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ASPHO Lectures 2021 > Inherited Bleeding Disordrs > Flashcards

Inherited Bleeding Disordrs Flashcards

1
Q

Prophylaxis dosing for Hemophilia A?

A
  • Factor VIII 25-40 IU/kg/dose 3x per week OR QOD

- some centres start with weekly dosing and escalate with bleeds

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2
Q

Prophylaxis dosing for Hemophilia B?

A
  • Factor IX 50-100IU/kg/dose 2x per week

- Some centres start with weekly dosing and escalate

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3
Q

What is a target joint?

A

-Multiple bleeds in the same joint: 3 bleeds in 6 months or 4 in a year

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4
Q

Options for management of chronic arthropathy in hemophilia?

A
  • Medical: Initiation of secondary prophylaxis
  • Surgical: Synovcectomy (open, arthroscopic, radioisotopic)
  • Other: Pain management, physiotherapy, casting, bracing, orthotics, walking/mobility aids
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5
Q

Management of intracranial bleeding in hemophilia with factor replacement?

A
  • 100% correction for at least 2 weeeks

- Continue treatment with prophylaxis dosing indefinitely

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6
Q

Management of retroperitoneal bleeding in hemophilia with factor replacement?

A
  • 80% correction for at least a few days

- Follow-up with short-term prophylaxis (weeks)

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7
Q

Management of muscle bleed in hemophilia with factor replacement?

A

-40-60% correction at least until can utilize muscle with no pain

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8
Q

Management of joint bleed in hemophilia with factor replacement?

A
  • 40-60% correction

- 1-3 doses generally suffice

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9
Q

Management of mucosal bleed in hemophilia with factor replacement?

A
  • 30-50% correction

- Add antifibrinolytics

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10
Q

Management of subcutaneous hematoms in hemophilia with factor replacement?

A
  • Observation generally sufficient

- Large hematomas in “bad” locations (e.g. buttocks) need factor

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11
Q

Management of surgery in hemophilia with factor replacement?

A
  • 100% correction pre-op

- Maintain trough of 50% until risk for bleeding is over

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12
Q

Factor recovery dosing for Factor VIII? Factor IX?

A

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)

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13
Q

What is desmopressin?

A

An analogue of anti-diuretic hormone

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14
Q

How does desmopressin work in hemophilia? When is it used? Why do desmopressin challenge?

A

-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

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15
Q

Important adverse effects of desmopressin?

A
  • Hyponatremia in patients <3 years

- Some patients develop hypotension and flushing –> first dose should be administered in clinic

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16
Q

Surgical management in hemophilia?

A
  • 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%
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17
Q

Management of dental extractions in hemophilia?

A
  • Factor replacement correction to 80-100%
  • Add antifibrinolytic agent (tranexamic or aminocaproic acid)
  • Pressure gauze
  • Desmopressin (not fully reliable)
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18
Q

Management of hematuria in hemophilia?

A
  • 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
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19
Q

Causes of failure of factor replacement?

A
  • Insufficient factor dose (weight based)

- Development of inhibitor

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20
Q

Management of factor replacement failure?

A
  • Test for inhibitor immediately
  • For bleeding, treat with bypassing agent
  • For patients on prophylaxis, suspend therapy
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21
Q

How do inhibitors complicate the management of hemophilia?

A
  • Bleeds are more difficult to treat
  • Prophylaxis not nearly as effective
  • Patients with inhibitors have higher morbidity and mortality
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22
Q

Patient related risk factors for inhibitor development? Treatment related risk factors for inhibitor development?

A

-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

23
Q

Which type of genetic mutation has highest rate of inhibitors?

A

Large deletions

24
Q

What test to diagnose inhibitors?

A

Bethesda Assay

25
Q

Management of transient inhibitors?

A
  • Clinically insignificant
  • Found during routine surveillance
  • No specific treatment - continue to use standard factor replacement, observe, follow titre
26
Q

Differences between high titre and low titre inhibitors?

A
  • 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
27
Q

Management of patients with inhibitors?

A

-Eradication of inhibitor using ITI, bleed management

28
Q

What is immune tolerance therapy? When is tolerance achieved?

A
  • 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
29
Q

Bleed management in low titre, low responder patients?

A
  • 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)
30
Q

Bleed management in high titre patients?

A
  • Must use bypassing agents
  • -Anti-inhibitor coagulant complex (a.k.a. activated prothrombin complex concentrates (APCC))
  • -Recombinant activated factor 7/rFVIIa
31
Q

Management of inhibitor patients?

A

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!

32
Q

What is in APCCs?

A

Plasma-derived mixture of factors II, VII, IX and X (some activated)

33
Q

How common is von Willebrand disease?

A
  • 1% of population by lab testing

- 1/500 symptomatic (“real cases”)

34
Q

Symptoms of vWD?

A
  • 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
35
Q

Function of vWF?

A
  • Platelet binding

- Carrier molecular for FVIII

36
Q

What factors can increase vWF?

A
  • Physiologic stress
  • DDAVP
  • Estrogen
  • Pregnancy
  • Acute phase reactant
37
Q

vWF binds to platelets via ________.

A

Glycoprotein 1b receptor

38
Q

Inheritance and physiologic defect of Type 1 vWD?

A

Type 1

  • Autosomal dominant
  • Heterozygous defect with reduced production of normal vWF
39
Q

Inheritance and physiologic defect of Type 2A vWD?

A

Type 2a

  • Autosomal dominant
  • Multimerization defect with absent large/intermediate size multimers
40
Q

Inheritance and physiologic defect of Type 2B vWD?

A
  • Autosomal dominant
  • Gain of function mutation in VWF (too adherent to platelets so large multimers are attached to platelets and not circulating)
41
Q

Inheritance and physiologic defect of Type 2M vWD?

A
  • Autosomal dominant

- Loss of function mutation (opposite of 2B) - vWF doesn’t bind well to platelets

42
Q

Inheritance and physiologic defect of Type 2N vWD?

A
  • Autosomal dominant - Compound heterozygotes with type 1

- Loss of vWF binding function to FVIII

43
Q

Inheritance of Type 3 vWD?

A
  • Autosomal recessive

- Absence of vWF production

44
Q

VWF antigen (VWF:Ag) test?

A

Immunologic test for the presence of vWF in plasma (doesn’t assess function)

45
Q

Ristocetin cofactor activity (VWF:Rcof)

A

-Platelet aggregration based test assessing vWF platelet binding function

46
Q

Diagnostic tests for vWD?

A
  • VWF:Ag
  • VWF:Rcof
  • Factor VIII activity
  • vWF multimer analysis
  • RIPA (2B)
47
Q

Treatment options for vWD?

A
  • 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
48
Q

Most common genetic aberrations in severe hemophilia A?

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

49
Q

How many patients with severe hemophilia will develop an intracranial hemorrhage in the first year of life?

A

5%

50
Q

Symptoms of retroperitoneal/iliopsoas muscle bleed?

A
  • 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)
51
Q

Why are factor levels not reliable enough for pre-natal testing?

A
  • Factor IX levels physiologically low in fetuses

- Factor VIII levels falsely elevated

52
Q

What is primary prophylaxis? Secondary? Tertiary?

A
  • 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
53
Q

Indications for prophylaxis?

A
  • In severe hemophilia to prevent hemophilic arthropathy - no later than after 2 joint bleeds, can be prior to any
  • Moderate hemophilia who bleed frequently

ASPHO Lectures 2021 (10 decks)

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