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PubMed2004

Molecular defects that affect platelet dense granules.

Platelet dense granules form using mechanisms shared by melanosomes in melanocytes and by subsets of lysosomes in more generalized cells. Consequently, disorders of platelet dense granules can reveal how organelles form and move within cells. Models for the study of new vesicle formation include isolated delta-storage pool deficiency, combined alphadelta-storage pool deficiency, Hermansky-Pudlak syndrome (HPS), Chediak-Higashi syndrome, Griscelli syndrome, thrombocytopenia absent radii syndrome, and Wiskott-Aldrich syndrome. The molecular bases of dense granule deficiency are known for the seven subtypes of HPS, as well as for Chediak-Higashi syndrome, Griscelli syndrome, and Wiskott-Aldrich syndrome. The gene products involved in these disorders help elucidate the generalized process of the formation of vesicles from extant membranes such as the Golgi.

Blood Platelet Disorders↗

PubMed2006

The Slc35d3 gene, encoding an orphan nucleotide sugar transporter, regulates platelet-dense granules.

Platelet dense granules are lysosome-related organelles which contain high concentrations of several biologically important low-molecular-weight molecules. These include calcium, serotonin, adenine nucleotides, pyrophosphate, and polyphosphate, which are necessary for normal blood hemostasis. The synthesis of dense granules and other lysosome-related organelles is defective in inherited diseases such as Hermansky-Pudlak syndrome (HPS) and Chediak-Higashi syndrome (CHS). HPS and CHS mutations in 8 human and at least 16 murine genes have been identified. Previous studies produced contradictory findings for the function of the murine ashen (Rab27a) gene in platelet-dense granules. We have used a positional cloning approach with one line of ashen mutants to establish that a new mutation in a second gene, Slc35d3, on mouse chromosome 10 is the basis of this discrepancy. The platelet-dense granule defect is rescued in BAC transgenic mice containing the normal Slc35d3 gene. Thus, Slc35d3, an orphan member of a nucleotide sugar transporter family, specifically regulates the contents of platelet-dense granules. Unlike HPS or CHS genes, it has no apparent effect on other lysosome-related organelles such as melanosomes or lysosomes. The ash-Roswell mouse mutant is an appropriate model for human congenital-isolated delta-storage pool deficiency.

Animals↗

PubMed1988

Platelet volume and intraplatelet adenine nucleotides in various hematologic disorders.

By recent advanced techniques, blood platelets have proved to be varied in size and metabolism in various hematologic disorders. We examined platelet volume and intraplatelet adenine nucleotides in 36 patients with various hematologic disorders in order to clarify the quantitative platelet abnormalities. Platelet volumes were smaller in patients with acute leukemia and aplastic anemia, and larger in patients with immune thrombocytopenic purpura (ITP). The amount of intraplatelet ADP was decreased and ATP/ADP ratio was increased in acute leukemia, aplastic anemia and myeloproliferative disorders (MPD), which strongly suggested the presence of storage pool deficiency in these patients. Intraplatelet ADP per volume was decreased in acute leukemia, aplastic anemia and MPD, and ATP per volume was decreased in aplastic anemia. ATP content was increased in ITP in proportion to the increased platelet volume. These parameters were examined in 36 patients with the following hematologic disorders: 7 acute leukemia treated with cytotoxic chemotherapy, 5 aplastic anemia, 3 paroxysmal nocturnal hemoglobinuria (PNH), 9 immune thrombocytopenic purpura (ITP), 5 hypersplenism and 7 myeloproliferative disorders (MPD).

Acute Disease↗

PubMed1975

Hereditary giant platelet syndrome. Absence of collagen-induced coagulant activity and deficiency of factor-XI binding to platelets.

The platelets from two related patients with the hereditary giant platelet syndrome were examined. They were larger than normal but otherwise ultrastructurally normal; they contained increased storage pools of adenine nucleotides and heparin-neutralizing activity and took up serotonin at an increased rate. They aggregated normally with ADP and collagen but failed to aggregate with bovine factor VIII and Ristocetin. Some change in shape occurred with ADP, and the reduction in adenylate energy change after addition of ADP to platelet-rich plasma was smaller than normal. Platelet coagulant activities including contact product forming activity, intrinsic factor-Xa forming activity and platelet factor 3 activity were normal or increased, but collagen-induced coagulant activity was absent whether tested in washed platelet suspensions or platelet-rich plasma. Platelet washing experiments showed decreased binding of factors V and VIII to hereditary giant platelets and no detectable factor XI in washed platelet suspensions. It is concluded that (1) the hereditary giant platelets studied lacked a binding mechanism for factors, V, VIII and XI; (2) the normal development of collagen-induced coagulant activity apparently depends upon the binding of factor XI to the platelet membrane; and (3) the defective prothrombin consumption observed in these patients may have resulted from the failure of their platelets to bind factor XI.

Adenine Nucleotides↗

PubMedDate not supplied

[The role of adenine nucleotides in the functional activity of platelets in hemophilia A].

Content of adenine nucleotides was studied in various pools of thrombocytes from donors and from patients with hemophilia A. Biochemical deficiency of adenine nucleotides appears to occur in the pool of thrombocytes obtained from patients with hemophilia A; estimation of ADP and ATP in the storage granules as well as of the nucleotides specific radioactivity may serve as a criterion of thrombocyte disfunction.

Adenine Nucleotides↗

PubMed2004

Soluble fibrin is the main mediator of Staphylococcus aureus adhesion to platelets.

BACKGROUND: Infective endocarditis (IE) caused by Staphylococcus aureus is associated with significant morbidity and mortality rates. Platelets play a dual role as adhesive cells forming associates with bacteria as well as specialized inflammatory cells. The specific role of the various factors involved in bacteria-platelet association has not yet been fully elucidated. METHODS AND RESULTS: We observed a dramatic increase in the capability to bind S aureus when platelets were activated with thrombin (from 5% to 30%, P<0.001). To pinpoint platelet-binding sites involved in the interaction, platelets from knockout mice and from patients with selective inherited deficiency of membrane proteins or of granules were used. CD36, GPIIb/IIIa, and P-selectin were excluded as receptors for S aureus. Platelets from patients with alpha-delta-storage pool disease and Gray platelet syndrome indicate the requirement of alpha-granule contents. Platelet activation by ADP did not promote platelet-S aureus associate formation, although these platelets were covered with bound fibrinogen. Only small numbers of associates between fibrinogen-covered bacteria and ADP-activated platelets were observed. Formation of fibrin alone was also not sufficient to induce association. Only when fibrin formation and platelet activation occurred together were large numbers of associates formed (P<0.001). A potential receptor for fibrin on S aureus is clumping factor A. Addition of thrombospondin-1 to control platelets increased the number of associates (P=0.02). CONCLUSIONS: Soluble fibrin but not fibrinogen is the main mediator of platelet-S aureus association. In addition, platelet activation and the release of alpha-granule contents, particularly thrombospondin-1, is a requirement for platelet-S aureus association.

Adenosine Diphosphate↗

PubMed1995

Mechanisms of platelet dysfunction and response to DDAVP in patients with congenital platelet function defects. A double-blind placebo-controlled trial.

To examine the impact of the underlying defective platelet mechanism on the response to 1-desamino-8-D-arginine vasopressin (DDAVP, Desmopressin), we studied the effect of intravenous infusion of 0.3 microgram/kg of DDAVP in a randomized double blind placebo-controlled trial with cross-over in 18 carefully characterized patients with congenital platelet defects (CPD) and BT > or = 9 min. Eleven patients had normal dense granule stores and normal thromboxane A2 (TxA2) production (Group I), 3 patients had normal granule stores but impaired TxA2 production (Group II), and 4 had delta-storage pool deficiency (Group III). DDAVP shortened BT at 50 min (DDAVP 14.6 +/- 2.2 vs placebo 19.6 +/- 2.3 min; n = 18; mean +/- SE; p = 0.003) and 4 h (17.0 +/- 2.2 vs 19.6 +/- 2.1 min, p = 0.055), and raised plasma FVIIIC and von Willebrand factor (vWF). At 50 min DDAVP shortened BT by > or = 5 min in 8 of 11 Group I patients (mean 9.7 +/- 1.3 vs 16.3 +/- 2.8 min; p < 0.008), 1 of 3 Group II patients (11.9 +/- 3.9 vs 17.7 +/- 6.6; p = NS) and none of Group III patients (mean 30 min both arms). Ten patients (Group I or II) were managed successfully during surgical procedures with DDAVP alone. We conclude that DDAVP shortens BT in majority of CPD patients with normal dense granule stores and suggest that BT response may be dependent on the underlying platelet defect. DDAVP is a useful modality in management of selected patients, particularly those with normal dense granule stores.

Bleeding Time↗

PubMed2006

The paradox of platelet activation and impaired function: platelet-von Willebrand factor interactions, and the etiology of thrombotic and hemorrhagic manifestations in essential thrombocythemia and polycythemia vera.

Patients with essential thrombocythemia (ET) and polycythemia vera (PV), complicated by microvascular ischemic or thrombotic events, have shortened platelet survival, increased beta-thromboglobulin, platelet factor 4, and thrombomodulin levels, and increased urinary thromboxane B2 excretion. These are all reversible by inhibition of platelet cyclooxygenase 1 with aspirin, and are therefore indicative of platelet activation and platelet-mediated thrombotic processes. The thrombotic tendency persists as long as platelet counts are above the upper limit of normal (400 x 10 (9)/L). Despite strong evidence of in vivo platelet activation, the ex vivo platelet function tests are impaired. Platelet dysfunction in ET and PV typically is characterized by a missing second-wave adrenaline aggregation, an increased adenosine diphosphate aggregation threshold, and reduced secretion products, but a normal arachidonic acid or collagen-induced aggregation. The proposed concept is that platelets in thrombocythemia (ET and PV) are hypersensitive. Due to the existing high shear stress in the microvasculature (end-arterial circulation), platelets spontaneously activate, secrete their products, form aggregates mediated by von Willebrand factor (vWF) that transiently plug the microcirculation, deaggregate, and then recirculate as exhausted defective platelets with secondary storage pool disease on ex vivo analysis. At increasing platelet counts from below to above 1000 x 10 (9)/L, the thrombotic condition changes into an overt spontaneous bleeding tendency as a result of a functional vWF deficiency that is caused by proteolysis of large vWF multimers. This is consistent with acquired type 2 von Willebrand syndrome (AvWS). AvWS is reversible by reduction of the platelet count to normal. The acquired JAK2 V617F gain of function mutation is the cause of trilinear myeloproliferative disease with the sequential occurrence of ET and PV. Heterozygous JAK2 V617F mutation with slightly increased kinase activity is enough for the induction of spontaneous megakaryopoiesis and erythropoiesis, and an increase of hypersensitive platelets is the cause of aspirin-sensitive, platelet-mediated microvascular ischemic and thrombotic complications in ET and early PV mimicking ET. Homozygous JAK2 mutation with pronounced increase of kinase activity is associated with pronounced trilinear megakaryocyte, erythroid, and granulocytic myeloproliferation, with the most frequent clinical picture of classical PV complicated by major thrombosis, in addition to the platelet-mediated microvascular thrombotic syndrome of thrombocythemia.

Aspirin↗

PubMed2002

Variable response of Hermansky-Pudlak syndrome to prophylactic administration of 1-desamino 8D-arginine in subsequent pregnancies.

Hermansky-Pudlak syndrome is characterised by oculocutaneous albinism and haemorrhagic diathesis. The bleeding tendency that is associated with this autosomal recessive disease is caused by storage-pool deficiency and has been reported to be controllable by prophylactic administration of 1-desamino 8D-arginine (desmopressin, DDAVP). The DDAVP prophylaxis at the first delivery of our patient did not prevent the severe haemorrhagic sequeal requiring transfusion of packed red cells and platelets, but the same preventive measure was successful at her second childbirth. Response to prophylactic DDAVP administration varies between as well as within patients with Hermansky-Pudlak syndrome.

Adolescent↗

PubMed2000

Platelet function disorders.

Platelet function defects comprise a large and heterogeneous group of bleeding disorders that range in severity from mild to severe. Patients may be asymptomatic; however, the majority who are diagnosed present with easy bruising and mucocutaneous bleeding, or with excessive haemorrhage following injury or surgery. As the complex internal biochemical and signal transduction pathways are further understood, and as structural analysis of platelets advances, more of the mechanisms leading to platelet function defects will be uncovered. Despite advances in the understanding of the etiology of these defects in function, treatment remains fairly rudimentary. For platelet function disorders associated with a defect in a plasma coagulation factor, such as vWD and afibrinogenemia, treatment consists of replacement of the deficient coagulation factor. Adjunctive therapies (such as antifibrinolytics, microfibular collagen, fibrin glue, etc.), DDAVP/Stimate, and platelet transfusions remain the mainstay of therapy available at this time. Corticosteroids may play a role in the management of some of these disorders and may lead to a shortening of bleeding time, especially in storage pool defects or release defects failing to respond to DDAVP/Stimate.

Animals↗

PubMed1985

Infectious and bleeding complications in patients with glycogenosis Ib.

Clinical, hematologic, and immunologic findings were reviewed in 21 patients with glycogenosis Ib. Fifteen of the patients suffered from moderate to severe bacterial infections. Ten patients had excessive epistaxis or bleeding from surgical sites, and eight suffered oral and anal mucosal ulceration. Sixteen of 21 patients exhibited chronic neutropenia associated with abnormalities in myeloid maturation and decreases in the bone marrow storage and peripheral marginating pools. Diminished neutrophil motility was documented in 14 of 15 patients tested, and adherence was decreased in three patients studied. Neutrophil microbicidal activity, reduction of nitroblue tetrazolium, and ingestion were normal in all patients tested. Bleeding times were prolonged in five of eight patients, and results of platelet function studies were abnormal in five individuals. Excessive bleeding in patients with glycogenoses Ia and Ib are similar and may be secondary to the functional deficiency of glucose-6-phosphatase. However, neutropenia, neutrophil dysfunction, and the resulting infectious complications are specific for Ib disease and may be related to abnormal glucose-6-phosphate transport.

Adolescent↗

PubMed2003

Platelet ADP receptors contribute to the initiation of intravascular coagulation.

While the adenosine 5'-diphosphate (ADP) pathway is known to enhance thrombus formation by recruiting platelets and leukocytes to the primary layer of collagen-adhering platelets, its role for the initiation of coagulation has not been revealed. Ex vivo inhibition of the P2Y12 ADP receptor by clopidogrel administration diminished the rapid exposure of tissue factor (TF), the major initiator of coagulation, in conjugates of platelets with leukocytes established by the contact of whole blood with fibrillar collagen. Under in vitro conditions, the P2Y12 and P2Y1 ADP receptors were both found to be implicated in the exposure of TF in collagen-activated whole blood. Immunoelectron-microscopy revealed that collagen elicited the release of TF from its storage pools within the platelets. Functional activation of the intravascular TF was reduced by inhibition of the ADP receptors, partially due to the disruption of the platelet-neutrophil adhesions. Injection of collagen into the venous system of mice increased the number of thrombin-antithrombin complexes, indicative for the formation of thrombin in vivo. In P2Y1-deficient mice, the ability of collagen to enhance the generation of thrombin was impaired. In conclusion, the platelet ADP pathway supports the initiation of intravascular coagulation, which is likely to contribute to the concomitant formation of fibrin at the site of the growing thrombus.

Adult↗

PubMed1998

The molecular basis for the role of zinc in developmental biology.

Zinc regulates the gene expression machinery. It affects the structure of chromatin, the template function of its DNA, the activity of numerous transcription factors and of RNA polymerases. Hence, it determines both the types of mRNA transcripts synthesized and the rate of transcription itself. Alterations in one or more of these zinc dependent processes have been proposed to account for the proliferative arrest and teratology induced by zinc deficiency. To examine this proposal, studies of zinc during X. laevis development have been initiated. The kinetics of X. laevis oocyte zinc uptake and storage and of zinc utilization during embryogenesis have been examined first. Vitellogenin carries zinc into the oocyte. Ten % of the total zinc (10 ng/egg) remains within the cytosol while 90% (90 ng/egg) is stored in the yolk platelets associated with lipovitellin. The cytosolic pool is the source of the zinc for all newly formed metalloproteins involved in embryo development. The yolk platelet zinc pool is stored for later use during early metamorphosis. It is now possible to examine zinc transfer to molecules, such as e.g. transcription factors, and the role of the metal in their function in development and organogenesis.

Animals↗

PubMed2003

Inherited bleeding disorders in Indian women with menorrhagia.

In order to define the prevalence of haemostatic defects in women presenting with menorrhagia in our region, the coagulation data on women bleeders investigated in the Department of Haematology, AIIMS, were analysed. A total of 337 of the 2200 menorrhagic women investigated were characterized to have an inherited bleeding disorder; 221 of these 337 women presented with menorrhagia alone while 116 also had other associated bleeding manifestations as prolonged bleeding from injury site, ecchymotic patches in the skin, epistaxis, haematomas, haemarthroses and major bleeds like intracerebral bleeding. The tests performed included bleeding time (BT), platelet count, prothrombin time (PT), prothrombin consumption index (PCI), activated partial thromboplastin time (APTT), PF3 release with adenosine diphosphate (ADP) at 0 and 20 min, total PF3 assay and platelet Aggregation studies with collagen, ADP, adrenaline, arachidonic acid and ristocetin. Coagulation factor assays, von Willebrand antigen estimation, ristocetin cofactor assay and electron microscopy were performed wherever necessary. Inherited platelet dysfunction was seen in 283 (83.9%) of the patients. Amongst these, isolated PF3 availability defect was seen in 163 (48.4%) cases. Glanzman's thrombasthenia was seen in 30 (8.9%) patients, Storage pool disease in eight (2.4%) patients, arachidonic acid pathway defect in five (1.5%) patients and Bernard-Soulier Syndrome in six (1.8%) patients. In 71 (21.1%) patients, the platelet function defect could not be classified into any specific subtypes. Inherited defects of coagulation were observed in 54 (16%) of the cases. Amongst these, von Willebrand disease (vWD) was the most frequent being seen in 40 (11.9%) of the cases. Factor XIII deficiency was seen in one (0.3%), factor X deficiency in four (1.2%), factor VII deficiency in one (0.3%) and factor XII deficiency in one (0.3%) of the patients. It is concluded that although hereditary platelet function defects constitute a large majority of women bleeders in India but among the coagulation defects, vWD is the commonest as reported from the caucasian population. It is thus suggested that in women presenting with menorrhagia, screening tests for haemostasis especially for vWD and inherited platelet function defects must be performed.

Adolescent↗

PubMed2003

Expression of human factor VIII under control of the platelet-specific alphaIIb promoter in megakaryocytic cell line as well as storage together with VWF.

Hemophilia A, which results in defective or deficient factor VIII (FVIII) protein, is one of the genetic diseases that has been addressed through gene therapy trials. FVIII synthesis does not occur in normal megakaryocytes. In hemophilia patients who have inhibitors to FVIII activity, megakaryocytes could be a protected site of FVIII synthesis and subsequent release. Since von Willebrand factor (VWF) is a carrier protein for FVIII, we hypothesize that by directing FVIII synthesis to megakaryocytes, it would traffick together with VWF to storage in megakaryocyte alpha-granules and the platelets derived from these cells. Such synthesis would establish a protected, releasable alpha-granule pool of FVIII together with VWF. When platelets are activated in a region of local vascular damage, FVIII and VWF could potentially be released together to provide improved local hemostatic effectiveness. To direct FVIII expression to the megakaryocyte lineage, we designed a FVIII expression cassette where the human B-domain deleted FVIII cDNA was placed under the control of the megakaryocytic/platelet-specific glycoprotein IIb (alphaIIb) promoter. We demonstrated by means of a functional FVIII activity assay that the biosynthesis of FVIII occurred normally in Dami cells transfected with FVIII. FVIII production was higher when driven by the alphaIIb promoter compared to the CMV promoter, and was increased about 8-fold following PMA treatment of the transfected Dami cells. Immunofluorescence staining of the transfected cells showed that FVIII stored together with VWF in the granules. The data indicate that the megakaryocytic compartment of hematopoietic cells may represent a potential target of gene therapy for hemophilia A-especially in those patients who have developed inhibitors to plasma FVIII.

Animals↗

PubMed1998

Genetic defects and clinical characteristics of patients with a form of oculocutaneous albinism (Hermansky-Pudlak syndrome).

BACKGROUND: Hermansky-Pudlak syndrome is characterized by oculocutaneous albinism, a storage-pool deficiency, and lysosomal accumulation of ceroid lipofuscin, which causes pulmonary fibrosis and granulomatous colitis in some cases. All identified affected patients in northwest Puerto Rico are homozygous for a 16-bp duplication in exon 15 of a recently cloned gene, HPS. We compared the clinical and laboratory characteristics of these patients with those of patients without the 16-bp duplication. METHODS: Forty-nine patients -- 27 Puerto Ricans and 22 patients from the mainland United States who were not of Puerto Rican descent -- were given a diagnosis on the basis of albinism and the absence of platelet dense bodies. We used the polymerase chain reaction to determine which patients carried the 16-bp duplication. RESULTS: Twenty-five of the Puerto Rican patients were homozygous for the 16-bp duplication, whereas none of the non-Puerto Rican patients carried this mutation. Like the patients without the duplication, the patients with the 16-bp duplication had a broad variation in pigmentation. Nine of 16 adults with the duplication, but none of the 10 without it, had a diffusing capacity for carbon monoxide that was less than 80 percent of the predicted value. High-resolution computed tomography in 12 patients with the 16-bp duplication revealed minimal fibrosis in 8, moderate fibrosis in 1, severe fibrosis in 1, and no fibrosis in 2. Computed tomography in eight patients without the duplication revealed minimal fibrosis in three and no fibrosis in the rest. Inflammatory bowel disease developed in eight patients (four in each group) between 3 and 25 years of age. CONCLUSIONS: The 16-bp duplication in exon 15 of HPS, which we found only in Puerto Rican patients, is associated with a broad range of pigmentation and an increased risk of restrictive lung disease in adults.

Adolescent↗

PubMed1994

A randomized, placebo-controlled trial of recombinant human granulocyte colony-stimulating factor administration in newborn infants with presumed sepsis: significant induction of peripheral and bone marrow neutrophilia.

Host defenses in the human neonate are limited by immaturity in phagocytic immunity. Such limitations seem to predispose infected newborns to neutropenia from an exhaustion of the neutrophil reserve. Among the critical defects thus far identified in neonatal phagocytic immunity is a specific reduction in the capacity of mononuclear cells to express granulocyte colony-stimulating factor (G-CSF) after stimulation. However, the safety, pharmacokinetics, and biological efficacy of administration of recombinant human (rh)G-CSF to infected human newborns to compensate for this deficiency is unknown. Forty-two newborn infants (26 to 40 weeks of age) with presumed bacterial sepsis within the first 3 days of life were randomized to receive either placebo or varying doses of rhG-CSF (1.0, 5.0 or 10.0 micrograms/kg every 24 hours [36 patients] or 5.0 or 10.0 micrograms/kg every 12 hours [6 patients]) on days 1, 2, and 3. Complete blood counts with differential and platelet counts were obtained at hours 0, 2, 6, 24, 48, 72, and 96. Circulating G-CSF concentrations were determined at hours 0, 2, 6, 12, 14, 16, 18, 24, and 36. Tibial bone marrow aspirates were obtained after 72 hours for quantification of the bone marrow neutrophil storage pool (NSP), neutrophil proliferative pool, granulocyte progenitors, and pluripotent progenitors. Functional activation of neutrophils (C3bi expression) was determined 24 hours after rhG-CSF or placebo administration. Intravenous rhG-CSF was not associated with any recognized acute toxicity. RhG-CSF induced a significant increase in the blood neutrophil concentration 24 hours after the 5 and 10 micrograms/kg doses every 12 and 24 hours and it was sustained as long as 96 hours. A dose-dependent increase in the NSP was seen following rhG-CSF. Neutrophil C3bi expression was significantly increased at 24 hours after 10 micrograms/kg every 24-hour dose of rhG-CSF. The half-life of rhG-CSF was 4.4 +/- 0.4 hours. The rhG-CSF was well tolerated at all gestational ages treated. The rhG-CSF induced a significant increase in the peripheral blood and bone marrow absolute neutrophil concentration and in C3bi expression. Future clinical trials aimed at improving the outcome of overwhelming bacterial sepsis and neutropenia in newborn infants might include the use of rhG-CSF.

Bone Marrow↗

PubMed1975

Content and thrombin-induced release of acid hydrolases in gel-filtered platelets from patients with storage pool disease.

The levels of four acid hydrolases, beta-N-acetyl glucosaminidase, beta-glucuronidase, beta-galactosidase, and acid phosphatase, and the extent of their release (release II) by thrombin was determined in platelets from nine normal subjects, nine patients with storage pool disease, and in normal platelets which had been exposed to aspirin. The levels of all four hydrolases were normal in patients with SPD. However, release of three of these hydrolases (acid phosphatase was an exception) by low concentrations of thrombin (0.015 and 0.04 U/ml) was decreased in the patients as a group, although considerable variation in the extent of release of each enzyme was noted. In contrast, aspirin failed to inhibit release II in normal platelets (except for a slight impairment in the release of beta-N-acetyl glucosaminidase), although release I (serotonin, ATP and ADP) was inhibited. All release defects could be overcome by using higher concentrations of thrombin (0.2 U/ml). The normal levels of acid hydrolases in the platelets of patients with SPD (who are deficient in the platelet dense granules) suggest that these enzymes are not normally stored in the dense granules, but rather in alpha-granules. The findings also support the conclusions of previous studies that the release reaction is impaired in SPD. This release defect appears to be different from that seen in normal platelets after exposure to aspirin.

Acetylglucosaminidase↗