Episode 070: Heme Consults Series: Von Willebrand Disease, Part 2
This week in our hematological consultation series, we continue our discussion on von Willebrand disease (vWD), this time focusing on the type 2 subtypes and we also discuss management.
In case you missed it, we recommend checking out episode 069 for Part I of this vWD series, covering taking a bleeding history and about Type 1 and Type 3 disease.
If you suspect vWD, what testing should we send?
Refer back to our prior episode for a detailed discussion, but briefly:
vWF antigen (vWF:Ag)
vWF functional assay AKA ristocetin cofactor assay (vWF:RCo)
Factor VIII activity level (FVIII:C)
Type and Screen
If patient has a history suggestive of bleeding disorder AND vWF antigen >50%, should evaluate for a functional disorder
vWF:RCo/vWF:Ag <0.7, implies functional disorder (You have more antigen (denominator), less activity (numerator); therefore smaller number
If type 2 group of vWD more likely, more advanced testing needed to determine the subtype:
Von Willebrand factor multimer analysis: Electrophoresis shows the proportion of vWF multimers of different molecular weights.
Ristocetin-induced platelet aggregation (RIPA): similar to the ristocetin cofactor activity (see vWD ep 1 show notes) but uses a low dose of ristocetin and includes the patient’s own platelets instead of standard test platelets.
This helps us determine if the vWF is too sensitive or too aggressive in grabbing onto platelets
vWF to Factor VIII binding assay: determines whether or not the vWF multimers are able to perform their chaperone function for fVIII.
vWF to collagen binding assay: determines how well vWF binds to collagen, and since the HMW multimers are the best at this, serves as a proxy for multimer analysis in some cases.
DDAVP stim challenge - Desmopressin administration will increase release of stored vWF:FVIII complex; measure levels immediately before giving DDAVP, 1 hr after, and 4 hr after.
Genetic testing - better, cheaper, and more widely available, may begin to supplant other specialty assays
If type 2 group of vWD more likely, more advanced testing needed to determine the subtype:
What are the subtypes of Type 2 vWD?
Type 2A (TFOC tip: “A” is high achieving to help you remember high molecular weight multimers)
Second most common type of congenital vWD (~15% of vWD)
Preferential loss of high molecular weight multimer, which are the most effective at assisting hemostasis; for some reason, the body is just better able to break down the high molecular weight multimers
Ristocetin-induced platelet aggregation studies show low activity
vWF RCo:Ag < 0.7 on screening tests
May still be responsive to DDAVP and warrants a trial
Of note: this is the type of acquired vWF problem that results from severe aortic stenosis or extreme thrombocytosis - both lead to abnormal activation of the highest molecular weight multimers
Type 2B (TFOC Tip: “B” binds platelets)
Less common (5% of vWD) T1 or T2A
Gain-of-function alteration where vWF binds to platelets too readily, and as a result the HMW multimers are lost and platelets are cleared out of circulation
See loss of HMW multimers like T2A but RIPA will show increased binding with low-dose ristocetin.
Chronic mild - moderate thrombocytopenia is not unusual
High yield: DDAVP not appropriate here as it will cause mass release of the dysfunctional vWF and further lower platelet count
Type 2M (TFOC Tip: “M” for matrix -the vWF can’t bind the extracellular matrix as well in the collagen subtype)
Rare, loss of function where either platelet binding is decreased (in essence, the opposite of T2B) or collagen binding function is decreased
Overall decrease in vWF levels, ratio <0.7, and normal distribution of multimers.
Genetic testing may be useful here
Type 2N (Normandy; TFOC Tip: Normandy = 8 letters [Factor VIII]))
Rare, loss of fVIII chaperone function
Usually will see normal vWF and low factor VIII (< 30% and usually more in the 5-15% range)
Need to do vWF:fVIII binding assay for diagnosis, or consider genetic testing
Often will have a phenotype similar to mild or moderate hemophilia A and can be misdiagnosed as hemophilia
A rare subtype of vWD that we need to consider in these cases is Platelet type von Willebrand disease (PT-vWD), or pseudo-vWD. What is that?
Gain of function mutation in GPIb that would present in an identical fashion to T2B vWD; here it is the PLATELETS that love to bind vWF (as opposed to Type 2B where the vWF loves to bind platelets)
PT-vWD is rare; T2BvWD is 10x common.
Genetic testing very reliable to differentiate (wide availability and less expensive).
“Cryoprecipitate challenge” test - patient’s platelets are mixed with cryoprecipitate and will aggregate for PT-vWD but not T2BvWD; high false positive rate unless washed platelets are used
“Mixing Study” type tests - similar to the RIPA, but uses patient platelet-poor plasma and washed, fixed test platelets. More accurate but not widely available.
What is the approach to perioperative management and bleeding management?
T1 and T2A types: If there is an appropriate response to DDAVP, one can use DDAVP for minor surgery and minor bleeding.
Type 2B, 2M, 2N, and 3: Exogenous factor replacement warranted as main strategy (much like hemophilia management)
Aim to restore activity level to 100% or 100 IU/dL, and then to keep it above 50% for several days following surgery -> 3-5 days for minor procedure, 7-14 days for major procedure
Because we’re targeting a specific activity level, T1vWD typically requires lower doses of factor compared to type 2 and 3
Subsequent doses are usually half the initial dose given at the approximate half life of the product used (between 8-24 hr for most patients)
Monitoring vWF levels is very important to adjust the dosing schedule
Remember that the “half life” will be patient specific:
For example: If your T1vWD patients has surgery, some patients will have rapid clearance of vWF, while others will ramp up production in response to the stress of surgery and may maintain >100% for a day or so following surgery all on their own
Monitor factor VIII activity; these patients don’t have any trouble making factor VIII despite their low levels on baseline testing; when normal vWF is introduced, their endogenous fVIII has an increased half life and one can end up dose stacking and thrombotic risk.
Try to keep fVIII below ~250%
RCoF levels may not be available every day depending on your local lab’s capabilities. It is reasonable to primarily trend vWF antigen levels and fVIII activity with intermittent correlation with RCoF in type 2A/B/M patients. RCoF activity is not valuable in type 2N, 1, or 3 patients since these patients should have activity levels that correlate well with antigen levels.
What are options for factor replacement?
Human-derived products that contains vWF complexed with factor VIII, dosed by RCoF activity units
The the ratio of vWF activity to factor VIII activity differs between products
Brand names: Humate-P, Alphanate, and Wilate; read label prior to administration.
Preferred is Humate-P as it has the highest ratio of vWF to factor VIII (2 to 1), less dose-stacking of factor VIII activity
Expect a rise in RCoF activity of a little less than 2x what you give in units/kg
Usually use a loading dose of 40-60 units/kg, but some T3 patients may need as much as 80/kg
Recombinant products: Vonvendi
Only approved in adults
No factor VIII contained, so needs to be co-administered with factor VIII for the loading dose in patients with very low baseline levels of fVIII; for patients with less decreased levels, their endogenous fVIII should increase to >40% within 6 hr of a dose of Vonvendi
Some patients who have issues with severe factor VIII dose stacking during recovery from surgery, this can be a good alternative
Dosed by RCoF units just like the human-derived options, but has a much longer half life and is predominantly composed of the most effective high-molecular weight multimers
The crew behind the magic:
Show outline: Dan Hausrath
Production and hosts: Ronak Mistry, Vivek Patel, Dan Hausrath
Editing: Resonate Recordings
Shownotes: Srijan Valasapalli
Social media management: Ronak Mistry
