Platelet Storage Pool Diseases

Platelet Storage Pool Diseases

Roger S. Riley, M.D., Ph.D.

Feature
Synonyms Epidemiology None.

Disease Facts
Inherited platelet storage pool defects are rarely diagnosed, although the true incidence is unknown. Acquired platelet storage pool defects induced by cardiovascular bypass is a common clinical problem. Patients with platelet storage pool disorders have absent or diminished or absent alpha or dense granules or granule contents. Primary hemostasis is deficient as a consequence and patients may develop platelet-type bleeding manifestations. The four major types of congenital platelet storage pool disease identified at present are described in Table I. In addition, storage pool defects are associated with a variety of other inherited diseases, including the Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, Wiskott-Aldrich syndrome, and thrombocytopenia-absent radius (TAR) syndrome. Disorder
Dense body deficiency Gray platelet syndrome Factor V Quebec Mixed -granule/dense body deficiency

Etiology & Pathogenesis

Etiology
Decreased dense bodies with decreased secretion of ADP and serotonin Decreased -granules and contents Severe multimerin deficiency, protease degradation of -granules Decreased -granules and dense bodies

Acquired platelet storage pool defects are seen in conjunction with systemic lupus erythematosus (SLE), cardiovascular bypass, hairy-cell leukemia, and other disorders with chronic platelet activation. In SLE, platelet-specific autoantibodies and immune complexes binding to the platelet surface lead to platelet activation and secretion of granule contents. In cardiopulmonary bypass, platelet activation is caused by contact with the membrane oxygenator. Pattern of Inheritance Clinical Presentation Variable, predominately autosomal recessive.

Patients with platelet storage pool defects present with platelet-type hemorrhagic signs that are similar to those found in patients with von Willebrands disease. Clinical problems may include bleeding into the skin and mucous membranes (petechiae, ecchymoses), epistaxis, menorrhagia, gastrointestinal hemorrhage, or bleeding after surgery or trauma. Musculoskeletal and intracranial hemorrhage is unusual. The clinical severity varies considerably depending on the relative degree of residual platelet function.

Platelet Storage Pool Diseases

Feature
Laboratory Features

Disease Facts
A mild to moderate thrombocytopenia may be present. Platelet morphology is normal in most diseases, although patients with the gray platelet syndrome have characteristic large, agranular platelets. The bleeding time os prolonged and other assays of primary hemostasis, such as the PFA-100 closure time are abnormal. Platelet aggregation studies are used to confirm the diagnosis and provide some indication of the etiology. A variety of specialized assays may be required for a definitive diagnosis. Bleeding time. Bleeding times are performed directly on the patient by technologists who are trained and experienced in this assay. A blood pressure cuff is placed on the upper arm and inflated to 40 mm Hg to provide uniform capillary pressure, and a standardized incision is made on the volar surface of the forearm with a standard cutting device (Surgicut). The incision is blotted with filter paper at 30-second intervals until bleeding ceases. The result is reported in minutes as the bleeding time. Unfortunately, in spite of the optimal technologist training and experience, and the establishment of standardized conditions for the performance of the bleeding time, there are a number of factors that severely limit its precision, accuracy, and reproducibility. These include the thickness and vascularity of the skin, the location of the incision, skin temperature, wound depth, and patient anxiety. Because of these influences, the upper range of the bleeding time varies from 6.5 minutes to 10 minutes in adults, and variations of 2 to 3 minutes between repeated bleeding times are not uncommon in individual patients. The bleeding time is inversely related to the platelet count and these two parameters show a linear relationship in patients with platelet counts < 100,000/ L. However, platelet function in thrombocytopenic patients cannot be reliably predicted from the bleeding time, and this assay does not provide any clinically useful information in patients with platelet counts < 100,000/L. Platelet aggregation. Aggregometry measures the in vivo response of platelets to various chemical agents (aggregating agents, platelet agonists), that induce platelet functional responses. Conventional platelet aggregometers are modified spectrophotometers which measure light transmission through platelet-rich plasma (PRP). Although the turbidity of fresh PRP limits light transmission, transmission progressively increases as platelet aggregation causes the formation of larger and larger particles. Unfortunately, platelet aggregation is a complex laboratory assay which is subject to many influences, not all of which can be controlled by the laboratory. These influences include chemical substances such as drugs and dietary components, specimen collection and processing, platelet count, assay conditions (i.e., pH, ionic strength, etc.), platelet agonists (Source, concentration, etc.), technical procedure, and interpretation of the results. The platelet agonists used in clinical laboratories to differentiate the various platelet function defects include ADP, epinephrine, collagen, ristocetin, and arachidonic acid. Other agonists, such as thrombin, vasopressin, serotonin, thromboxane A2 (TXA2), platelet activating factor, and other agents are used by research and some specialized clinical laboratories. ADP binds to a specific receptor (CD41) associated with the GPIIb/IIIa complex and Ca++. The reversible binding of fibrinogen to this complex induces a platelet shape change (biconcave disk to spiky sphere), followed by the release of arachidonic acid and thromboxane A2 generation, and eventually and dense granule release. The shape change is reflected as a slight downturn in the aggregometry tracing (increased turbidity, followed by a reversible primary wave of aggregation and then an irreversible secondary wave.

Platelet Storage Pool Diseases

Pattern of Inheritance

These changes can be seen in aggregometry studies at a final ADP concentration of 2 mmol/L. Lower concentrations may be enzymatically degraded without inducing a platelet effect or may induce only primary aggregation, while higher concentrations mask the distinction between primary and secondary waves. Epinephrine (adrenaline) induces platelet aggregation without a shape change. Activation of the fibrinogen receptor is followed by primary and secondary aggregation. Although a weak agonist alone, epinephrine exerts a synergistic effect in association with other agonists. Arachidonic acid directly induces thromboxane A2 release and granule release without membrane interactions if cyclooxygenase and the more distal parts of platelet metabolism are normally active. Arachidonic acid (ACA), at a final concentration of 0.5 - 1.5 mmol/L, induces a short lag phase, followed by a large monophasic wave of aggregation. Collagen places an extremely important natural role in platelet function, since exposure to the exposed subendothelial collagen fibers (especially type III collagen) of damaged vasculature subendothelium is the normal initiating event of platelet activation. The specific receptor(s) for collagen is presently unknown, but platelet-collagen interactions (at low collagen concentrations, 1 mg/L) result in activation of the prostaglandin pathway, with thromboxane A2 formation and release of granular contents. Higher collagen concentrations ( 2 mg/L) induce calcium flux, and granule release without prostaglandin activation. Several commercial preparations of collagen are available for platelet aggregation studies. Aggregometry tracings with collagen include a concentrationdependent lag phase (10 - 60 seconds) followed by a shape change and then by a large monophasic wave. The response to collagen is a sensitive measure of the platelet prostaglandin pathway, since all components of the arachidonic acid cascade must be functional. Ristocetin interacts with the FVIII:R/vWF and CD42b (GP Ib) on the platelet surface to induce platelet aggregation. Ristocetin at the proper concentration (1.0 - 1.25 mg/ml) induces a biphasic response. The primary aggregation wave is caused by an interaction between platelet CD42b and vWF, and the magnitude of this response reflects the amount of vWF in the plasma. A secondary wave follows the release of endogenously-stored platelet mediators. Platelet aggregation at a lower ristocetin concentration (0.3 - 0.5 mg/mL) is also used in cases of suspected von Willebrand's disease, since this induces aggregation in type IIb vWF, but not in normal subjects or patients with other vWF variants.

Treatment

Platelet concentrates are used cautiously to prevent the risk of platelet alloimmunization. Medications that induce platelet dysfunction, especially aspirin, must be avoided. Gene therapy is under evaluation for some diseases. Alves-Filho JC: Toll-like receptors on platelets: the key for disseminated intravascular coagulation in sepsis? Thromb Res 115:537, 2005 Baldini MG, Myers TJ: One more variety of 'storage pool disease'. Jama 244:173, 1980 Biddle DA, Neto TG, Nguyen AN. Platelet storage pool deficiency of alpha and delta granules. Arch. Pathol. Lab. Med. 125:1125-1126, 2001. Cattaneo M: Inherited plateletbased bleeding disorders. J Thromb Haemost 1:1628, 2003 Clemetson KJ: Platelet receptors and their role in diseases. Clin Chem Lab Med 41:253, 2003 Curry H: Bleeding disorder basics. Pediatr Nurs 30:402, 2004 Engelmann G, Morgenstern E, Wolf N, Mayatepek E. Deltastorage pool disease in infancy with absence of blood serotonin associated with psychomotor retardation. Pediatr. Hematol. Oncol. 18:355-357, 2001. Favaloro EJ: Clinical application of the PFA100. Curr Opin Hematol 9:407, 2002 Harrison P: Measuring platelet function? Hematol J 5 Suppl 3:S164, 2004 Hayward CP: Inherited platelet disorders. Curr Opin Hematol 10:362, 2003

References

Platelet Storage Pool Diseases

References Hayward CP, Weiss HJ, Lages B, et al. The storage defects in grey platelet syndrome and alphadeltastorage pool deficiency affect alpha-granule factor V and multimerin storage without altering their proteolytic processing. Br. J. Haematol. 113:871-877, 2001. Hickerson DH, Bode AP: Flow cytometry of platelets for clinical analysis. Hematol Oncol Clin North Am 16:421, 2002 Huizing M, Boissy RE, Gahl WA: Hermansky-Pudlak syndrome: vesicle formation from yeast to man. Pigment Cell Res 15:405, 2002 Huizing M, Gahl WA: Disorders of vesicles of lysosomal lineage: the Hermansky-Pudlak syndromes. Curr Mol Med 2:451, 2002 Iannello S, Fabbri G, Bosco P, et al: A clinical variant of familial Hermansky-Pudlak syndrome. MedGenMed 5:3, 2003 Imai K, Nonoyama S, Ochs HD: WASP (Wiskott-Aldrich syndrome protein) gene mutations and phenotype. Curr Opin Allergy Clin Immunol 3:427, 2003 Jamieson GA, Okumura T, Fishback B, et al: Platelet membrane glycoproteins in thrombasthenia, Bernard-Soulier syndrome, and storage pool disease. J Lab Clin Med 93:652, 1979

Kottke-Marchant K, Corcoran G: The laboratory diagnosis of platelet disorders. Arch Pathol Lab Med 126:133, 2002 Kunishima S, Kamiya T, Saito H: Genetic abnormalities of BernardSoulier syndrome. Int J Hematol 76:319, 2002 Metcalfe P: Platelet antigens and antibody detection. Vox Sang 87 Suppl1:82, 2004 Michelson AD: How platelets work: platelet function and dysfunction. J Thromb Thrombolysis 16:7, 2003 Nair S, Ghosh K, Kulkarni B, et al: Glanzmann's thrombasthenia: updated. Platelets 13:387, 2002 Norton A, Allen DL, Murphy MF: Review: platelet alloantigens and antibodies and their clinical significance. Immunohematol 20:89, 2004 Notarangelo LD, Mori L: WiskottAldrich syndrome: another piece in the puzzle. Clin Exp Immunol 139:173, 2005 Ochs HD: The Wiskott-Aldrich syndrome. Isr Med Assoc J 4:379, 2002 Orange JS, Stone KD, Turvey SE, et al: The Wiskott-Aldrich syndrome. Cell Mol Life Sci 61:2361, 2004

Pati H, Saraya AK: Platelet storage pool disease. Indian J Med Res 84:617, 1986 Pujol-Moix N, Hernandez A, Escolar G, Espanol I, MartinezBrotons F, Mateo J. Platelet ultrastructural morphometry for diagnosis of partial delta-storage pool disease in patients with mild platelet dysfunction and/or thrombocytopenia of unknown origin. A study of 24 cases. Haematologica. 85:619-626, 2000. Ramasamy I: Inherited bleeding disorders: disorders of platelet adhesion and aggregation. Crit Rev Oncol Hematol 49:1, 2004 Rand ML, Leung R, Packham MA: Platelet function assays. Transfus Apheresis Sci 28:307, 2003 Rao AK, Jalagadugula G, Sun L: Inherited defects in platelet signaling mechanisms. Semin Thromb Hemost 30:525, 2004 Santoso S: Human platelet alloantigens. Transfus Apheresis Sci 28:227, 2003 Zahavi J, Marder VJ: Acquired "storage pool disease" of platelets associated with circulating antiplatelet antibodies. Am J Med 56:883, 1974