Hemophilia

Question 1

Define Mild, Moderate and Severe Hemophilia

Answer 1

Mild - 5-40%
Moderate - 1-5%
Severe - <1%

Question 2

What is Hemophilia B Leyden?

Answer 2

Hemophilia B Leyden is a mutation affecting the Factor IX Promoter. This is influenced by sex hormones, so the disease phenotype will become more mild as the patient ages.

Question 3

A) How many males have severe hemophilia A?

B) How many males have severe hemophilia B?

C) How many female carriers have a mild hemophilia phenotype?

Answer 3

A) 50-66%

B) 33-50%

C) 25%

Question 4

What cut-off is required to affect the PTT (Factor level)

Answer 4

Under 15% for Hemophilia A, maybe less for B

Question 5

What is serious bleeding in Hemophilia?

How do you manage it?

Answer 5

Serious bleeding:
CNS bleeds, including eyes, Deep muscular bleeds, Hip bleeds, Bleeding severe enough to need pRBC, Bleeding that could affect organ function (airway), Intra-abdominal/GI bleeding, Iliopsoas bleeds, Failure of conservative therapy, Trauma bleeding

Management:
Factor should immediately be brought to >100%, and maintained thereafter >50%. This is done by providing Factor replacement at the half-life of the factor (8-12hrs for FVIII, 18-24hrs for FIX)

Question 6

How do you treat Hemarthrosis in Hemophilia?

Question 7

What is the in-vivo recovery of FVIII and FIX

Answer 7

FVIII has an in-vivo recovery of 2 units per 1 unit/kg provided.
I.e. for a 60kg patient trying to raise to 100% activity you would give (60x0.5x100) or 3000 units

FIX has an in-vivo recovery of 1 unit per 1 unit/kg provided.
I.e. for a 60kg patient trying to raise to 100% activity you would give (60x1x100) or 6000 units

Question 8

How if factor activity on Emicizumab measured?

Answer 8

A BOVINE Chromogenic Factor VIII assay must be used. Standard FVIII assay is non-reliable.

Question 9

How long should treatment for a bleed be given for:
A) Hemarthrosis
B) Target joint
C) Muscular bleed / Deep Laceration (not iliopsoas)
D) Iliopsoas bleed
E) CNS bleed
F) Serious site bleed (GI/Neck/Intra-abdominal)
G) Major OR

Answer 9

A) Target ~50 for 1-2d
B) Target 100 for 1-2d
C) Target ~50 for 2-3d
D) Target 100 for d1-d2, THEN MAINTAIN >50 for d3-d5 (5d)
E) Target 100 for 1wk, THEN MAINTAIN >50 for a further 2 weeks (3 weeks total)
F) Target 100 for 1wk, THEN MAINTAIN >50 for a further 1 week (2 weeks total)
G) Pre-op Target ~100 (60-80 for HemB), and then maintain >50 until wound healing (10-14d - 2 weeks total)

In general we target >100 for severe bleeding/target joint, and >50 for other site bleeds. Maintenance then depends on the site, with Serious Site and CNS typically continued for anywhere from 5d to 3 weeks. For less “severe” bleeding like hemarthrosis or muscular can continue unless bleeding stopped. Consider prophylaxis afterwards for patients not on it already.

Question 10

Define a target joint

Answer 10

3 or more bleeds into a joint within the preceding 6 months

Question 11

How do we treat bleeding in Hemophilia patients with Inhibitors?

Answer 11

If Inhibitor is weak (always been <5BU) can consider higher dose replacement

If inhibitor is strong (has been >5BU at ANY point) then need a bypass agent:

Can use either aPCC or rFVIIa EXCEPT in Emicizumab patients, where rFVIIa should be given due to TMA documented in patients receiving aPCC. If aPCC is given NO MORE than 100 units/kg in any 24 hour period should be given.

Question 12

What is high-dose Factor replacement?

Answer 12

For patients with <5BU inhibitors can try high-dose replacement. This is done as:

Replace to 100%, then give a further 50% dosing for every 1 BU.

I.e. for a 60kg patient with an inhibitor of 3BU we give

(0.5 x 60 x 100) + (3 x 0.5 x 60 x 50) = 3000 + 4500 = 7500 units

Question 13

Which patients are most at risk of developing inhibitors?

Why?

Answer 13

Patients with Hemophilia A or severe disease

Typically because HA has gene deletions as opposed to inhibiting point mutations in HB, therefore antigenic portions are missing from the FVIII in HA patients. Severe disease because there is very low level of factor circulating, so may not become tolerant to FVIII/FIX.

Question 14

Is there preference for recombinant or plasma-derived factor replacement?

Answer 14

In general, no. The SIPPET trial demonstrated more inhibitors with Recombinant vs PD

Critiques: Not all patients followed out to 50 Exposure days, Newer generation Recombinant was poorly represented, done in a mostly Egyptian population so uncertainty of applicability to general population.

WFH currently makes no recommendations on PD vs Recombinant

Question 15

What are 6 risk factors for inhibitor development

Answer 15

Age at first exposure (debated)
Inflammation during exposures (i.e. on-demand vs prophylactic)
Dose intensity and frequency
Number of exposures
Immune response genes 

Severity of disease phenotype
Hemophilia A > Hemophilia B
Black ethnic background
POSSIBLY Recombinant vs PD products

Question 16

Causes of acquired coagulation inhibitors?

Answer 16

Idiopathic (50%)
Post-partum
Malignancy (Solid organ / Hematological)
Autoimmune disease (RA/SLE)
Medication related (IFN/Penicillin/Sulfa/Phenytoin/Fludarabine)

Question 17

What is a Bethesda Unit?

Answer 17

The reciprocal dilution of patient plasma that results in 50 percent factor VIII activity is defined as one Bethesda unit (BU)

Question 18

What IST do you use to treat Acquired coagulation inhibitors

Answer 18

1L: Always use steroids, typically for 4-6 weeks prior to tapering

2L: Another agent is indicated if EITHER Activity level is <1% OR >20BU. That agent is either Cyclophosphamide (1.5-2mg/kg) or Rituximab (4 doses of 375mg/m2 weekly).

3L agents include Cyclosporine or Cladribine

Question 19

What agents can be used to stop bleeding in ACQUIRED coagulation inhibitor (Not congenital)

Answer 19

<5BU inhibitor can consider human FVIII

> =5BU inhibitor give either rFVIIa, aPCC or Recombinant Porcine FVIII