscle bleed in hemophilia with factor replacement?
-40-60% correction at least until can utilize muscle with no pain
Management of joint bleed in hemophilia with factor replacement?
- 40-60% correction
- 1-3 doses generally suffice
Management of mucosal bleed in hemophilia with factor replacement?
- 30-50% correction
- Add antifibrinolytics
Management of subcutaneous hematoms in hemophilia with factor replacement?
- Observation generally sufficient
- Large hematomas in “bad” locations (e.g. buttocks) need factor
Management of surgery in hemophilia with factor replacement?
- 100% correction pre-op
- Maintain trough of 50% until risk for bleeding is over
Factor recovery dosing for Factor VIII? Factor IX?
Factor VIII: 1 IU/kg increases factor level by ~2%
Factor IX: 1 IU/kg increases factor level by ~1% for all plasma-derived factor IX products; 0.7% for rFIX (3 available products e.g. Benefix)
What is desmopressin?
An analogue of anti-diuretic hormone
How does desmopressin work in hemophilia? When is it used? Why do desmopressin challenge?
-Increases circulating vWF thereby increasing FVIII levels in most patients with mild hemophilia A
-Not indicated in Factor IX deficiency/Hemophilia B
-Only effective in mild hemophilia A; generally for
mucocutaneous bleeding and minor procedures (dental)
-Desmopressin challenge first because some mild mutations are non-responsive
Important adverse effects of desmopressin?
- Hyponatremia in patients <3 years
- Some patients develop hypotension and flushing –> first dose should be administered in clinic
Surgical management in hemophilia?
- Ensure patient does not have an inhibitor
- Replace factor to 100% immediately prior to procedure
- Repeat bolus doses to maintain a trough >50% until bleeding risk has passed
- Can use continuous infusion if many days of factor will be needed (major surgery)
- Antifibrinolytic drugs can be added, especially for mucous membrane surgery
- Factor VIII: 50IU/kg immediately prior to procedure, followed by 50IU/kg q12h (can adjust to maintain a trough >50%). Continuous infusion would be (~3IU/kg/hr) to maintain a trough > 50%
- Factor IX: 120-140 IU/kg of rFIX (or 100 IU/kg of pdFIX) immediately prior to procedure, followed by same dose q12-24h. Continuous infusion would be 6IU/kg/hr to maintain a trough >50%
Management of dental extractions in hemophilia?
- Factor replacement correction to 80-100%
- Add antifibrinolytic agent (tranexamic or aminocaproic acid)
- Pressure gauze
- Desmopressin (not fully reliable)
Management of hematuria in hemophilia?
- Factor replacement correction to 80-100%
- Hydration at 1.5-2x maintenance
- Antifibrinolytics CONTRAINDICATED
- Desmopressin not reliable enough
- Limited data for glucocorticoids, though often given
Causes of failure of factor replacement?
- Insufficient factor dose (weight based)
- Development of inhibitor
Management of factor replacement failure?
- Test for inhibitor immediately
- For bleeding, treat with bypassing agent
- For patients on prophylaxis, suspend therapy
How do inhibitors complicate the management of hemophilia?
- Bleeds are more difficult to treat
- Prophylaxis not nearly as effective
- Patients with inhibitors have higher morbidity and mortality
Patient related risk factors for inhibitor development? Treatment related risk factors for inhibitor development?
-Patient related:
–Severity of hemophilia
(severe>moderate>mild)
–Family history (identical twin>sibling>uncle or grandfather)
–Molecular defect (large deletion>nonsense>inversion>missense)
–Race (Black>White)
-Treatment related: Product type?; number of exposure days; intensity of exposure; cumulative exposure
Which type of genetic mutation has highest rate of inhibitors?
Large deletions
What test to diagnose inhibitors?
Bethesda Assay
Management of transient inhibitors?
- Clinically insignificant
- Found during routine surveillance
- No specific treatment - continue to use standard factor replacement, observe, follow titre
Differences between high titre and low titre inhibitors?
- High titre: >5 BU, always high responders (rapid anamnestic response - if give factor VIII, level will rise), must use bypassing agents to treat and/or prevent bleeding
- Low titre: <5 BU, low responder (no anamnestic response), can be treated with factor replacement at higher than usual doses
Management of patients with inhibitors?
-Eradication of inhibitor using ITI, bleed management
What is immune tolerance therapy? When is tolerance achieved?
- Regular (usually daily) infusions of FVIII (or rarely FIX) to “educate” immune system to become tolerant of factor replacement in patients with inhibitors
- Over 6-18 months
- Tolerance achieved when patient has a recovery of >66% and a half-life of >6 hours
- There are different regimens
Bleed management in low titre, low responder patients?
- Can use standard factor VIII replacement therapy but need higher doses
- No validated formula, but can multiple inhibitor titre by IU/kg that you would give to a non-inhibitor patient
- Re-check inhibitor titre to ensure not rising (anamnesis)
Bleed management in high titre patients?
- Must use bypassing agents
- -Anti-inhibitor coagulant complex (a.k.a. activated prothrombin complex concentrates (APCC))
- -Recombinant activated factor 7/rFVIIa
Management of inhibitor patients?
rFVIIa
- Bleed treatment: 90-120mcg/kg/dose is US licensed dose - repeated q2-3h until bleed resolution
- -Outside US, 270mcg/kg/dose is licensed
- Surgical ppx
- Ppx - licensed outside US
APCC
- Bleed treatment: 50-100IU/kg/per dose q8-12h. Not to exceed 200IU/kg/day
- Surgical ppx
- PPx - 75 IU/kg qod
Desmopressin ineffective in inhibitor patients!
What is in APCCs?
Plasma-derived mixture of factors II, VII, IX and X (some activated)
How common is von Willebrand disease?
- 1% of population by lab testing
- 1/500 symptomatic (“real cases”)
Symptoms of vWD?
- Mostly mucocutaneous bleeding, except type 3 which also has hemophilia-like bleeding
- Epistaxis, easy bruising, oral bleeding, post-surgical (oropharyngeal) bleeding
- Menorrhagia and post-partum bleeding in females of child-bearing age
Function of vWF?
- Platelet binding
- Carrier molecular for FVIII
What factors can increase vWF?
- Physiologic stress
- DDAVP
- Estrogen
- Pregnancy
- Acute phase reactant
vWF binds to platelets via ________.
Glycoprotein 1b receptor
Inheritance and physiologic defect of Type 1 vWD?
Type 1
- Autosomal dominant
- Heterozygous defect with reduced production of normal vWF
Inheritance and physiologic defect of Type 2A vWD?
Type 2a
- Autosomal dominant
- Multimerization defect with absent large/intermediate size multimers
Inheritance and physiologic defect of Type 2B vWD?
- Autosomal dominant
- Gain of function mutation in VWF (too adherent to platelets so large multimers are attached to platelets and not circulating)
Inheritance and physiologic defect of Type 2M vWD?
- Autosomal dominant
- Loss of function mutation (opposite of 2B) - vWF doesn’t bind well to platelets
Inheritance and physiologic defect of Type 2N vWD?
- Autosomal dominant - Compound heterozygotes with type 1
- Loss of vWF binding function to FVIII
Inheritance of Type 3 vWD?
- Autosomal recessive
- Absence of vWF production
VWF antigen (VWF:Ag) test?
Immunologic test for the presence of vWF in plasma (doesn’t assess function)
Ristocetin cofactor activity (VWF:Rcof)
-Platelet aggregration based test assessing vWF platelet binding function
Diagnostic tests for vWD?
- VWF:Ag
- VWF:Rcof
- Factor VIII activity
- vWF multimer analysis
- RIPA (2B)
Treatment options for vWD?
- Increase circulating vWF
- -Desmopressin (releases stored vWF from Weibel-Palade bodies in endothelium) - Type 1 and maybe type 2A
- -Replacement with plasma-derived vWF concentrate
- Inhibit fibrinolysis
- -Antifibrinolytics
- Hormonal therapy
- -Effective for menorrhagia management
- –Estrogen increases vWF and FVIII
- –Reduced blood flow to endometrium
- Topical therapy
- -Antifibrinolytics for oral bleeding
- -Topical thrombin for oral or nose bleeding
- -Cellulose or collagen embedded gauze
Most common genetic aberrations in severe hemophilia A?
- 40-50% have intron 22 inversion in the factor VIII gene
- 50% have a specific point mutation in exons or at splice junctions in the factor VIII gene
How many patients with severe hemophilia will develop an intracranial hemorrhage in the first year of life?
5%
Symptoms of retroperitoneal/iliopsoas muscle bleed?
- Pain in flank, groin or rarely thigh (referred pain)
- Pain exacerbated and localized to RLQ by extending the leg (stretching the muscle)
- Difficulty walking (typically walk hunched over to relax the iliopsoas)
Why are factor levels not reliable enough for pre-natal testing?
- Factor IX levels physiologically low in fetuses
- Factor VIII levels falsely elevated
What is primary prophylaxis? Secondary? Tertiary?
- Primary proph: Initiation of factor prior tto any joint bleeding, or before second joint bleed/any obvious joint disease
- Secondary proph: After second joint bleed/onset of joint disease in order to prevent further bleeding
- Tertiary proph: After onset of joint disease
Indications for prophylaxis?
- In severe hemophilia to prevent hemophilic arthropathy - no later than after 2 joint bleeds, can be prior to any
- Moderate hemophilia who bleed frequently
