Screening and diagnosis of inherited platelet disorders

Figures & data

Figure 1. Causes of platelet function disorders and inherited thrombocytopenias. The figure summarizes the genes and pathways that contribute to the pathogenesis of platelet disorders, which includes regulatory genes that have impacts on the early or later stages of megakaryopoiesis, as summarized in Lentaigne et al. [13].

Table 1. Overview of different inherited thrombocytopenias.

Pathology	Implicated gene(s)	Inheritance pattern	Platelet size	Other hematologic features	Other syndromic features
Tangier disease [14]	ABCA1	AR or AD	Normal	Giant α-granules Hepatosplenomegaly Reduction in δ-granules	Low HDL cholesterol Peripheral neuropathy Premature atherosclerosis
Sitosterolemia [15,16]	ABCG5, ABCG8	AR	↑	Hemolytic anemia Splenomegaly Stomatocytosis	Hypercholesterolemia Premature atherosclerosis Xanthomas
Baraitser-Winter syndrome with macrothrombocyto-penia [17]	ACTB	AD	↑	Eosinophilia Leukocytosis	Cardiac and renal defects Craniofacial dysmorphism Hearing loss Infections Intellectual disability
ACTN1-related thrombocytopenia [18,19]	ACTN1	AD	↑	Platelet anisocytosis	None
ANKRD26-related thrombocytopenia [20,21]	ANKRD26	AD	Normal	Leukocytosis Polycythemia Predisposition to leukemia Reduction in α-granules	None
ARPC1B deficiency [22]	ARPC1B	AR	↓	Bleeding diathesis Eosinophilia Immunodeficiency	Allergies Autoimmunity Eczema Vasculitis
Takenouchi-Kosaki syndrome [23]	CDC42	AD	↑	None	Cardiac, genitourinary, and lymphatic defects Facial dysmorphism Intellectual disability
Thrombocytopenia Cargeeg; CYCS-related thrombocytopenia [24]	CYCS	AD	Normal	None	None
DIAPH1-related thrombocytopenia [6]	DIAPH1	AD	↑	None	Deafness
ETV6-related thrombocytopenia and leukemia predisposition [7,25]	ETV6	AD	Normal, rarely ↓	Bleeding diathesis Macrocytosis Predisposition to leukemia	None
Paris-Trousseau and Jacobsen syndrome [26–28]	FLI1, del11q23	AD	Slightly ↑	Bleeding diathesis Giant α-granules	Cardiac defects Developmental delay Skull dysmorphism
FLNA-related thrombocytopenia [29]	FLNA	X-linked	↑	Bleeding diathesis	Periventricular nodular heterotopia Otopalatodigital syndromes
Congenital autosomal recessive small-platelet thrombocytopenia [30]	FYB	AR	↓	Bleeding diathesis	None
GALE-related thrombocytopenia [31]	GALE	AR	↑	Bleeding diathesis Neutropenia	None
GATA1 X-linked thrombocytopenia with dyserythropoietic anemia [32,33]	GATA1	X-linked	Slightly ↑	Platelet dysfunction Hemolytic anemia with clinical features similar to β-thalassemia	Congenital erythropoietic porphyria
GFI1b-related thrombocytopenia [34]	GFI1B	AD	↑	Bleeding diathesis Marked reduction in α-granules	None
GNE myopathy with congenital thrombocytopenia [35,36]	GNE	AR	↑	Bleeding diathesis	Glomerulonephritis Myopathy
Bernard-Soulier syndrome [37]	GP1BA, GPIBB, GP9	AR	↑	Bleeding diathesis	None
Platelet-type von Willebrand disease [38]	GP1BA	AD	Normal to slightly ↑	Bleeding diathesis Reduced von Willebrand factor activity with a reduced ratio of activity to antigen	None
Radioulnar synostosis with amegakaryocytic thrombocytopenia [39,40]	HOXA1/MECOM	AD/AR	Normal	B-cell deficiency Progression to bone marrow aplasia	Bilateral radioulnar synostosis Cardiac and renal malformations Clinodactyly Hearing loss
IKZF5-related thrombocytopenia [41]	IKZF5	AD	Normal	Reduction in α-granules	None
ITGA2B/ITGB3-related thrombocytopenia [42,43]	ITGA2B, ITGB3	AD	↑	Bleeding diathesis Platelet αIIbβ3 deficiency Platelet anisocytosis	None
Erythrokeratosis with thrombocytopenia syndrome [44,45]	KDSR	AR	Normal	Bleeding diathesis	Harlequin ichtyosis Keratoderma
Thrombocytopenia-2 [46]	MASTL	AD	Normal	Bleeding diathesis	None
Thrombocytopenia, anemia and myelofibrosis syndrome [47,48]	MPIG6B	AR	↑	Anemia Bleeding diathesis Hepatosplenomegaly Myelofibrosis	None
Congenital amegakaryocytic thrombocytopenia [49,50]	MPL	AR	Normal to slightly ↓	Progression to bone marrow aplasia	None
MYH9-related disease [51]	MYH9	AD	↑	Bleeding diathesis Döhle-like inclusion bodies	Cataract Glomerulopathy Hearing loss Liver enzymes elevation
Gray platelet syndrome [52]	NBEAL2	AR	↑	Bleeding diathesis Marked reduction in α-granules Progressive myelofibrosis with splenomegaly	None
Stormorken syndrome [53]	ORAI1	AD	Normal	Bleeding diathesis Immunodeficiency	Ectodermal dysplasia Muscular hypotonia
Quebec platelet disorder [54]	PLAU	AD	N	Delayed-onset bleeding Platelet-dependent gain -of-function defect in fibrinolysis due to megakaryocyte-specific overexpression of PLAU	Arthropathy secondary to joint bleeds
PRKACG-related thrombocytopenia [55]	PRKACG	AR	↑	Bleeding diathesis	None
Noonan syndrome [56]	PTPN11	AD	Normal	Bleeding diathesis Predisposition to leukemia	Cardiac defects Facial dysmorphism Short stature Skeletal malformations
PTPRJ-related thrombocytopenia [57]	PTPRJ	AR	↓	Bleeding diathesis	None
Thrombocytopenia with absent radius [58]	RBM8A	AR	Normal	Bleeding diathesis Platelet count generally improves during first 2 years of life	Bilateral radial aplasia Cardiac, renal, and CNS malformations
Roifman syndrome [59]	RNU4ATAC	AR	Normal	Increased δ-granules Hypogammaglobulinemia	Growth retardation Infections Intellectual disability Retinal dystrophy Skeletal dysplasia
Familial platelet disorder with predisposition to myeloid malignancy [60]	RUNX1	AD	Normal to slightly ↑	Bleeding diathesis Predisposition to myelodysplastic syndrome and leukemia	None
SLC35A1-related thrombocytopenia [61]	SLC35A1	AR	↑	Bleeding diathesis	Ataxia Choreiform movements Delayed psychomotor development Epilepsy Microcephaly
SLFN14-related thrombocytopenia [62]	SLFN14	AD	↑	Bleeding diathesis Reduction in δ-granules	None
SRC-related thrombocytopenia [63]	SRC	AD	↑	Myelofibrosis Splenomegaly	Facial dysmorphism Osteoporosis Premature edentulism
Stormorken syndrome/York platelet syndrome [53,64,65]	STIM1	AD/AD	Normal	Anemia Bleeding diathesis Immunodeficiency Reduction in α-granules	Asplenia Facial dysmorphism Ichtyosis Intellectual disability Myopathy
Inherited thrombocytopenia from monoallelic THPO mutation [66]	THPO	AD	Normal to slightly ↑	Hypogammaglobulinemia	Developmental delay Facial dysmorphism
TPM4-related thrombocytopenia [67]	TPM4	AD	↑	Bleeding diathesis	None
TRPM7-related thrombocytopenia [68]	TRPM7	AD	↑	Bleeding diathesis	None
TUBB1-related thrombocytopenia [69]	TUBB1	AD	↑	Bleeding diathesis	None
Wiskott-Aldrich Syndrome/X-linked thrombocytopenia [70]	WAS	X-linked	↓	Immunodeficiency	Autoimmunity Eczema Increased risk of malignancies
Wiskott-Aldrich syndrome 2 [71]	WIPF1	AR	Normal	Immunodeficiency	Autoimmunity Eczema Increased risk of malignancies

AD: autosomal dominant; AR: autosomal recessive.

Note. In some inherited platelet disorders that are associated with low platelet counts, including Quebec platelet disorder and familial platelet disorder with predisposition to myeloid malignancy, platelet counts can be normal in some affected persons.

Table 2. Overview of inherited platelet function disorders associated with a normal platelet count. The conditions listed have a normal platelet size.

Pathology	Implicated gene(s)	Inheritance pattern	Key hematologic features	Other syndromic features
Scott syndrome [73–75]	ANO6	AR	Bleeding diathesis with impaired platelet procoagulant activity	None
Ephrin type-B receptor 2-related disease [76]	EPBH2	AR	Bleeding diathesis Impaired platelet aggregation with multiple agonists, including ADP, collagen, arachidonic acid, and thromboxane analogue	None
Leukocyte adhesion deficiency-III [77–79]	FERMT3	AR	Bleeding diathesis Glanzmann-like defects in aggregation Leukocytosis	Infections Osteopetrosis
GPVI-related disease [80,81]	GP6	AR	Bleeding diathesis Absent collagen aggregation	None
Hermansky-Pudlak syndrome [82–84]	HPS 1,3,4,5 and 6 AP3B1 AP3D1 BLOC1S3 BLOC1S6 DTNBP1	AR	Bleeding diathesis δ-granule deficiency Neutropenia	Granulomatous colitis Infections Oculocutaneous albinism Pulmonary fibrosis
Glanzmann thrombasthenia [43]	ITGA2B ITGB3	AR	Bleeding diathesis Absent aggregation responses to all agonists (agglutination is present with ristocetin)	None
Chediak-Higashi syndrome [85]	LYST	AR	Bleeding diathesis δ-granule deficiency Lymphohystiocytosis	Infections Oculocutaneous albinism Oral ulcerations and periodontal disease Peripheral and central neurologic manifestations
Autism with platelet dense granule defect [86]	NBEA	AD	Abnormal δ-granule structure	Autism
P2Y12-related disease [87,88]	P2RY12	AR	Bleeding diathesis Reversible ADP aggregation even at high ADP concentrations	None
Cytosolic phospholipase A2 syndrome [89]	PLA2G4A	AR	Bleeding diathesis Impaired aggregation with collagen Impaired thromboxane A2 generation	Gastrointestinal ulcers
Aspirin-like syndrome [90,91]	PTGS1	AD/AR	Bleeding diathesis Aspirin-like defect in aggregation responses	None
RASGRP2- related disease [92,93]	RASGRP2	AR	Bleeding diathesis Aggregation defects resemble Glanzmann thrombasthenia	None
TBXA2 receptor-related disease [94,95]	TBXA2R	AD	Bleeding diathesis Impaired aggregation with arachidonic acid and thromboxane analogue	None
Ghosal syndrome [96]	TBXAS1	AR	Bleeding diathesis	Osteopetrosis
Arthrogryposis-renal dysfunction-cholestasis syndrome [97,98]	VIPAS39 VPS33B	AR	Bleeding diathesis	Arthrogryposis Cardiac defects Cholestasis Growth failure Ichtyosis Infections Renal dysfunction

AD: autosomal dominant, AR: autosomal recessive.

Table 3. Likelihood of experiencing bleeding for commonly encountered platelet function disorders.

Bleeding symptom	Odds ratio (95% CI)
Excessive bruising
Female	207 (22–1971)
Male	87 (4.2–1777)
Transfusion for hemorrhage	100 (5.9–1800)
Minor wound bleeding > 1 h	44 (2.5–790)
Excessive oral/dental bleeding	43 (5.4–350)
Epistaxis > 15 min	28 (7.3–110)
Excessive surgical bleeding	20 (5.1–77)
Wound healing problem	15 (3.8–55)
Excessive bleeding from trauma	12 (1.4–105)
Hematuria from urinary tract infection	5.2 (1.3–21)
Gastrointestinal bleeding	4.1 (1.5–12)
Excessive bleeding from childbirth or miscarriage	17 (2.9–93)
Heavy menstrual bleeding	8.8 (2.1–37)

Risk for experiencing different bleeding symptoms and problems (estimated in reference [129]) are shown as odds ratios (with 95% confidence intervals) for persons with a platelet function disorder (diagnosed based on confirmed impaired aggregation with multiple agonists by light transmission aggregometry and/or δ-granule deficiency), compared to general population controls.

Table 4. Likelihood of a bleeding disorder based on findings for different platelet function disorder tests [9,24,141,144].

Test	Criteria	Odds ratio (95% CI)
Light transmission aggregometry using platelet count adjusted PRP	Abnormal findings with ≥2 agonists vs. 0–1	23 (5–105)
Light transmission aggregometry using native PRP	Abnormal findings with ≥2 agonists vs. 0–1	27 (4–214)
Dense granule ATP release by luminescence	Abnormal findings with ≥2 agonists vs. 0–1 on two tests	1.5 (0.6–3.9)
Whole mount TEM	δ-granule deficiency (DGD) on two tests	97 (5.4–1740)

Figure 2. Light transmission platelet aggregation findings for a control subject. The aggregation tracing illustrates that there is significant aggregation with all agonists, except with the lower concentration of ristocetin, which is expected. The maximal aggregation with each agonist falls within the reference interval. See Table 6 for the reference interval for each agonist.

Figure 3. von Willebrand factor loss-of-function and gain-of-function defects, evaluated by light transmission platelet aggregometry. Panel (A) illustrates ristocetin-induced platelet aggregation findings for a person with type 2A von Willebrand disease, who had delayed aggregation with ristocetin due to their loss-of-function defect. The maximal aggregation attained was within the reference interval, despite the delayed response. Panel (B) illustrates the findings for a person with type 2B von Willebrand disease and significant thrombocytopenia, whose gain-of-function defect in von Willebrand factor resulted in increased aggregation with the lower concentration of ristocetin. The responses to other agonists were within the expected range for a platelet rich plasma sample with a very low platelet count. See Table 6 for maximal aggregation data.

Figure 4. Aggregation findings for Bernard-Soulier syndrome. There is no agglutination or aggregation evident with ristocetin, whereas the responses to other agonists are within the expected range. See Table 6 for maximal aggregation data.

Figure 5. Aggregation findings for Quebec platelet disorder. There is reduced primary aggregation and no secondary aggregation with epinephrine, which is a hallmark feature of the disorder. This subject also had reduced maximal aggregation, and deaggregation, with thromboxane analogue U46619 as an incidental finding. See Table 6 for maximal aggregation data.

Figure 6. Aggregation findings for Glanzmann thrombasthenia. A response is evident with ristocetin but there is no response, apart from shape change, with other agonists. With ristocetin, the maximal response achieved is reduced, reflecting that there is agglutination but no aggregation. See Table 6 for maximal aggregation data.

Figure 7. Example of aggregation findings for δ-granule deficiency. Findings are shown for representative subject with confirmed platelet δ-granule deficiency (average: 1.2 δ-granules/platelet; reference interval: 4.9–10.0 δ-granules/platelet). Aggregation findings in this disorder can range from non-diagnostic to showing multiple abnormalities, particularly with weak agonists. This person’s maximal aggregation responses were within the reference interval with all agonists except there was a reduced response to the lower concentration of collagen and reduced secondary aggregation with epinephrine. See Table 6 for maximal aggregation values compared to the reference interval.

Figure 8. Examples of aggregation abnormalities with multiple agonists due to RUNX1 haploinsufficiency and unknown causes. Panel (A) shows the findings for a person with RUNX1 haploinsufficiency and mild thrombocytopenia, who had reduced aggregation with collagen and thromboxane analogue U46619, shared with other affected family members (not shown), who also had reduced maximal aggregation with arachidonic acid. Panel B shows the findings for an individual from a family with an autosomal dominant platelet disorder of unknown molecular cause, who had abnormal responses to multiple agonists that were particularly evident with arachidonic acid and thromboxane analogue U46619 as well as lower concentrations of collagen. See Table 6 for the maximal aggregation data of these subjects.

Figure 9. Aggregation abnormalities associated with aspirin or an aspirin-like defect. There is no aggregation with arachidonic acid whereas the aggregation response to thromboxane analogue U46619 is completely normal. Additionally, there is absent secondary aggregation with epinephrine (not shown) and reduced maximal aggregation with the lower concentration of collagen. See Table 6 for maximal aggregation data.

Table 5. International Society on Thrombosis and Haemostasis recommended investigations for suspected inherited platelet function disorders.

Line of investigation	Recommended tests
Confirmation of a bleeding diathesis	Personal and family history of bleeding and assessment of associated syndromic findings Bleeding assessment tool
Initial investigation	Complete blood count Blood smear Exclusion of a coagulopathy and von Willebrand disease (with prothrombin time, activated partial thromboplastin time, von Willebrand disease screen) Light transmission platelet aggregometry Granule release by luminometry or ELISA Flow cytometry
Second line investigations	Extended agonist panel for LTA Extended panel flow cytometry Platelet procoagulant activity Transmission electron microscopy evaluations of granules and ultrastructure Clot retraction Mixing tests (e.g. for distinguishing platelet type- from type 2B von Willebrand disease)
Optional investigations	Genetic testing Others (e.g. serum thromboxane)

Recommendations are from reference [9].

Table 6. Maximal aggregation findings for representative cases with platelet function disorders, evaluated by light transmission platelet aggregometry.

Agonist	Final agonist concentration	Maximal aggregation (%) reference interval	Figure 2. Normal control	Figure 3(A). Type 2A VWD	Figure 3(B). Type 2B VWD*	Figure 4. BSS*	Figure 5. QPD	Figure 6. GT	Figure 7. δ-granule deficiency	Figure 8(A). PFD due to RUNX1 haploinsufficiency*	Figure 8(B). PFD of unknown molecular cause	Figure 9. Aspirin-like defect
ADP	2.5 μM	>24	96	ND	23	85	32	1	65	37	16	29
ADP	5.0 μM	>43	97	ND	26	85	68	2	76	46	32	61
Collagen	1.25 μg/mL	>51	95	ND	12	ND	90	1	47	ND	5	32
Collagen	5 μg/mL	>85	93	ND	71	87	91	10	90	57^†	63	85
Epinephrine	6 μM	>9	95	ND	37	ND	4	0	53	ND	13	24
AA	1.6 mM	>77	95	ND	72	ND	94	5	89	61	0	1
U46619	1 μM	>70	96	ND	7	86	12	1	74	14^†	3	81
Ristocetin	0.5 mg/mL	˂7	2	1	40^†	0	2	1	1	1	2	1
Ristocetin	1.25 mg/mL	>75	85	86	62	0^†	92	69	82	59	79	81

ND: not done.

Patient and control subject findings are compared, including data for the aggregation tracings shown in Figures 3–9 and additional agonists responses. Abnormal maximal aggregation results are indicated with bold font.

*Denotes a thrombocytopenic sample.

^†Denotes abnormal maximal aggregation when compared to the authors’ reference interval for low platelet count samples.

Table 7. International recommendations on preanalytical variables for platelet aggregation studies by light transmission aggregometry.

Preanalytical variable	CLSI [181]	ISTH [11]
Pre-collection recommendations	Assess medication and dietary history; Avoid any substance affecting platelet function for at least 14 days Patient should ideally be fasting and avoid fatty meals prior to collection	Collection after a short rest Refrain from smoking at least 30 min before and from caffeine at least 2 h before testing Drug questionnaire must be administered prior to blood collection; NSAIDs should be stopped at least 3 days and aspirin at least 10 days before testing
Blood collection	Blood should be drawn with minimized stasis; with a needle of 19–21 gauge; in a 105–109 mM sodium citrate tube with an anticoagulant to blood ratio of 1:9	Blood should be drawn with minimal or no venostasis; with a needle of at least 21 gauge; in polypropylene or siliconized glass tubes; in a buffer anticoagulant (sodium citrate 109 or 129 mM)
Transportation	Hand carried at room temperature without vibration or shaking	No recommendation
Storage temperature	Samples should be stored at room temperature	Samples should be stored at room temperature
Preparation of PRP	Centrifugation at 170 g for 15 min at room temperature	Centrifugation at 200 G for 10 min at room temperature
Preparation of PPP	Centrifugation at 1500 G for at least 15 min	Centrifugation at 1500 G for 15 min
Assessment of PRP quality	Check for interfering lipemia, icteria and red cell contamination Platelet count should be <10 × 10^9/L PRP with a platelet count above 400 × 10^9/L should be diluted with PPP to standardized PRP count of 200–250 × 10^9/L	Hemolyzed samples should be discarded Check the PRP platelet count Samples with a platelet count <150 × 10^9/L should be interpreted with caution, but may be tested to exclude GT, BSS, and type 2B VWD Platelet count should not be adjusted to a standardized value with PPP

Table 8. International recommendations on analytical variables for platelet aggregation studies by light transmission aggregometry.

Analytical variable	CLSI [181]	ISTH [11]
Temperature	Testing should be done at 37 °C	Testing should be done at 37 °C
Use of control	A known normal drug-free control must be run in parallel	A known normal subject must be run in parallel
Preparation of the minimal and maximal values	0 and 100% values must be set with autologous PRP and PPP, respectively	0 and 100% values must be set with autologous PRP and PPP, respectively
Stirring	According to the manufacturer	Sample should be stirred at 1000 rpm
Monitoring time	Aggregation must be monitored for 5 min, up to an additional 5 min to detect delayed aggregation	Aggregation must be monitored for 3 min, up to 10 min for agonists that do not reach maximal aggregation by 3–5 min
Time to completion	Testing should be completed within 4 h of the blood sampling	Testing should be completed within 4 h of the blood sampling

Table 9. Summary of recommended agonists for platelet aggregation studies by different international guidelines.

Agonist	Targeted receptor	CLSI [181]	North American guideline [8]	ISTH [11]
ADP Higher concentrations should be used if abnormal	P2Y1 and P2Y12	0.5–10 μM	2–10 μM	2 μM, to start
Collagen (type I fibrillary^a or Horm^b) Higher concentrations should be used if abnormal	GPVI and α2β1 Also evaluates signaling pathways	1–5 μg/mL	Start at a low concentration validated to detect NSAIDs	2 μg/ml, to start
Epinephrine Higher concentrations should be used if abnormal^c	α2-adrenergic receptors and some signaling pathways	0.5–10 μM	5–10 μM	5 μM
Thromboxane analogue (U46619) Higher concentrations should be used if abnormal^c	Thromboxane receptors (TPα and TPβ) and some signaling pathways	1–2 μM	1 μM	1 μM
Arachidonic acid Higher concentrations should be used if abnormal^d	Thromboxane pathway (TPα and TPβ) and some signaling pathways	0.5–1.6 mM	0.5–1.65 mM	1 mM
Thrombin receptor activating peptide Higher concentrations should be used if abnormal^d	PAR-1 and PAR-4	No recommendation	No recommendation	10 μM
Ristocetin Low concentration High concentration	Agglutination mediated by GP1bIXV and von Willebrand factor, followed by aggregation (αIIbβ3)	≤0.6 mg/mL 0.8–1.5 mg/mL	0.5–0.6 mg/mL 1.2–1.5 mg/mL	0.5–0.7 mg/mL 1.2–2 mg/mL

^aRecommended by the CLSI.

^bRecommended by the ISTH.

^cThe North American guideline recommends only one concentration.

^dOnly the ISTH recommends using a higher concentration.

Table 10. Approach to interpreting platelet aggregation studies by light transmission aggregometry. The approach has been updated from published guidance [8].

Finding on aggregation	Interpretation
Absent or reduced with arachidonic acid Normal with thromboxane analogue Reduced with collagen Absent secondary aggregation with epinephrine Normal to reduced aggregation with ristocetin	Suggestive of an aspirin-like defect, which is often acquired from drugs that inhibit COX1 but can be congenital
Absent aggregation with all agonists except ristocetin, which is reduced as aggregation does not occur after agglutination Thrombocytopenia with significantly impaired to absent aggregation with all agonists except ristocetin	Suggestive of inherited GT, but can also be seen in acquired GT Potential case is variant GT, which should be further evaluated by flow cytometry analysis of αIIbβ3
Absent aggregation with high concentrations of ristocetin	Suggestive of BSS, which is associated with varying degrees of thrombocytopenia If the finding is associated with macrothrombocytopenia, it may affect the amount of aggregation with other agonists Suggestive of VWD if normal platelets
Increased aggregation with low concentrations of ristocetin	Suggestive of type 2B VWD or platelet-type VWD To evaluate for a potential false positive finding, consider repeating and checking VWF levels
Markedly impaired aggregation and disaggregation with ADP Reduced aggregation with a number of other agonists	Suggestive of an ADP receptor defect affecting P2Y12 Note: P2Y1 affects shape change with ADP
Isolated, abnormal aggregation with collagen	Possible defect in collagen receptors but a false positive abnormality is much more common than a true positive
Abnormal aggregation with at least 2 agonists but does not fit the pattern of other problems in this table	Suggestive of a platelet function disorder not otherwise specified Both arachidonic acid and thromboxane analogue U46619 are impaired in many of these disorders, including those cause by pathogenic RUNX1 mutations If the response to ADP is abnormal, the cause is unlikely to be δ-granule deficiency (DGD)
Abnormal aggregation with 1 agonist excluding collagen and ristocetin	Finding is non-diagnostic False positives are common with thromboxane analogue U46619
Absent secondary aggregation with epinephrine, and a reduced primary wave with epinephrine	Might suggest QPD, which is sometimes also associated with reduced MA with ADP, collagen, thromboxane analogue U46619 Epinephrine aggregation is normalized in QPD if the testing is performed with added luciferin/luciferase reagent

Figure 10. Examples of normal and abnormal lumiaggregometry findings. Each tracing show simultaneous evaluation of light transmission platelet aggregation (upper part of each tracing) and ATP release (lower part of each tracing), evaluated by lumiaggregometry. In panel (A), the ATP release with strong agonists (e.g. collagen), begins at the same time as aggregation. In panel (B), the ATP release with epinephrine, which is a weak agonist, is delayed until the start of secondary aggregation. In panel (C), there are several abnormal findings: aggregation and ATP release are absent with thromboxane analogue and aggregation and ATP release are reduced with arachidonic acid. Panels (A,C) also show the normal, rapid ATP release with thrombin (aggregation was not monitored as thrombin clots the sample).

Figure 11. Transmission electron microscopy images of whole platelets in whole mount preparations of control and δ-granule deficient (DGD) samples. The image from the control platelet (left) shows numerous electron dense structures and the majority of these structures have smooth contours and a uniform electron density, which is typical of δ-granules. The platelet from the δ-granule deficient subject contains only one electron dense granule, consistent with their low δ-granule count and confirmed δ-granule deficiency.

Figure 12. Thrombograms compare platelet rich plasma thrombin generation profiles for representative control and platelet function disorder subjects. The control sample generated more thrombin than the samples from the subjects with confirmed Quebec platelet disorder (QPD) or a familial platelet function disorder due to RUNX1 haploinsufficiency (RUNX1). The defects in these platelet function disorders include impairments in the ability of platelets to support thrombin generation.

Figure 13. Examples of flow cytometry analysis to confirm the glycoprotein deficiencies for cases with Glanzmann thrombasthenia (GT) and Bernard-Soulier syndrome (BSS). The panels compare the relative mean fluorescent intensity (MFI) from flow cytometry analysis of control compared to patient samples, evaluated with fluorescent antibodies to the platelet glycoprotein (GP) receptor αIIbβ3 that is deficient in GT (upper panel) and to the GPIbα and GPIX components of the platelet GPIb/IX/V complex that is deficient in BSS (lower panel).

Table 11. Summary of key consensus recommendations from the International Society on Thrombosis and Haemostasis on using flow cytometry for the assessment of disorders of platelet number and function [311].

Variable	Recommendations
Clinical utility	Diagnosis of: Inherited or acquired deficiencies of platelet surface glycoproteins (BSS, GT, GPVI defects) Platelet α-granule secretion defects Defects in signaling pathways (RASGPR12, P2Y12, TXA2R) GFI1B macrothrombocytopenia (CD34) Procoagulant activity disorders (Scott and Stormkorken syndromes) Assessment or monitoring of: Increased platelet activation in prothrombotic states P2Y12 antagonists Immature platelet fraction
Pre-analytical variables General Analysis of surface molecules Analysis of agonist-induced platelet activation Analysis of monocyte-platelet aggregates	Medication history should be assessed Blood sampling should avoid procedures that might cause platelet activation Citrate is the first-choice anticoagulant Samples should rest for a minimum of 30 min then stored at room temperature A stabilizing solution may be used to allow delayed flow cytometry analysis of some platelet antigens Should be done on fresh whole blood samples within 24 h from collection Should be done on fresh whole blood samples within 4 h from collection Should be performed immediately after blood collection or in fixed whole blood
Instrument and reagent standardization	Must detect forward and side scatter Must detect at least two fluorescence signals at <1000 FITC molecule per cell Software for data acquisition should allow data storage in a sharable format Validated antibodies should be used as per the manufacturer recommendations Less commonly used antibodies should be validated
Platelet flow cytometry methods	Protocols should include: Instrument description User-configurable settings Description of the reagents used (source, lot number, target protein, concentration) Positive and negative controls Strategies for gating and event analysis A local reference interval for healthy individuals should be done locally
Reporting and quality control	Should be standardized Should allow for external audits

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