Inherited Platelet Function Disorder Panel

Inherited platelet function disorders (IPFD) consist of a heterogeneous group of diseases in which patients may exhibit normal platelet counts, but have variable bleeding symptoms. Inherited platelet function disorders are present at birth, however, in many cases, symptoms may not be apparent until later in life or after trauma with patients otherwise being largely asymptomatic. Diagnosis is further complicated by the fact that acquired platelet disorders are symptomatically similar to IPFDs (Diz-Küçükkaya 2013. PubMed ID: 24319190; Handin 2005. PubMed ID: 16304410; Othman 2013. PubMed ID: 23982907). 

Conditions that can lead to acquired platelet function disorders include liver disease (Roberts et al. 2010. PubMed ID: 19995396), uremia (Weigert and Schafer. 1998. PubMed ID: 9704663), myeloproliferative disorders (Kaifie et al. 2016. PubMed ID: 26944254), and diabetes mellitus (Ferroni et al. 2004. PubMed ID: 15304032). In addition, use of aspirin and other medications are some of the most common causes of platelet dysfunction, therefore, obtaining a history of medication use is crucial in diagnosing platelet function disorders.

Defects in platelet function include primarily absent or reduced aggregation and adhesion and reduced secretion from platelet storage organelles (Nurden et al. 2012. PubMed ID: 22726100). Diagnosis of PFDs typically involves platelet function testing including aggregometry, electron microscopy and morphology analysis, and quantitative analysis of platelet receptors using flow cytometry (Nurden et al. 2012. PubMed ID: 22726100). While bleeding diatheses can vary, in severe cases, bleeding episodes can be life-threatening due to intracranial hemorrhage, massive gastrointestinal or genitourinary bleeding. Consequently, accurate diagnosis of an inherited platelet function disorder is critical in determining a proper therapeutic approach. Genetic testing for IPFDs helps distinguish inherited disorders from acquired conditions and identifies the gene and associated disorder. For example, diagnosis of an IPFD may indicate pre-operative platelet transfusions or use of antifibrinolytic agents or recombinant factor treatments to prevent and curtail symptoms.

This panel test is designed to focus primarily on IPFDs related to defects in platelet adhesion/coagulation, receptor function, and secretion (Handin 2005. PubMed ID: 16304410; Nurden et al. 2012. PubMed ID: 22726100). This test does not include genes that are associated primarily with a decrease in platelet numbers such as MPL and WAS. Please see our Thrombocytopenia Panel testing options for comprehensive tests related to decreased platelet numbers. IPFDs due to defects in platelet adhesion and aggregation include Bernard-Soulier syndrome, Scott Syndrome, and familial platelet disorder. Defects in receptor function include Glanzmann’s thrombasthenia, thromboxane A2 receptor deficiency, glycoprotein IV deficiency, GPVI and GPIa collagen receptor deficiencies, and ADP receptor deficiency. Defects in storage granules include Hermansky-Pudlak syndrome.

Inherited platelet function disorders follow either an autosomal recessive or autosomal dominant pattern of inheritance. Pathogenic variants in the CD36, ITGA2, ITGB3, ITGA2B, AP3B1, BLOCK1S3, DTNBP1, EPHB2, HPS1, HPS3, HPS4, HPS5, HPS6, ANO6, GP1BA, GP9, GP1BB, P2RY12, and GP6 genes follow autosomal recessive inheritance (Handin 2005. PubMed ID: 16304410; Watson et al. 2013. PubMed ID: 23516995; Berrou et al. 2018. PubMed ID: 30213874). Thromboxane A2 receptor deficiency and familial platelet disorders are inherited in an autosomal dominant manner through pathogenic variants in the TBXA2R, TBXAS1, and RUNX1 genes, respectively (Hirata et al. 1994. PubMed ID: 7929844; Mumford et al. 2013. PubMed ID: 23279270, Song et al. 1999. PubMed ID: 10508512). Pathogenic variants in the IPFD genes include missense, nonsense, splicing variants, and copy number variants that result in loss or reduced function of the gene products. Copy number variants have been reported for most of the IPFD genes, though they occur less frequently than other types of pathogenic variants. De novo variants have also occasionally been observed for the IPFD genes, but in most cases pathogenic variants are inherited from parental carriers. 

The CD36 gene encodes platelet surface-expressed glycoprotein IV (GPIV) which serves as the primary receptor for platelet – collagen interactions (Tandon et al. 1989. PubMed ID: 2468670).

EPHB2 encodes a transmembrane tyrosine kinase receptor that binds ephrin-B1 and initiates platelet signaling required for aggregation and activation  (Berrou et al. 2018. PubMed ID: 30213874).

The ITGB3 and ITGA2B proteins make up the αIIbβ3 integrin complex, also known as CD41 and GpIIb/IIIa. Activation of the αIIbβ3 integrin complex allows platelets to bind fibrinogen and join to form platelet plugs at sites of vessel injury (Nurden et al. 2013. PubMed ID: 23929305).

ITGA2 encodes alpha-2 integrin, which is a membrane glycoprotein that makes up a subunit of collagen receptors on the platelet surface (Noris et al. 2006. PubMed ID: 16525577).

Gene products of the Hermansky-Pudlak-associated genes AP3B1, BLOCK1S3, DTNBP1, HPS1, HPS3, HPS4, HPS5, HPS6 belong to the BLOC (Biogenesis of Lysosome-related Organelle Complexes) groups of proteins that function during formation and/or trafficking of lysosome-related vesicles (Huizing et al. 2008. PubMed ID: 18544035).

The GP1BA, GP1BB, and GP9 genes encode glycoproteins that make up subunits of the von Willebrand factor receptor (Nurden et al. 2012. PubMed ID: 22726100).

ANO6 is a phospholipid scramblase which upon binding calcium increases surface expression of phosphatidylserine (PS) to the outer leaflet of the plasma membrane. This event is critical for supporting platelet procoagulation function as the negatively charged PS enhances activation of coagulation zymogens to drive formation of fibrin clots (Lhermusier et al. 2011. PubMed ID: 21958383; Harper and Poole.2013. PubMed ID: 24357800).

The P2RY12 gene encodes a platelet ADP receptor which plays critical roles in regulating hemostasis and thrombosis. At sites of vessel injury, ADP is released and binds to the ADP receptors to activate platelet aggregation (Jin and Kunapuli. 1998. PubMed ID: 9653141).

GP6 encodes a platelet collagen receptor and is co-associated with another platelet receptor GPIb-IX-V (Jung et al. 2012. PubMed ID: 22773837). In response to collagen binding to GPVI, this adhesion/signaling complex initiates platelet aggregation and initiates secretion of secondary coagulation agonists such as ADP and thromboxane A2 (Arthur et al. 2007. PubMed ID: 17910626).

TBXAS1 encodes thromboxane synthase which catalyzes conversion of prostaglandin endoperoxide into thromboxane A2 which induces vasoconstriction and platelet aggregation (Chase et al. 1993. PubMed ID: 8325653). The TBXA2R gene encodes the thromboxane A2 receptor present on platelets, vascular endothelium, monocytes, and smooth muscle cells. In platelets, thromboxane A2 binds the receptor to mediate platelet aggregation and promote clotting (Wu et al. 1981. PubMed ID: 6263954). 

RUNX1 encodes a transcription factor involved in hematopoiesis and proper platelet function including granule secretion and aggregation (Michaud et al. 2002. PubMed ID: 11830488; Walker et al. 2002. PubMed ID: 12060124; Jalagadugula et al. 2010. PubMed ID: 20876458).

Due to the array of syndromic and non-syndromic forms of IPFDs, and given a continually growing list of genes found in small numbers of families with IPFDs, the overall clinical sensitivity of this panel is difficult to determine. However, while individual IPFDs are rare, it has been suggested that in aggregate, IPFDs may be as prevalent as von Willebrand disease (vWD), the most common inherited bleeding disorder which is found in ~1% of the general population (Werner et al. 1993. PubMed ID: 8229521).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 99.7% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).