Episode 069: Heme Consults Series: Von Willebrand Disease, Part 1

medicine

Aug 16

Written By TheFellowOnCall HemeOncPodcast

We resume our hematological consultation series with an overview of von Willebrand disease (vWD), the most common inherited bleeding disorder. In this episode, we talk about the initial steps we should take to evaluate suspected vWD and how to differentiate the various subtypes. We will focus on vWD type 1 and 3! Be sure to tune in next week as we discuss vWD type 2 and management.

How do we approach a patient with potential bleeding disorder?

Go through the patient’s bleeding history and try to quantify the patient’s bleeding symptoms.

The International Society of Thrombosis / Hemostasis (ISTH) Bleeding Assessment Tool is a systematic way to go through history
The tool takes you through a series of bleeding symptoms with 0-5 points assigned depending on the severity of each symptom.
When to suspect a bleeding disorder:

Males: Score of 4 or more
Females: Score of 6 or more

It is important to not rely too heavily on this score. These scores are only useful in the right clinical context!
Remember that platelet dysfunction disorders, such as vWD, present more with mucosal bleeding as compared to factor deficiency disorders, such as hemophilias, which present with “ortho” or deep tissue bleeding.

What is von Willebrand factor (vWF) and how does it work?

vWF is a glycoprotein multimer that has several roles in hemostasis and plays a role in angiogenesis as well

It is present in a variety of molecular weights. The largest molecular weight multimer has the most important job in hemostasis.
The multimers are in folded (inactive) form when in circulation and unfold in areas of turbulent blood flow (e.g. an endothelial damage site).
ADAMTS13 (a metalloprotease) cleaves large multimers into smaller ones which are less active. It acts at the VWF A2 domain which is only exposed when the multimer can partially unfold.

vWF also acts as a chaperone for factor VIII and increases its half-life in the circulation (binds to D’D3 domain, which is relevant for vWD type 2N)

What is the role of vWF in primary hemostasis?

Binds to collagen at the site of vascular injury
Binds to platelets via their “vWF receptor” (GPIb receptor) and interacts with the GPIIb/IIIa domain (primarily a fibrinogen receptor) as well
Has a role in slowing platelets down
Helps platelets interact with each other
Note that elevated vWF is common under stress (all coagulation factors tend to increase under stress). It is a physiological response!

What tests should we order for patients with suspected vWD?

vWF antigen (quantitative measure of how much the VWF is present in circulation)

Often abbreviated vWF:Ag
Usually expressed as a percent of normal, but may also be expressed in international units
50-150% is considered normal range

vWF functional testing:

Often abbreviated vWF:RCo
Measures binding of vWF to the platelet GPIb receptor
Ristocetin cofactor assay:

Ristocetin is an antibiotic that causes vWF to unfold, which then causes platelets to aggregate
Uses standardized formalin fixed “test platelets” as its platelet substrate with the patient’s plasma as the source of vWF
The degree of aggregation is measured, which is also expressed as a percent of normal just like the antigen level

Some places use automated forms of testing, which usually include platelet function testing.

Assess the binding of vWF to recombinant GPIb, which has been fixed to some solid medium like an ELISA plate
Some assays use normal GPIb and add ristocetin to activate vWF. Others use a strong gain-of-function variant of GPIb that allows for vWF binding independent of ristocetin.
Probably the way of the future, as they are automated and there is no need for test platelets

Factor VIII activity:

Often abbreviated FVIII:C (clotting assay)
Usually run as part of a vWD panel.
It is important to know if there is discordance between vWF activity, antigen levels, and factor VIII activity.

Type and screen:

Useful in interpreting borderline cases where antigen level and activity might be slightly low
Patients with type O blood have a lower normal range for VWF level and activity

Why is repeat testing important?

If the patient has bleeding symptoms and a VWF Ag level between 30% and 50%, the level should be confirmed with repeat testing since the levels fluctuate in response to transient stressors.

How common is vWD?

vWF is the most common inherited bleeding disorder and has an estimated prevalence of 1:1000
About 1% of the population has levels below normal range! (even though they may or may not have the bleeding phenotype)

What are the types of vWF?

Use Arabic numerals not Roman numerals!
Type 1 and type 3 are quantitative disorders

Not enough VWF

Type 2 subtypes are qualitative disorders

VWF function is compromised

What is type 1 vWD?

Most common type, about 75% of vWD diagnoses

Autosomal dominant inheritance
vWF levels range between 10 and 50% of normal
Mostly related to decreased vWF production

There is a newly recognized “type 1C” (C for clearance) where the factor is merely cleared out more rapidly than normal

What is type 3 vWD?

Uncommon
Autosomal recessive inheritance
Absent or nearly absent vWF (<10%)
Clinically similar to hemophilia A - since factor VIII chaperone function is so important to extending the factor’s half life, patients will also have profoundly low factor VIII levels

What is the desmopressin (DDAVP) challenge test and why is it useful?

Used as follow up testing for adult patients with type 1 vWD to determine whether or not they have a response to DDAVP
Not used in type 3 vWD - they don’t have enough vWF to respond
DDAVP increases the release of stored vWF:FVIII complexes from the endothelium.
If the patient mounts a sufficient response, DDAVP can be used for treatment of minor bleeding or before minor surgical procedures
DDAVP trial can also help figure out if the patient has type 1C vWD

How is the DDAVP challenge done?

DDAVP is administered with vWF levels measured immediately before giving, 1 hour after, and 4 hours after
If the patient’s vWF level increases by twofold or more from baseline and remains elevated over 50% at 4 hours, the patient can use DDAVP along with antifibrinolytic agents like tranexamic acid (TXA) or aminocaproic acids (ACA) for minor bleeds and procedures
If the level does not reach twofold or more, then DDAVP will not be a reliable treatment
If the level reaches twofold at 1 hour, but falls by more than 30% from the peak at 4 hours, this should raise suspicion for type 1C