Inherited platelet function disorders are of variable severity and unknown frequency and may be difficult to diagnose. Nevertheless, they are increasingly recognized as an important cause of bleeding in pediatrics, particularly in adolescent girls with menorrhagia, where they may be more common than von Willebrand disease. This article reviews the presentation of these disorders, summarizes the most common types of platelet function disorders, discusses the challenges in diagnostic testing, and details treatment and supportive care options.
Key points
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Patients with platelet function disorders (PFD) have abnormal primary hemostasis and typically present with bruising, epistaxis, and especially menorrhagia.
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PFD are more common than previously recognized and may be more common than von Willebrand disease, especially in adolescents with menorrhagia.
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Severe PFD such as Bernard-Soulier syndrome and Glanzmann thrombasthenia are rare but fairly straightforward to diagnose.
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Milder PFD are more common but may be more difficult to diagnose and may not be identified with the readily available platelet function screen tests.
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Advanced testing for PFD includes platelet light transmission aggregometry, electron microscopy, and biochemical analysis; such testing is less widely available and should be overseen by a pediatric hematologist.
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Supportive care measures such as oral contraceptives, antifibrinolytic agents, and iron replacement are the mainstay of management for patients with symptomatic PFD.
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Desmopressin, platelet transfusions, and recombinant activated factor VII may be indicated in certain clinical settings.
Introduction: nature of the problem
Previously thought to be a rare disorder, primary abnormalities of platelet function are increasingly recognized in pediatrics and can result in bleeding symptoms of varying severity (reviewed in Refs. ). In fact, recent studies have suggested that platelet function disorders (PFD) are at least as common as von Willebrand disease (VWD) in specific patient populations, such as adolescents with menorrhagia. However, the diagnosis of PFD is challenging, especially for the less severe abnormalities.
Platelets are critical for the process of primary hemostasis. At the time of vessel injury, the subendothelium is exposed, leading to the binding of von Willebrand factor (VWF) multimers to collagen ( Fig. 1 ). In the setting of shear forces from flowing blood, this large molecule stretches, exposing binding sites for platelets. Once bound to collagen through the bridging VWF protein (via the platelet surface glycoprotein [GP]Ib/IX/V complex), enhanced by the binding of platelet agonists such as thrombin, epinephrine, and ADP, to surface receptors, platelets are activated. Activation results in a rapid cytoskeletal rearrangement, which leads to a configurational change and then recruitment of and aggregation with other platelets, primarily via the surface GPIIb-IIIa (mediated by fibrinogen and VWF). The activation of intracellular signaling pathways leads to the secretion of thromboxane. Platelet granules release their contents (dense [δ] granules contain serotonin and ADP, and α granules contain growth factors and adhesive proteins). The release of these granules contributes to the “second wave” of platelet aggregation, which involves recruiting and activating of additional platelets, contributing to the strength of the platelet plug formed. Platelets also serve as an important “platform” on which the proteins of the coagulation cascade interact.
These surprisingly complex cell fragments are critical to the initiation and perpetuation of thrombus formation. Abnormalities of platelet surface GPs, agonist receptors, intracellular signaling pathways, cytoskeleton structure, and granule content or release can lead to mild or severe bleeding disorders ( Fig. 2 ). Although a detailed description of the specifics of each of these disorders is beyond the scope of this review, the most common and severe of these disorders are summarized in Table 1 , along with clinical features and diagnostic results. More detailed discussions of specific PFD are available in several recent reviews.
| Class of Abnormality | Defect | Severity and Inheritance | Clinical Features | Laboratory Diagnosis | Special Comments a |
|---|---|---|---|---|---|
| Platelet surface GP | |||||
| BSS | Absent GP1b/IX/V expression |
|
| Platelet aggregation: no agglutination with ristocetin | Confirm with flow cytometry or immunoblot for GP1b expression |
| GT | Absent GPIIb/IIIa expression |
|
| Platelet aggregation: severe impairment to all agonists except ristocetin | Confirm with flow cytometry or immunoblot for GP IIb/IIIa expression |
| Platelet-type (“pseudo”) VWD | GPIbα mutation → increased avidity for VWF |
|
| Platelet aggregation: increased agglutination to low-dose ristocetin Decreased high-molecular weight VW multimers | Platelet-mixing studies and genetics required to distinguish from VWD type 2B |
| Platelet receptors for soluble agonists | |||||
| Absent or abnormal receptor for platelet agonists |
| Variable | Platelet aggregation: impaired aggregation to specific agonist | — |
| Platelet granules | |||||
| δ-storage pool deficiency | Deficiency of dense granules |
| “Nonsyndromic” or “syndromic”:
|
|
|
| Gray platelet syndrome | Deficiency of α granules |
| “Gray, ghostly” platelets, may be abnormally large ± thrombocytopenia
| Platelet aggregation: may have impaired response to thrombin and collagen | Confirm with platelet EM |
| αδ-granule disorder | Deficiency of α and δ granules |
| Normal platelet count | Platelet aggregation: impaired 2nd wave | Reduced secretion of ATP or serotonin Confirm with platelet EM |
| Quebec platelet disorder | Abnormal proteolysis of α granules from increased expression of urokinase plasminogen activator |
| ± thrombocytopenia Excessive fibrinolysis, resembles defect of secondary hemostasis
| Platelet aggregation: impaired to epinephrine | Reduced α granules |
| Signal-transduction pathways | |||||
| Cyclooxygenase deficiency | — | Mild-moderate | Aspirin-like defect | Platelet aggregation: absent to arachidonic acid, diminished to other agonists | Absent COX expression by immunoblot |
| Thromboxane synthase defects | — | Mild-moderate | — | — | — |
The classic textbook PFD, including Bernard-Soulier syndrome (BSS, absent GP1b/IX/V) or Glanzmann thrombasthenia (GT, absent GPIIb/IIIa), are associated with severe bleeding symptoms, are relatively straightforward to diagnose, and are fortunately, rare disorders. In contrast, milder PFD are more subtle in their presentation, and much more challenging to diagnose. There is increasing recognition that such mild disorders are far more common than previously recognized and may even be more common than VWD. For example, in a retrospective review of 105 patients with heavy menstrual bleeding referred to a pediatric hematology clinic for evaluation, 62% were diagnosed with a bleeding disorder. Of these, platelet storage pool deficiency (36%) was 4 times as common as VWD (9%), and an additional 8% had other platelet function defects. In contrast, other studies have found different proportions of bleeding disorders in such patients. A study by Mikhail and colleagues of 61 adolescents with menorrhagia referred to a different hematology center demonstrated that 36% had VWD and only 7% had platelet aggregation abnormalities. Such differences reflect, in part, referral differences as well as varying definitions of both menorrhagia and bleeding disorders, and even more importantly, differences in diagnostic testing. Nevertheless, these recent studies reinforce the importance of considering a PFD when evaluating a patient with excessive bleeding, particularly an adolescent with menorrhagia.
Introduction: nature of the problem
Previously thought to be a rare disorder, primary abnormalities of platelet function are increasingly recognized in pediatrics and can result in bleeding symptoms of varying severity (reviewed in Refs. ). In fact, recent studies have suggested that platelet function disorders (PFD) are at least as common as von Willebrand disease (VWD) in specific patient populations, such as adolescents with menorrhagia. However, the diagnosis of PFD is challenging, especially for the less severe abnormalities.
Platelets are critical for the process of primary hemostasis. At the time of vessel injury, the subendothelium is exposed, leading to the binding of von Willebrand factor (VWF) multimers to collagen ( Fig. 1 ). In the setting of shear forces from flowing blood, this large molecule stretches, exposing binding sites for platelets. Once bound to collagen through the bridging VWF protein (via the platelet surface glycoprotein [GP]Ib/IX/V complex), enhanced by the binding of platelet agonists such as thrombin, epinephrine, and ADP, to surface receptors, platelets are activated. Activation results in a rapid cytoskeletal rearrangement, which leads to a configurational change and then recruitment of and aggregation with other platelets, primarily via the surface GPIIb-IIIa (mediated by fibrinogen and VWF). The activation of intracellular signaling pathways leads to the secretion of thromboxane. Platelet granules release their contents (dense [δ] granules contain serotonin and ADP, and α granules contain growth factors and adhesive proteins). The release of these granules contributes to the “second wave” of platelet aggregation, which involves recruiting and activating of additional platelets, contributing to the strength of the platelet plug formed. Platelets also serve as an important “platform” on which the proteins of the coagulation cascade interact.
These surprisingly complex cell fragments are critical to the initiation and perpetuation of thrombus formation. Abnormalities of platelet surface GPs, agonist receptors, intracellular signaling pathways, cytoskeleton structure, and granule content or release can lead to mild or severe bleeding disorders ( Fig. 2 ). Although a detailed description of the specifics of each of these disorders is beyond the scope of this review, the most common and severe of these disorders are summarized in Table 1 , along with clinical features and diagnostic results. More detailed discussions of specific PFD are available in several recent reviews.
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