Our January, 2020 Quick Question was based on our December 26, 2019 case, 5 YO Girl with Systemic Bleeding. This case generated discussion from experts around the world, whose comments are provided below. But first, here is the question and responses.
Question: What diagnosis fits no aggregation reponse to ADP , collagen, and AA? The question attracted 64 votes.
A. Bernard-Soulier syndrome: 2 votes, 3%
B. Glanzmann thrombasthenia 33 votes, 53%
C. Aspirin-like syndrome, 6 votes, 9%
D. von Willebrand disease, 11 votes, 17%
E. Storage pool deficiency 6 votes, 9%
F. Factor XIII deficiency, 6 votes, 9%
Our experts concluded Glanzmann's thrombasthenia on the basis of the history and lab results. Von Willbrand disease attracted several votes, presumably on the basis of the reduced ristocetin-induced platelet aggregation assay response. However, in von Willebrand disease, we anticipate the responses to ADP , arachidonic acid, and collagen to be normal. Bob Gosselin commented that he has seen a Glanzmann family and their ristocetin response was slightly suppressed, so he was not surprised by this result.
It may be that a signalling disorder, (aspirin-like disorder) which usually implies an inherited enzyme deficiency in the cyclooxygenase pathway, could yield similar results, though there is typically a partial aggregation response. To differentiate, we could perform GPIIb/IIIa flow cytometry or molecular diagnosis to pinpont the abnormality. Factor XIII deficiency should not affect aggregometry results. Congenital storage pool disorder is associated with albinism.
From Dr. Emmanuel Favaloro: This looks like a case of Glanzmann thrombasthenia (GT ). So that is what I voted for in your survey. I do not think it is von Willebrand disease (VWD ). Type 3 VWD would look like a Bernard Soulier Syndrome (BSS ) in respect to absent ristocetin response, although BSS would also express large platelets and thrombocytopenia. BSS and type 3 VWD can be further distinguished by von Willebrand factor (VWF ) testing (VWF undetectable in type 3 VWD ; normal in BSS ). Many other forms of VWD may express abnormal platelet aggregation to ristocetin, but aggregation to other agents should be normal. This case shows abnormal aggregation to all agonists except ristocetin (OK, it was noted as 'reduced’, but this may be an absence of secondary wave common in GT ). The only other differential may be a cyclooxygenase pathway defect, which would express similar defects, but I don’t think it is that either. I believe the aggregation defect in GT appears in general more severe than in cyclooxygenase pathway defects, but I am no expert in these, both being rare in our geography. I don’t think it is likely that the young ones have both ingested aspirin either! GT is an autosomal recessive disorder, rare in developed countries, but less rare in countries where consanguinity is more common. Not to say that that this is the case here, as chance encounters between carriers will also potentially lead to GT in their offspring. Really bad ‘luck' to have 2/2 affected children. GT is due to defects/deficiency in GPIIb/IIIa, or what the modernists call integrin αIIbβ3, which in activated platelets binds the major adhesive glycoproteins (e.g., fibrinogen, VWF , fibronectin) that enables adjacent platelets to bind to one another, and thus facilitating platelet aggregation. The firm diagnosis of GT may require evaluation of GPIIb/IIIa (integrin αIIbβ3) by flow cytometry, or else these days by genetic testing. I have sent you some suggested references.
More from Dr. Favaloro after George sent him the patient's lab result and hematologist notes: OK, thanks for the follow up; so, the family has seen a hematologist and also an OB/gyn and essentially the conclusion is "familial Glanzmanns. " That would also be my conclusion. I can’t see this being a VWD. I don’t think its a cyclooxygenase pathway defect either. Management of these cases is difficult; platelet transfusion is generally reserved for major/life threatening bleeds due to adverse risks, especially allo-immunisation and reduced efficacy later. rFVIIa is increasingly used for bleeds in these patients if the family has access. In extreme cases, a bone marrow/stem cell transplant could be considered. Pregnancy management will be an issue for the girl if she wants to have babies. On third thoughts, maybe even the PFA can help - C/ADP should be normal in aspirin-like defect? but not in Glanzmann? We’ve identified many patients with VWD , but we see very few with Glanzmann, and we avoid testing patients on aspirin. I think I’ve only seen 1 or 2 patients with a genuine cyclooxygenase pathway defect in my entire working caree.
From Bob Gosselin: One does get an abnormal ristocetin response with GT as the platelets try to aggregate, just cannot due to lack of receptor. My experience with GT PLT PRP aggs (N=4) is you see a little bump with complete disaggregation, but not much else. You see more complete aggregation with complete disaggregation with the whole blood chemiluminscence method (N=2), but those tracings you provided look like PRP method, and consistent with GT expectation. VWD eval would not be useful, as it is highly unlikely to see a dual abnormality. Not going to be able to distinguish a signaling disorder with whole blood lumiaggregometry as there is no aggregation with IIbIIIa receptor agonists, so that would be of limited value. I think the only way you can possibly vet a signaling disorder with GT is using flow and perhaps non-traditional agonists such as TRAP or thrombin. There are places that do PLT abnormality genetic screening panel such as Blood Center of Wisconsin and Machaon that screen for unusual and common PLT abnormalities (BT , BSS , MYH9, GATA, etc), but again my impression is this a classic GT presentation.
Re menstrual cycle, it has been noted that oral contraceptives will reduce (but not obliterate) menorrhagia in females with GT . I would guess she would warrant PLT transfusions with/without rVIIa if actively bleeding. Years ago, we had a couple of sisters with GT that were getting weekly PLT transfusions and I asked for Pre/Post PFA tests. One sister corrected and one did not…suggestive of and immune response to therapy.
Bob references Dr. Paul Harrison in Birmingham, England. In follow-up, Dr. Harrison says that flow and/or genetics are required and suggested arrangements could be made manage specimens. These arrangements are in progress.