Hereditary Platelet Disorders and Acquired Platelet Function Disorders
Pathophysiology
ACQUIRED PLATELET DYSFUNCTION
Final report on the aspirin component of the ongoing Physicians' Health Study: Steering Committee of the Physicians' Health Study Research Group.
N Engl J Med. 1989; 321:129-135.
Description: This is the study that documents the proven association between aspirin use and risk of bleeding (for many other drugs, there is only evidence for abnormal in vitro platelet aggregation or prolonged bleeding times, which may or may not have clinical significance).
PubMed citation number: 9484723
Bleeding complications associated with cardiopulmonary bypass.
Woodman RC, Harker LA.
Blood. 1990;76:1680-1697.
Description: A nice review of the mechanisms underlying platelet dysfunction during and after cardiopulmonary bypass.
PubMed citation number: 2224118
Congenital Platelet Dysfunction
ADHESION
Bernard-Soulier Syndrome.
López JA, Andrews RK, Afshar-Kharghan V, Berndt MC.
Blood. 1998;91:4397-4418.
Description: A quite comprehensive review, detailing not only the structure and function of GP Ib-IX-V, but also the pathophysiology, genetics, diagnosis, clinical characteristics, and treatment of Bernard-Soulier Syndrome. It also serves as an excellent source of references for further reading.
PubMed citation number: 9616133
AGGREGATION
Glanzmann's thrombasthenia: the spectrum of clinical disease.
George JN, Caen JP, Nurden AT.
Blood. 1990;75:1383-1395.
Description: A detailed review of the clinical manifestations of Glanzmann’s thrombasthenia in a large cohort of patients. This review also describes the division of Glanzmann's Thrombasthenia into Type I, II, and variants, but this division is based on functional data, and predates more modern understanding of pathophysiology, so it is of only historical interest.
PubMed citation number: 2180491
SIGNALING/SECRETION
Heterogeneous defects of platelet secretion and responses to weak agonists in patients with bleeding disorders.
Weiss, HJ Lages B.
Br J Haematol. 1988;68:53-62.
Description: A study of 11 patients thought to have platelet secretory defects. Eight of them were found to have so-called weak agonist-response defects (WARDs), in which platelets were found to have decreased rates and extent of aggregation in response to weak agonists (agonist that induce secretion only after aggregation), but normal response to strong agonists (agonists that induce secretion in absence of aggregation). This suggests that these 11 patients had defects in the responses that precede secretion. The other 3 patients were found to have defects in the secretory mechanism itself.
PubMed citation number: 3345296
Positional cloning of a gene for Hermansky-Pudlak syndrome, a disorder of cytoplasmic organelles.
Oh J, Bailin T, Fukai K, et al.
Nature Genet. 1996;14:300-306.
Description: The first paper to report successful cloning of the HSP1 gene. The protein encoded by the gene is hypothesized to be a component of multiple cytoplasmic organelles. The authors also characterize mutations in Puerto Rican, Swiss, Irish, and Japanese families.
PubMed citation number: 8896559
The Wiskott-Aldrich syndrome.
Ochs HD.
Semin Hematol. 1998;35:332-345.
Description: A review written by 1 of the first 2 investigators to clone the WASP gene. It describes the clinical and genetic features of classic Wiskott-Aldrich syndome and X-linked thrombocytopenia (in which the same gene is also mutated), what is known of the structure and function of the WASP gene, and options for treatment of these disorders.
PubMed citation number: 9801262
Newly recognized cellular abnormalities in the gray platelet syndrome.
Drouin A, Favier R, Massé J-M, et al.
Blood. 2001;98:1382-1391.
Description: A study of 3 pediatric patients with gray platelet syndrome. They were found to have abnormalities of neutrophil granules. In these patients, cultured megakaryocytes appeared to abnormally process von Willebrand factor, with secretion into the extracellular space rather than normal alpha-granule packaging. In contrast, the processing of P-selectin appeared to be normal.
PubMed citation number: 11520786
Asp1424Asn MYH9 mutation results in an unstable protein responsible for the phenotypes in May-Hegglin anomaly/Fechtner syndrome.
Deutsch S, Rideau A, Bochaton-Piallat M-L, et al.
Blood. 2003;102:529-534.
Description: Familial macrothrombocytopenias with leukocyte inclusion bodies are a rare group of autosomal dominant disorders with mild bleeding tendencies. May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome have all been shown to be allelic variations of a single genetic disorder involving the MYH9 gene. It is hypothesized that these disorders are caused by defects in megakaryocyte demarcation membranes and defective thrombopoiesis. The function of the protein encoded by MHY9 is not fully understood. In this paper, the authors characterize MHY9 protein localization and expression, as well as mRNA stability, to better understand the pathophysiology of these syndromes.
PubMed citation number: 12649151
PROCOAGULANT ACTIVITY
Scott syndrome: a disorder of platelet coagulant activity.
Weiss HJ.
Semin Hematol. 1994;31:312-319.
Description: A description of Scott syndrome, a rare but severe bleeding disorder characterized by defects in the membrane catalytic tenase activity and prothrombinase activity. This defect results from an impaired binding of coagulation factors Va and VIIIa by activated platelets, reflecting a diminished surface exposure of phosphatidylserine.
PubMed citation number: 7831576
CONGENITAL THROMBOCYTOPENIC DISORDERS
Inherited thrombocytopenias: toward a molecular understanding of disorders of platelet production.
Geddis AE, Kaushansky K.
Curr Opin Pediatr. 2004;16:15-22.
Description: A review that summarizes current understanding of the molecular and genetic defects underlying several congenital thrombocytopenic disorders, many of which are also associated with platelet dysfunction. PubMed citation number: 14758109
Diagnosis
A critical reappraisal of the bleeding time.
Channing Rodgers RP, Levin J.
Semin Thromb Hemost. 1990;16:1-20.
Description: A comprehensive review of 862 articles that attempts to define the sensitivity and specificity of the bleeding time for detecting various types of platelet dysfunction or bleeding risk using ROC analysis.
PubMed citation number: 2406907
Treatment
Desmopressin (DDAVP) in the treatment of bleeding disorders: the first 20 years.
Mannucci PM.
Blood. 1997;90:2515-2521.
Description: A review of desmopressin use that includes history, mechanisms, and indications.
PubMed citation number: 9326215
Hemostatic drugs.
Mannucci PM.
N Engl J Med. 1998;339:245-253.
Description: Review of various drugs used in the management of hemorrhagic disorders.
PubMed citation number: 9673304
Review
The clinical importance of acquired abnormalities of platelet function.
George JN, Shattil SJ.
N Engl J Med. 1991;324:27-39.
Description: A classic review of acquired platelet dysfunction.
PubMed citation number: 1984161
Inherited defects of platelet function.
Nurden AT, Nurden P.
Rev Clin Exp Hematol. 2001;5:314-334.
Description: A fairly comprehensive review of several inherited defects of platelet function. It primarily describes the pathophysiology and genetic basis for each defect, including defects of platelet adhesion, signaling, secretion, aggregation, and procoagulant activity. As most of these syndromes are quite rare, detailed references for them are beyond the scope of this reading list. This reference serves as a source of general information about these disorders and of references for further reading.
PubMed citation number: 11844132
Inherited defects in platelet signaling mechanisms.
Koneti Rao A.
J Thromb Haemost. 2003;1:671-681.
Description: A review of inherited platelet defects organized according to the different physiologic functions of platelets. It includes disorders not found in the previous review.
PubMed citation number: 12871400