Pediatric Bleeding Disorders: Von Willebrand Disease (VWD)

00:02 In this lecture, we’ll discuss bleeding disorders in children.

00:06 So we can think of bleeding disorders based on how we know clots form.

00:11 First, there is tissue damage and then both platelets and the coagulation cascade occurs that help form that clot.

00:19 In children, there can be problems with both the coagulation cascade and platelet activation.

00:25 We’ll discuss platelet activation first.

00:28 So here’s an inherit cartoon where you can see how platelets activate together and collide together and there are 2 major problems that can happen with platelets that can lead to platelet dysfunction.

00:41 One is problems with Von Willebrand’s factor and the other was intrinsic problems within that platelet.

00:47 Let’s start with Von Willebrand’s factor.

00:50 So Von Willebrand disease is a genetic defect in Von Willebrand factor.

00:55 It is the most common inherited bleeding disorder in children.

00:59 We have to remember that Von Willebrand’s factor does two different things.

01:03 First, it does bind the platelets, but then also it acts as a carrier protein for factor VIII.

01:10 So these patients may have problems with factor VIII as well.

01:15 So there are many different types of Von Willebrand’s disease and I’d like to go through a few of them.

01:21 Some of them are important to understand and some are so rare that we can just discuss them briefly.

01:28 So type 1 is very common.

01:31 It’s the most common type of Von Willebrand disease.

01:34 It’s autosomal dominant and it affects about three-quarters of patients.

01:39 The severity of the disease can vary a lot from mild to severe.

01:44 Type 2A is also autosomal dominant and is present in about 15% of patients.

01:50 Usually they have moderate degree of severity of illness.

01:54 The same thing can be said of type 2B, again, autosomal dominant, about 5% of patients and again moderate degree of illness.

02:03 And then there are the rare types.

02:05 There is the platelet-type which is extremely rare, but is a gain of function mutation and these patients actually have hypercoagulability rather than a bleeding disorder.

02:16 Type 2M is fairly rare and these patients have a normal level of Von Willebrand’s factor but it doesn’t work correctly.

02:25 Type 2N is autosomal recessive.

02:27 These patients have a low factor 8 level and often, these patients are mistaken for a patient with hemophilia.

02:35 And there's type 3 which is extremely rare, but these patients are very sick, they have a completely unmeasurable amount of Von Willebrand’s factor and resultingly a low factor VIII as well.

02:48 So how do these patients present? Well, they will present absolutely with easy bruising, bleeding, bleeding from the nose and mouth and excessive menorrhagia.

02:59 So the easy bruising is usually spontaneous.

03:02 These bruises are usually large and they’re often in unusual locations.

03:08 Sometimes, you might think that this child might have been a victim of child abuse, but in fact they have Von Willebrand’s disease.

03:15 They will often bleed excessively from minor lacerations with prolonged bleeding and they may get excessive scarring of those lacerations.

03:24 Nose and mouth bleeding is common and these patients usually have frequent nose bleeds.

03:31 Often times, these nose bleeds are hard to control and require afferent spray and ice and all kinds of intervention that most kids don’t require.

03:39 They also will bleed excessively with tooth loss or simply when they’re brushing their teeth.

03:46 In terms of menorrhagia, we usually pick this up in young girls who are having their first period and they will have dramatically increased bleeding with their menses.

03:55 And the menses will last longer than usual.

03:58 So if we wish to diagnose Von Willebrand’s disease in a child who is presenting with excessive bleeding, we get a PT/PTT and in most of these cases, it’s normal.

04:08 This is because their factor VIII is working enough that they have a normal coagulation cascade.

04:15 However, if we further investigate, we will find further testing which reveals a diagnosis of VWD.

04:22 The first test we will get is a VWF antigen. This is measuring directly quantity of VWF proteins in the blood.

04:32 A level below 30% indicates VWD.

04:36 A level over 50% is normal, and in the 30-50% range the disease may be suspected if there is a history of bleeding in the child.

04:46 We can also test the activity of the VWF that is in the blood, not just the quantity that is there.

04:53 For this, we will bind the VWF to various binding partners. Usually, we’ll use a GP1b receptor on platelets, or we can bind it to collagen.

05:05 The most common test for function is the “ristocetin cofactor” which assesses GP1b binding.

05:12 Ristocetin was an antibiotic that they took off the market because it caused thrombocytopenia and the reason it did that is because it bound to Von Willebrand’s factor.

05:22 Results are interpreted just like the antigen levels. A level below 30% indicates VWD.

05:29 A level over 50% is normal, and in the 30-50% range the disease may be suspected if there is a history of bleeding in the child.

05:37 The factor VIII level is obtained but will be different in different patients depending on the subtype of disease as we discussed earlier, and a normal level does not preclude VWD as a diagnosis.

05:49 We no longer use either a bleeding time, or a platelet function assay, which are older methods of testing for bleeding disorders in children.

05:57 The PFA had a high false positive rate, and the bleeding time was inaccurate and time-intensive to perform.

06:07 So how do we treat Von Willebrand’s? Well, we usually start with a DDAVP challenge.

06:13 DDAVP increases Von Willebrand factor and presence of factor VIII.

06:18 It’s not effective for all subtypes of disease, for example, type 3, it will have not much effect at all, but it is good for types 1 and 2.

06:27 DDAVP is usually used as a nasal spray.

06:31 Also, we have to watch for hyponatremia.

06:34 Remember, DDAVP causes insertion of aquaporin channels and causes reclaiming of free fluid, so these patients may develop a low sodium.

06:45 Von Willebrand’s factor viii is usually reserved for patients with very severe disease and for a severe bleeding event, we will usually give factor VIII as well as recombinant Von Willebrand’s factor.

06:58 And we may use topical thrombin to mucous membranes to help them stop the bleeding.

07:05 There are some other unusual platelet aggregation problems where the platelets have an inherit problems sticking together.

07:12 The patient will have a normal number of platelets, they just won’t be working correctly.

07:16 These patients tend to present with severe bleeding disorders.

07:20 The normal number of platelet is there.

07:21 They will have a normal Von Willebrand’s factor and a normal PTT and PT.

07:27 So, it can be a challenge to make this diagnosis and a platelet function assay is the way to do it.

07:32 When you think about this, remember Glanzmann’s thrombasthenia, this is probably the most important kind to remember for a test.