Week of 14–20 September 2026¶
What evidence is there to support the FVIII and FIX targets in the guidelines around the time of surgery?¶
Answer: The evidence is weak. Perioperative FVIII and FIX targets rest on product labeling, consensus guidelines, pharmacokinetics, and a small body of observational/PK studies rather than controlled trials.
- Nordic Hemophilia Guidelines — for major surgery, recommend peak targets of 70–100 IU/dL, with trough targets of 70 IU/dL (days 1–3), 50 IU/dL (days 4–6), and 30 IU/dL (days 7–9); minor surgery target is 50 IU/dL. These targets were validated in a Nordic real-world evidence study of surgeries under extended half-life rFVIIIFc/rFIXFc (the source below).
- Weight-based dosing overshoots — in mild hemophilia A, current weight-based perioperative dosing frequently produces FVIII levels above target (Schütte et al., 2019), further supporting PK-guided dosing in the postoperative setting to reduce overexposure and adverse effects.
If I want to achieve a higher trough FVIII level, which is better — increasing the dose or the frequency?¶
Answer: Increasing the frequency is more efficient than increasing the dose.
PK rationale: trough depends on the ratio of dosing interval to half-life. For a short-half-life protein, doubling the dose adds only about one extra half-life of coverage near the end of the interval, whereas shortening the interval compounds far better.
- Collins et al. quantified this: to hold a trough of 1–1.5 IU/dL in a 70-kg adult (median t½ 10.4 h), the dose per infusion needed was 120 IU daily vs 700 IU every other day vs 3570 IU every third day — a ~30-fold swing in per-infusion dose. Stretching the interval demands exponentially more factor to hold the same trough.
- Crossover PK study (Hua et al., daily 5 IU/kg vs every-other-day 10 IU/kg — equal total factor): at steady state the daily regimen produced double the trough (6% vs 3%) (Haemophilia 2017).
- rFVIIIFc simulation (Berntorp et al.): a longer half-life relaxes the trade-off. rFVIIIFc's lower clearance gave higher troughs and fewer days below threshold at similar or reduced factor use — e.g. at the same 3×30 IU/kg, the first-week trough was ~7.8 vs 2.7 IU/dL for rFVIIIFc vs conventional rFVIII (Haemophilia 2016).
What is the evidence surrounding prophylaxis in VWD (specifically type 3)?¶
Answer: Unlike hemophilia, prophylaxis is not yet universally established as standard of care in VWD. Expert consensus and guidelines suggest prophylaxis for patients with "severe and frequent" bleeding — but there is no accepted definition of "severe and frequent."
- Common indications in our practice: joint bleeding/disease, recurrent severe oral mucosal bleeding, GI bleeding (usually least responsive), and heavy menstrual bleeding. Where possible we enroll patients in clinical trials.
- Retrospective data: a small body of retrospective evidence shows prophylaxis reduces the annualized bleeding rate (ABR) versus no prophylaxis, with the greatest effect for joint bleeding (hemarthrosis) and less effect for mucosal bleeding.
- Type 3 (WIL-31 sub-analysis): plasma-derived VWF/FVIII concentrate (wilate) prophylaxis produced substantial reductions across all bleeding sites versus on-demand treatment — knee and arm muscle bleeds reduced to zero and ankle joint bleeds reduced by >90%.
For guideline and background context, see the ASH ISTH NHF WFH 2021 VWD guidelines and this Nature Reviews Disease Primers review.
What are good resources for rare clotting factor deficiency?¶
Answer: Two references for the diagnosis and management of the rare inherited coagulation factor deficiencies — the guideline linked below, alongside a current overview: Rare inherited coagulation disorders: no longer orphan and neglected (Mohsenian et al., RPTH 2024).
Source: Guideline for the diagnosis and management of the rare coagulation disorders