At a Glance
Glanzmann Thrombasthenia (GT), translated as “weak platelets,” is a rare inherited moderate to severe bleeding disorder, rarely acquired with acute promyelocytic leukemia, with a prevalence of likely 1 in 1 million births. GT is an autosomal recessive disorder with asymptomatic heterozygous carriers.
GT is seen with increase prevalence in populations with high consanguineous marriage rates (e.g., South Indian Hindus, Iraqi Jews, French Gypsies, Jordanian nomadic tribes). The vast majority of cases are described outside of the United States.
GT is due to a qualitative or quantitative defect in αIIbβ3 integrin (GPIIb/IIIa), the primary fibrinogen receptor, leading to an inability to aggregate platelets despite normal adhesion. This fibrinogen receptor on the surface of the platelet mediates incorporation of platelets into a multiplatelet aggregate at sites of endothelium damage. Currently there are more than 100 mutations that encode both integrins (αIIb and β3) with three subtypes described.
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Patients typically present in early childhood with moderate to severe mucocutaneous bleeding, including menorrhagia, epistaxis, gingival bleeding, GI hemorrhage, and ecchymosis. Epistaxis can be severe, leading to iron deficiency anemia.(Table 1)
Table 1.
| Type I disease | Type II disease | GT variant disease |
|---|---|---|
| Absent platelet aggregation and clot retraction | Absent platelet aggregation but normal clot retraction | No common unifying feature |
What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?
If there is clinical suspicion for GT, it is reasonable to rule out other causes of mucocutaneous bleeding with a Prothrombin time (PT), Partial thromboplastin time (PTT), complete blood count (CBC), fibrinogen activity, and von Willebrand disease panel (ristocetin cofactor assay, VWF antigen, FVIII activity), all of which will be normal. In addition, platelet morphology and quantity will be normal with GT. Utilizing the platelet function analyzer (PFA-100) to screen for GT is reasonable, as nearly all cases will have a significantly prolonged closure time.
To verify the diagnosis, light transmission platelet aggregometry should be done to demonstrate the absent response to all standard platelet agonists (e.g., arachidonic acid, adenosine diphosphate (ADP), collagen, epinephrine). There is a primary wave response to ristocetin but no secondary wave response, indicating an inability to aggregate.
Definitive diagnosis can be made by defective or absent Glycoprotein expression of IIb/IIIa by flow cytometry followed by commercial gene sequencing to evaluate for the specific mutations that encode the IIb and IIIa glycoproteins.(Table 2)
Table 2.
| PFA-100 | Platelet Aggregometry | Flow Cytometry |
|---|---|---|
| Prolonged closure time in both Collagen/ADP and Collagen/Epinephrine cartridges | Absent aggregation in the presence of all agonists | Absent or defective GP expression of GP IIb or GP IIIa |
Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?
There are a few challenges in making the diagnosis, mostly delay in diagnosis, since most screening hemostatic tests will be normal, as well as having normal platelet morphology.
It is possible that if only a PFA-100 is performed that there could be an incorrect assumption that the patient has a delta-storage pool deficiency or von Willebrand disease, which both have similar closure time patterns. The platelet aggregometry pattern is classic for GT alone.
A thorough drug history is recommended prior to performing a PFA-100 or other platelet studies, since recent NSAID or aspirin use (within the last 8 days) can lead to false-positive results. In addition there are herbal medications and foods (garlic and fatty foods) that can prolong the closure time in the collagen/epinephrine cartridge. Abstaining from these foods/herbals prior to testing is recommended.
What Lab Results Are Absolutely Confirmatory?
Demonstration of the absence of platelet aggregation to all platelet agonists via light transmission platelet aggregometry, as well as deficient or defective GP expression of IIb and IIIa via flow cytometry, are both highly suggestive of a diagnosis of GT. Molecular demonstration of one of the 100 known mutations encoding for glycoproteins IIb and IIIa is absolutely confirmatory for GT.
What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?
Failure to make a timely diagnosis of GT can lead to excessive and/or fatal bleeding, especially following surgical procedures. Platelet alloimmunization is common, and early identification of this disorder and utilizing HLA matched platelets is key to prevention of alloantibodies.
Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?
Rarely in screening for GT, the PFA-100 can be normal if there is a subvariant GT involved; however, GT classically causes significantly prolonged closure times.
The PFA-100 performance is affected by the hematocrit, von Willebrand factor (VWF), and platelet count. If the platelet count is low (<100,000), the hematocrit is low (<28%), or the VWF antigen is low (as seen with VWD), prolongation of the closure time can occur, leading one to an incorrect diagnosis.
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