The diagnosis of a mild inherited platelet function disorder is often elusive because of the overlap of bruising and bleeding symptoms with those seen in normal individuals, and the difficulty in obtaining accurate and reproducible laboratory results. There are further problems in the diagnosis of these disorders in children, particularly young children, who may not have been exposed to hemostatic challenges during their lifetime. In these cases, bleeding symptoms specific to childhood, such as post-circumcision bleeding, cephalohematoma and umbilical stump bleeding, may be of greater significance.

The bleeding history is an important initial, non-invasive step in determining the likelihood of a bleeding disorder being present in a child. A bleeding history is often taken in a non-standardized manner, and the interpretation of the responses can vary according to the prior experience of the observer. Scoring systems exist for assessing the severity of bleeding symptoms in children with immune thrombocytopenia [1,2]. However, in terms of inherited disorders of platelet function, only the bleeding phenotype associated with the rare Quebec platelet disorder has been evaluated in this way [3]. A recently developed pediatric bleeding questionnaire (PBQ) [4], which is based on the MCMDM-1VWD Bleeding Questionnaire [5,6], incorporates pediatric-specific bleeding symptoms (postcircumcision bleeding, cephalohematoma, umbilical stump bleeding, post-venepuncture bleeding, macroscopic hematuria and conjunctival hemorrhage) and quantifies bleeding severity in children. A score of ≥ 2 predicts a diagnosis of von Willebrand disease (VWD) [4], but the PBQ has not been applied to children with a prior diagnosis of a platelet function disorder.

Although it is clear that some inherited platelet disorders, such as Glanzmann thrombasthenia, are associated with significant bleeding [7], it is debatable as to whether others, such as MYH9-related macrothrombocytopenia, cause an increased risk of bleeding at all [8].

In order to address some of these issues, we evaluated the use of the PBQ in a cohort of children with a platelet disorder. Ethical approval for the study was obtained from the Research Ethics Board at The Hospital for Sick Children, Toronto, Canada. Children (aged 0–18 years) with a historical diagnosis of an inherited platelet disorder were recruited from the Bleeding Disorders Clinic. Investigations included determination of the platelet count, blood film examination, platelet aggregation studies (using agonists: ADP, 3 μm; epinephrine, 40 μm; collagen, 10 μg mL−1; and arachidonic acid, 1.6 mm) and, where relevant, quantitation of glycoprotein IIb–IIIa by flow cytometry [9,10] and of dense granules by whole mount electron microscopy [11], and immunofluorescence analysis of neutrophil non-muscle myosin heavy chain IIA [12]. Diagnosis of a platelet disorder was made according to criteria defined by the Rare Inherited Bleeding Disorders Subcommittee of the Association of Hemophilia Centre Directors of Canada ( Informed consent was obtained from the child or parent/guardian prior to inclusion in the study. The PBQ was administered by interview of parent/child by a physician or research nurse. Bleeding score was calculated by two independent observers. The use of prophylactic hemostatic therapy, referring to the administration of desmopressin (DDAVP) or platelet concentrates prior to a dental or surgical procedure in order to prevent bleeding, was also recorded and contributed to the bleeding score [13]. A clinically significant symptom was defined as one severe enough to require consultation with a healthcare professional, medical/surgical intervention or blood transfusion [13].

Bleeding score was determined for 23 children with a platelet function disorder, 12 females and 11 males, with a median age of 10.3 years (range: 0.6–18 years). Bleeding score according to gender, age group and diagnosis is shown in Table 1. The median bleeding score was 8.0 (range: 1–20). Twenty-two of 23 children (96%) had a significant bleeding score, defined as a bleeding score of ≥ 2 [4], providing evidence that platelet function disorders can cause mucocutaneous bleeding in childhood. Only one child (a 9-year-old female with MYH9-related macrothrombocytopenia) had a bleeding score of < 2. One child < 6 years of age was evaluated, a 7-month-old female with Glanzmann thrombasthenia, who was determined to have a bleeding score of 8. No correlation between bleeding score and age was identified. The median bleeding score tended to be higher in females than in males: this could be accounted for, in part, by menorrhagia, as menorrhagia requiring consultation or intervention occurred in all three menstruating females.

Table 1.   Bleeding score according to sex, age group and diagnosis in children with an inherited platelet function disorder (n = 23)
 Number of patientsAge (years), median (range)*Bleeding score, median (range)*
  1. *For categories in which there are four or fewer patients, all values of bleeding score are shown.

 Male1112.2 (6.5–18.0)8.0 (3–19)
 Female129.9 (0.6–17.8)10.5 (1–20)
Age group (years)
 6–9108.8 (6.5–9.5)9.0 (1–20)
 10–14812.8 (10.3–14.2)13.0 (2–19)
 15–18417.3 (16.4–18.0)7.5 (3–16)
 Glanzmann thrombasthenia47.6 (0.6–10.3)8, 10, 13, 14
 Dense granule deficiency712.7 (7.1–14.1)7.0 (2–15)
     Hermansky–Pudlak syndrome211.8, 16.84, 6
 MYH9-related macrothrombocytopenia39.2 (7.3–18)1, 3, 12
 Noonan syndrome29.5, 14.217, 8
 Ehlers–Danlos syndrome28.9, 9.27, 20
 Undefined platelet function disorder316.4 (12.2–17.8)9, 16, 19
Total2310.3 (0.6–18.0)8.0 (1–20)

Clinically significant bleeding symptoms were present in the following proportions of the study cohort: bleeding after tooth extraction, 75% (9/12 children who underwent tooth extraction); surgical bleeding, 73% (8/11 children who had surgery); epistaxis, 43% (10/23); prolonged bleeding from minor wounds, 43% (10/23); bruising, 30% (7/23); oral cavity bleeding, 22% (5/23); gastrointestinal bleeding, 13% (3/23); hemarthrosis, 9% (2/23); and, muscle hematoma, 4% (1/23). Pediatric-specific bleeding symptoms requiring consultation had occurred in 35% of children (8/23), and consisted of: post-circumcision bleeding, 33% (2/6 of circumcised male patients); macroscopic hematuria, 17% (4/23); and umbilical stump bleeding, 9% (2/23). Significant post-venepuncture bleeding occurred in 4% (1/23) of patients, as did significant conjunctival hemorrhage. No patient had cephalohematoma of any severity. One child (a 12-year-old male with an undefined platelet function disorder) had three pediatric-specific bleeding symptoms, all of which required consultation.

There was significant heterogeneity in the scores obtained between diagnostic groups, with children with an undefined platelet function disorder or Glanzmann thrombasthenia having the highest scores, and those with MYH9-related macrothrombocytopenia or dense granule deficiency, the lowest (Table 1). Bleeding in children with Ehlers–Danlos syndrome and Noonan syndrome was also significant, with bleeding scores ranging from 7 to 20. Bleeding diathesis occurring in association with Noonan syndrome has been variably attributed to deficiency of factor XI, thrombocytopenia and abnormal platelet aggregation [14]; both patients in our cohort had normal platelet counts, but prolonged closure times as measured by platelet function analyzer (PFA)-100, with both collagen/epinephrine and collagen/ADP cartridges. Bleeding in patients with Ehlers–Danlos syndrome often occurs in the absence of laboratory abnormalities, but has been seen in association with defects in platelet aggregation [15]; in our cohort, the child with the bleeding score of 7 had reduced platelet aggregation responses to epinephrine and arachidonic acid, with a prolonged PFA-100 closure time with the collagen/epinephrine cartridge, and the child with the bleeding score of 20 had a reduced aggregation response to epinephrine only. Whether bleeding occurs in MYH9-related disorders is controversial [8]; in the three children in our cohort with this diagnosis, bleeding scores were 12, 3 and 1. Three children with an undefined platelet function disorder had a median bleeding score of 16.0. Laboratory abnormalities in these children were persistently reduced platelet aggregation responses to: ADP only (with prolonged PFA-100 closure times with both cartridges; bleeding score of 9); epinephrine and arachidonic acid (bleeding score of 19); and ADP, epinephrine and arachidonic acid (bleeding score of 16).

A clinically significant bleeding score was most frequently obtained for menorrhagia in menstruating females, bleeding after tooth extraction, surgical bleeding, epistaxis or prolonged bleeding from minor wounds. These frequencies of mucocutaneous bleeding symptoms are similar to those seen in a cohort of 100 children with VWD who were recently evaluated using the same questionnaire and score [13]. Clinically significant hemarthrosis occurred in two patients with Glanzmann thrombasthenia, and muscle hematoma occurred in one patient with an undefined platelet function disorder. A significant proportion of children (35%) had a history of pediatric-specific bleeding symptoms, in particular post-circumcision bleeding, macroscopic hematuria and bleeding from the umbilical stump, making these useful additions to the questionnaire.

We conclude that the PBQ is a potentially useful means of assessing bleeding severity in children with inherited platelet disorders. Our data show that bleeding in children with platelet function disorders manifests at an early age, often as pediatric-specific symptoms such as post-circumcision bleeding. Bleeding scores vary between different diagnostic groups and between children with the same diagnosis, giving the potential for stratification of bleeding severity and therefore prediction of bleeding risk during surgical or dental procedures. We have also highlighted clinically relevant mucocutaneous bleeding symptoms in two children with MYH9-related macrothrombocytopenia. Validation studies in children prospectively evaluated for a platelet function disorder are required prior to using the PBQ in clinical practice.


  1. Top of page
  2. Acknowledgements
  3. Disclosure of Conflict of Interests
  4. References

We thank W. Kahr and F. Pluthero, The Hospital for Sick Children, Toronto for performing the immunofluoresence analysis. The project was funded by a Canadian Hemophilia Society Care Until Cure Grant. T. T. Biss was sponsored by Baxter Bioscience Canada for her fellowship post at The Hospital for Sick Children.

Disclosure of Conflict of Interests

  1. Top of page
  2. Acknowledgements
  3. Disclosure of Conflict of Interests
  4. References

The authors state that they have no conflict of interest.


  1. Top of page
  2. Acknowledgements
  3. Disclosure of Conflict of Interests
  4. References
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