Quebec platelet syndrome: from the bench to the family

Bleeding manifestations were quantitatively assessed in 23 affected and 104 unaffected members of a single family with the Quebec platelet disorder, an autosomal dominant trait caused by deficient platelet alpha granule procoagulant proteins.

McKay and colleagues (page 159) describe a careful, systematic evaluation of bleeding problems in a very large kindred with the Quebec platelet disorder (QPD). The pathophysiology of QPD is well defined. It is an autosomal dominant trait with increased megakaryocyte expression and storage of urokinase-type plasminogen activator (u-PA). The u-PA generates plasmin, causing degradation of platelet fibrinogen and other α-granule proteins important for hemostasis. Measurements of platelet u-PA and α-granule fibrinogen degradation products allow accurate identification of affected family members and clear distinction from unaffected family members. To assess the nature and severity of bleeding problems among family members, McKay and colleagues developed a questionnaire specific for QPD. Their study has important lessons for hematologists who investigate and manage patients with bleeding disorders.

First, the methodology is a model for clinical research. Too often clinical research is based on sound laboratory methods, but the patient observations are not quantitative and may not be reproducible. In this study the patient observations are made with rigorous attention to quantitative analysis.

Second, McKay and colleagues documented that some bleeding symptoms, such as very large bruises and bruises that tracked downward, occurred exclusively among affected family members, while the frequency of other bleeding symptoms, such as nosebleeds that lasted longer than 15 minutes, were not different between affected and unaffected family members. These observations remind us that healthy people do bleed, a simple but often overlooked fact, and that characterization of bleeding as abnormal may be difficult. Instruments such as this questionnaire provide the ability to define and measure abnormal bleeding. These instruments will allow quantitative estimates of the risk of bleeding with inherited disorders, comparable with our current ability to estimate risks for thrombosis in patients with inherited thrombophilia traits.

Third, the quantitative assessment by McKay and colleagues documented heterogeneity of bleeding manifestations among affected and unaffected family members. In such a large kindred, this may be expected because bleeding symptoms ultimately result from the interactions among multiple risk factors. For example, some unaffected family members who reported bleeding symptoms may have had undiagnosed von Willebrand disease type 1, a common risk factor for excessive bleeding. Some family members affected by QPD who reported less bleeding may have also inherited the factor V Leiden trait or another prothrombotic trait, which could diminish the risk for bleeding. The use of quantitative measures of bleeding symptoms will allow greater understanding of the interactions of multiple common inherited traits on the risks for excessive bleeding.

Fourth, the types of bleeding symptoms manifested by patients with QPD are intriguing. We teach our students that clinical evaluation can distinguish patients who have abnormalities of primary hemostasis, such as platelet disorders, from patients who have abnormalities of coagulation, such as hemophilia. We say that abnormalities of primary hemostasis are manifested by the prompt occurrence of mucocutaneous bleeding, while abnormalities of coagulation are manifested by delayed bleeding with hemarthroses and large visceral hematomas. Patients with QPD had both types of bleeding. In addition to mucocutaneous bleeding, affected family members commonly reported joint bleeds and bleeding that began 12 hours or more after trauma. These clinical manifestations are consistent with the abnormalities of QPD, since it is not only a disorder of platelet function with abnormalities of aggregation but also a disorder of fibrin clot formation and fibrinolysis.

Therefore read this article not only to learn about the clinical manifestations of a rare inherited platelet abnormality, read it to learn how the application of quantitative and reproducible clinical assessments can reveal new insights into hematologic disorders.FIG1