Episode 039: Hemophilia 101, Pt 4

In this episode, we discuss the acute management of the bleeding patient with acquired hemophilia.

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Prior to starting this episode, we highly recommend you listen to Episode 036 to review:

• Approach to Hemophilia (physical exam, workup)

• Review coagulation cascade

When to suspect acquired hemophilia?

• For a suspected acquired hemophilia, want to ensure you are looking at prior coagulation studies (if available); suspect if patient has spontaneous bleeding with abnormal coags (with prior coags normal)

Case presented in this episode (helps to better understand below):

75M with PMHx HTN, HLD, CLL who was lost to follow up for CLL (but never required treatment). Had presented to ED with bilateral back pain with significant bruising. He also had ROS +SOB, fatigue. Exam notable for flank bruising. Labs concerning for severe anemia and elevated PTT

Since there is an abnormal PTT, proceed with mixing study.

• In acquired hemophilia, mixing study will not correct

  • Why? An antibody is interfering with the function of one of the proteins in the coagulation pathway.

  • What does “correct” mean? It needs to go to normal range.

    • In inherited hemophilia, recall that patient’s activity levels will correct

  • Putting this in clinical context, the patient who is bleeding with an abnormal coagulation assay you need to suspect as having acquired hemophilia

  • Once again, check factor activity levels to assess which protein’s function is interfered with

    • Most often factor VIII is most affected

What are Bethesda Units and why are they important?

• This is a unit of measure to quantify how “strong” the inhibitor is

• Based on the idea of reciprocal dilutions of the patient’s plasma with control plasma and then testing factor activity

• The Bethesda assay result that we want is the reciprocal of the dilution at which 50% of factor activity is observed

• Example: 

  • Patient presents with spontaneous bleeding of the thigh. They have no prior history of spontaneous bleeding and a normal family history. PTT is abnormal and does not correct with mixing study. 

  • You check factor VIII activity level was 6%, and so now you are suspicious of an inhibitor. 

    • Perform 1:2 dilution → let’s say 21% activity

    • Perform 1:5 dilution → let’s say 50% activity

    • Perform 1:10 dilution → let’s say 75% activity

  • So here, the 1:5 dilution resulted in 50% activity; so the reciprocal of ⅕ is 5, therefore we would say the inhibitor titer is 5BU

  • Why does this matter?

  • Bethesda units in acquired vs. congenital hemophilia are slightly different

    • Congenital: Recall that patients can form inhibitors to factor replacement in congenital hemophilia

      • Patients with <5BU often have their inhibitors disappear spontaneously

      • Patients with BU > 5 have “high responding inhibitors”. These can become undetectable overtime, but many times, these will rise 4-7 days after factor is given in future events (amnestic response) 

    • Acquired: A means of assessing “what’s ahead of us” and also a way to measure if “eradication therapy” is working to get rid of the auto-antibody.

How do we treat patients with acquired hemophilia?

• How do we stabilize the acute bleed?

  • The patient is bleeding so we need to force a clot

  • Consider use of bypassing agent

    • Since often FVIII is the protein targeted, use recombinant factor VIIa to bypass the intrinsic pathway

      • Has short half life

    • Also can consider use of FEIBA (factor eight inhibitor bypassing agent)

• How do we treat the underlying cause?

  • Suppress the immune system:

    • Steroids or rituximab (anti-CD20 antibody)

    • Oral cyclophosphamide + steroids

    • If there is an underlying malignancy (such as CLL), treat the underlying cause

  • Likely will be a prolonged course of steroids

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References:

https://pubmed.ncbi.nlm.nih.gov/30396835/ : Review on treatment of acquired hemophilia A

https://pubmed.ncbi.nlm.nih.gov/22517903/ : Results of the EACH2 registry which showed improvements in inhibitor eradication with cyclophosphamide + steroids than steroids alone or with rituximab based regimens.

The crew behind the magic: 

• Show outline: Ronak Mistry

• Production and hosts: Ronak Mistry, Vivek Patel, Dan Hausrath

• Editing: Vivek Patel

• Shownotes, graphics, social media management: Ronak Mistry