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Biomedical subjects

James G White

Publications and source records attributed to James G White.

At least 19 recordsLinked to original sources
PubMed2006

Intestinal disease in Hermansky-Pudlak syndrome: occurrence of colitis and relation to genotype.

BACKGROUND & AIMS: Hermansky-Pudlak syndrome (HPS), a rare autosomal recessive disorder characterized by oculocutaneous albinism and platelet dysfunction, results from mutations in 1 of at least 7 different genes. Some patients develop a fatal pulmonary fibrosis and others a disabling colitis. This study aimed to document the occurrence of colitis among HPS patients, characterize gastrointestinal tract involvement in HPS, and analyze the distribution of colitis among HPS genotypes. METHODS: Of the 122 HPS patients followed at the National Institutes of Health Clinical Center between 1993 and 2005, 24 were evaluated by endoscopy for gastrointestinal complaints. The histology of gastrointestinal biopsies was retrospectively examined to assess for inflammatory changes, granulomata, and pigmented macrophages. These data were compared with symptoms and HPS genetic subtypes. RESULTS: At colonoscopy, 7 of 23 patients (30%) had endoscopic mucosal abnormalities, including nodularity, erythema, petechiae, or erosions. Six of these 7 patients (86%) had findings of colitis on biopsy. Of the 16 patients with normal-appearing colonic mucosa, 2 patients (12%) had colitis on biopsy. Pigmented macrophages were also observed in the colonic lamina propria in 16 of the 23 patients (70%). Of the 8 patients with confirmed colitis, 7 had the HPS-1 subtype, and 1 had the HPS-4 subtype. CONCLUSIONS: There is an increased frequency of colitis in our population of 122 HPS patients (8/122, 7%) and in HPS patients referred specifically for symptom evaluation (8/24, 33%). Colitis was found in patients with HPS-1 and HPS-4 genotypes.

Adolescent↗
PubMed2006

Why human platelets fail to kill bacteria.

Recent investigations have suggested that bacteria are taken up by platelets in the same manner as by polymorphonuclear (PMN) leukocytes and monocytes. The phagocytic vacuole containing the organism is completely separated from the cell exterior and the cytoplasm in order to form a killing chamber. Yet, earlier studies demonstrated that platelets do not kill bacteria. The present work has provided a basis for the lack of platelet bactericidal activity. Platelets incubated with Staphylococcus aureus 502A or RN 450 for intervals up to 2 h can take up organisms into sequestration vacuoles that resemble the phagosomes formed by PMN and monocytes. However, staining with tannic acid which forms an electron dense stain with osmic acid reveals that the phagosomes in PMN and monocytes are completely separated from the cell exterior and the cytoplasm. As a result, they are true killing chambers. The engulfment vacuoles containing bacteria in platelets on the other hand are almost never sealed from the cell exterior. Osmium black reaction product stains the inside of the engulfment vacuole and channels of the open canalicular system connecting it to the cell exterior. Thus platelets do not form the killing chamber phagosomes observed in leukocytes and, as a result, cannot kill bacteria.

Blood Platelets↗
PubMed2006

Localization of a lysosomal enzyme in platelets from patients with the White platelet syndrome.

The White platelet syndrome (WPS) is an autosomal dominant platelet disorder. Platelet structural abnormalities include the presence of Golgi complexes in up to 13% of their cells, frequently accompanied by centrioles, deficient numbers or absent alpha granules in 30-40% of their platelets and masses of dense tubular system (DTS) channels often forming areas of cytoplasmic sequestration. The degradation of cytoplasm and organelles in the sequestered areas suggested the possibility that hydrolytic enzymes remained in the DTS and were being transferred to sequestration vacuoles. The present study has used ultrastructural cytochemistry to localize the sites of a lysosomal enzyme, aryl sulfatase, in normal and WPS platelets. Enzyme reaction product, lead sulfide, was localized to lysosomal organelles in normal platelets, and only in rare examples appeared in the DTS. Aryl sulfatase activity was found in the Golgi complexes, a few lysosomes, much of the DTS and areas of cytoplasmic sequestration in WPS platelets. The findings indicate that aryl sulfatase, and, most likely, proteins destined for alpha granules in WPS platelets are not completely transferred from the endoplasmic reticulum to Golgi complexes, then to Golgi vesicles and finally to lysosomal and alpha granules in the parent cell before the platelets are delivered to the circulation.

Arylsulfatases↗
PubMed2005

Successful bilateral lung transplantation for pulmonary fibrosis associated with the Hermansky-Pudlak syndrome.

Hermansky-Pudlak syndrome (HPS) is a genetic disorder characterized by oculocutaneous albinism, a bleeding diathesis, and in a subset of patients, pulmonary fibrosis. Lung transplantation, the only curative therapy for pulmonary fibrosis, has not been previously reported as a successful treatment strategy for patients with HPS because the bleeding diathesis was thought to contraindicate major thoracic surgery. We successfully performed bilateral sequential lung transplantation in a patient with pulmonary fibrosis and HPS after transfusion of 6 units of platelets. Lung transplantation is a viable therapeutic option in patients with pulmonary fibrosis and only a mild bleeding diathesis associated with HPS.

Adult↗
PubMed2005

Platelets are covercytes, not phagocytes: uptake of bacteria involves channels of the open canalicular system.

Recent studies have suggested that uptake of bacteria by human platelets is more similar to ingestion of the same organisms by neutrophils than previously considered. Platelet pseudopods surround a bacterium by a process of circumferential adherence until the organism is fully enclosed in a vacuole consisting of internalized extracellular space surrounded by plasma membrane. The surface connected, open canalicular system (OCS) is not involved in the process of platelet phagocytosis. The present investigation has reviewed the literature on platelet-particle and platelet-bacterial interaction, and added a new study of the process of bacterial engulfment employing tannic acid as an electron dense tracer. The osmium black reaction product formed by tannic and osmic acids during fixation stained the glycocalyx on the platelet exterior surface and lining channels of the OCS. It also stained the vacuoles containing bacteria in platelets as well as channels of the OCS connected to the engulfment vacuole and exterior surface of the cell. Alpha granules releasing their contents into the OCS and into engulfment vacuoles were also stained by osmium black. The only way that tannic acid could reach and stain the interior surface of engulfment vacuoles during fixation was through patent channels of the OCS. In contrast, neutrophils do not contain an OCS, and phagocytic vacuoles containing organisms are never stained by tannic acid. Thus the platelet is a covercyte, not a phagocyte, and uptake of the bacteria does involve channels of the OCS.

Blood Platelets↗
PubMed2005

Golgi complexes in hypogranular platelet syndromes.

The white platelet syndrome (WPS) is an autosomal dominantly inherited hypogranular platelet disorder characterized by the presence of fully developed Golgi complexes from parent megakaryocytes in 13% or more of their circulating platelets. The present study has evaluated several other hypogranular platelet disorders to determine if perpetuation of Golgi complexes in circulating cells is a common link in those inherited conditions. Only platelets from patients with the gray platelet syndrome (GPS) and one patient with alpha delta platelet storage pool deficiency (alpha delta SPD) had more Golgi complexes in their cells than were found in normal thrombocytes. Platelets from patients with the Hermansky-Pudlak syndrome, two other patients with alpha delta SPD and the individual with Medich giant platelet disorder had the same frequency of Golgi complexes in circulating cells as normal controls. Thus, the presence of large numbers of fully developed Golgi complexes in circulating platelets appears unique to the WPS.

Bernard-Soulier Syndrome↗
PubMed2005

A 'touch' of the White platelet syndrome.

Investigations into structural defects in platelets from a large family with the White platelet syndrome (WPS) separated the members into three groups. The first group of 22 members was the subject of our first report (White JG, Key NS, King RA, Vercellotti GM. The white platelet syndrome: A new autosomal dominant platelet disorder. Platelets 2004;15:173-184). A third group of 13 members had no abnormalities of platelet ultrastructure. The second group of 17 members, the focus of the present study, had a 'touch' of the WPS. Platelet counts, mean platelet volumes (MPVs) and platelet responses to aggregating agents were normal in 'touch' patients in contrast to platelets of those with the full WPS in whom these parameters were abnormal. Up to 13% of the full WPS platelets contained large, fully developed Golgi complexes, up to seven in number, extruding innumerable vesicles from the trans-Golgi face and filling the cytoplasm of many platelets. Many Golgi complexes had centrioles associated with them. 'Touch' platelets had one or two Golgi complexes of intermediate size in 3-5% of their platelets. Golgi vesicles were uncommon and centrioles absent. Gray platelets and hypogranular cells were infrequent in patients with a 'touch' of the WPS, whereas up to 44% of the platelets from those with the WPS were gray or hypogranular. Elements of the dense tubular system were prominent in full WPS platelets, together with their formation into areas of cytoplasmic sequestration and autodigestion. These features were absent in 'touch' platelets. As commonly observed in full WPS platelets, mitochondria were larger and more numerous than alpha granules in some 'touch' cells. Both 'touch' and full WPS platelets frequently contained giant and rod-shaped granules. Dense bodies, however, were normal in size and number in 'touch' platelets, and half normal size in full WPS platelets. The separation of ultrastructural abnormalities in the two varieties of the WPS suggests that genetic defects involve more than a single gene and the genes are variable in their penetrance. Genetic studies to determine if this is the case are currently in progress.

Blood Coagulation Disorders, Inherited↗
PubMed2005

Stored platelets contain residual amounts of tissue factor: evidence from studies on platelet concentrates stored for prolonged periods.

BACKGROUND: The advent of new strategies for pathogen reduction has raised the question of whether platelet (PLT) concentrates (PCs) exposed to longer periods of storage retain adequate hemostatic function. STUDY DESIGN AND METHODS: The effects of prolonged storage on adhesive and procoagulant functions of PLTs in PCs have been analyzed. The ability of PLTs to interact with surfaces was assessed by en face electron microscopy. Exposure of anionic phospholipids or tissue factor (TF) antigen on PLTs was assessed by flow cytometry and by immunocytochemical methods at the ultrastructural level. Studies were performed in six different PCs followed 0, 3, 5, 7, and 11 days of storage. RESULTS: A progressive impairment of PLT-adhesive functions was observed after 5 days of storage. A progressive increase in expression of anionic phospholipids and development of procoagulant activity (PCA) measured by a modified prothrombin time (mPT) was observed along the storage. Incubation of PLTs with a specific anti-TF resulted in prolongation of the mPT by approximately 10 to 15 percent. Flow cytometry revealed minimal TF expression at later storage times. Immunocytochemical studies showed minimal TF labeling when studies were performed on PLT whole mounts. Labeling was markedly improved when PLTs were previously exposed to sonication. CONCLUSION: Prolonged storage of PCs was associated with decreased PLT-adhesive capacities and enhanced PCA. Current preparation procedures and storage media have important limitations for preserving PCs for longer than 1 week. PLTs in PCs retain residual amounts of TF as assessed by immunocytochemical and functional assays. The origin and hemostatic significance of this TF should be investigated further.

Anions↗
PubMed2004

Platelet membrane fragments enhance the procoagulant effect of recombinant factor VIIa in studies with circulating human blood under conditions of experimental thrombocytopenia.

The mechanism of action of recombinant factor VIIa (rFVIIa), which is being considered as an alternative treatment for the control of bleeding episodes in patients with thrombocytopenia, has not been fully characterized. This study was undertaken to explore the effects of rFVIIa and platelet microvesicles on hemostasis in an experimental model of thrombocytopenia. Damaged arterial segments were exposed to thrombocytopenic blood (shear rate 600 s(-1)) either with or without the addition of rFVIIa and/or platelet microvesicles. The presence of fibrin and platelets on the subendothelium were morphometrically quantified and immunolocalization techniques and electron microscopy were used for a more detailed analysis. Both rFVIIa and platelet microvesicles consistently improved fibrin formation on the damaged vascular subendothelium, and microvesicles were shown to be localized at different levels of the fibrin lattice. Further, under conditions of moderate thrombocytopenia, addition of platelet microvesicles potentiated the procoagulant action of rFVIIa. This effect may be due to the phospholipid surface provided by the platelet microvesicles. These studies support the concept that, under conditions of thrombocytopenia, both rFVIIa and platelet microvesicles enhance fibrin formation at sites of vascular damage.

Arteries↗
PubMed2004

The White platelet syndrome: a new autosomal dominant platelet disorder.

The present study has evaluated 46 members from four generations of a large family with mild to moderate bleeding symptoms, prolonged bleeding times and poor responses to all aggregating agents. Twenty-one members of the family had all of the abnormal structural features of the disorder brought to Minnesota in 1870 by Esther White and, therefore, referred to as the White platelet syndrome (WPS). Their platelet counts were decreased and mean platelet volumes increased. Four to 13% of their platelets contained large, fully developed Golgi complexes actively budding smooth and coated vesicles and frequently associated with centrioles. Such structures are usually present in megakaryocytes only during the major phase of granulopoiesis. As many as seven Golgi complexes and five centrioles were present in single platelets. Alpha granule formation appeared incomplete in patient platelets. The organelles were often immature in appearance and markedly decreased in number in many of their cells. As a result 30% or more of WPS platelets were "gray platelets" similar to, yet very different from the cells in patients with the gray platelet syndrome. Other abnormal features included cytoplasmic sequestration by residual dense tubular system membranes, autodigestion, larger than normal mitochondria and half normal-sized dense bodies. Thirteen of the 46 family members had a "touch" of WPS. Three to 5% of their platelets contained Golgi complexes. However, gray platelets were not present among their circulating cells. The WPS is a unique autosomal dominant condition that can be classified among the platelet granule deficiency disorders.

Blood Coagulation Disorders, Inherited↗
PubMed2004

Neutrophils in the gray platelet syndrome.

A recent report of three siblings with the gray platelet syndrome (GPS) and two others, a brother and sister, has indicated that patients with the GPS have gray neutrophils, as well as gray platelets. Their neutrophils are markedly deficient in secondary granules and vesicles and the empty cytoplasm appears gray on peripheral blood smears. We have evaluated five patients with the GPS, including the original case described by Raccuglia (Am J Med 1971; 51: 818-28). The results indicate that GPS neutrophils have normal secondary granules, and they are not gray on peripheral blood smears or in thin sections. The patients described in the recent report by the French workers appear to have a familial hypogranular neutrophil and platelet disorder, but it does not appear to be the GPS.

Alkaline Phosphatase↗
PubMed2004

Medich giant platelet disorder: a unique alpha granule deficiency I. Structural abnormalities.

Human platelet granule deficiency disorders include the gray platelet syndrome (GPS), alpha delta storage pool deficiency, the Hermansky-Pudlak syndrome and the White platelet syndrome. The present study describes a patient with a lifelong history of easy bleeding, thrombocytopenia and giant platelets. Her cells were found to have normal numbers of dense bodies, but a markedly decreased number of alpha granules. Many platelets had no alpha granules and resembled the gray platelets of patients with GPS. However, the empty vacuoles without granule contents that fill the cytoplasm of GPS platelets were not present in significant numbers in her platelets. In addition to the decrease in alpha granules the patients platelets contained membranous inclusions resembling cigars or scrolls. Usually, only one scroll open at each end was present, but many platelets contained two and some as many as five. Freeze-fracture revealed an absence of intramembranous particles in many layers of the scrolls. They occur in no other human platelet disorder, but are common in platelets from the Wistar-Furth rat. Thus, the patient is a unique variant of human platelet granule deficiency disorders unlike any described previously.

Adult↗
PubMed2004

Cellular, molecular and clinical characterization of patients with Hermansky-Pudlak syndrome type 5.

Hermansky-Pudlak syndrome (HPS) is a disorder of lysosome-related organelles such as melanosomes and platelet dense granules. Seven genes are now associated with HPS in humans. An accurate diagnosis of each HPS subtype has important prognostic and treatment implications. Here we describe the cellular, molecular, and clinical aspects of the recently identified HPS-5 subtype. We first analyzed the genomic organization and the RNA expression pattern of HPS5, located on chromosome 11p14, and demonstrated tissue-specific expression of at least three alternatively spliced HPS5 mRNA transcripts, coding for HPS5A and HPS5B proteins, that differ at their 5'-ends. Genetic screening of 15 unassigned HPS patients yielded six new HPS5 mutations in four patients. Clinically, our HPS-5 patients exhibited iris transillumination, variable hair and skin pigmentation, and absent platelet dense bodies, but not pulmonary fibrosis or granulomatous colitis. In two patients with homozygous missense mutations, hemizygosity was ruled out by gene-dosage multiplex polymerase chain reaction, and immunocytochemical analyses of their fibroblasts supported the HPS-5 diagnosis. Specifically, LAMP-3 distribution was restricted to the perinuclear region in HPS-5 fibroblasts, in contrast to the normal LAMP-3 distribution, which extended to the periphery. This specific intracellular vesicle distribution in fibroblasts, in combination with the clinical features, will improve the characterization of the HPS-5 subtype.

Adult↗
PubMed2003

Giant electron-dense chains, clusters and granules in megakaryocytes and platelets with normal dense bodies: an inherited thrombocytopenic disorder I. Megakaryocytes.

A woman and her male child were referred because of life-long thrombocytopenia, moderately increased platelet size, and absence of laboratory findings suggesting immune thrombocytopenia or defective platelet function. Evaluation of their platelets in the electron microscope revealed the presence of organelles never seen before in human cells. The present study has focused on megakaryocyte pathology to be sure the aberrant platelet organelles originated in the parent cell. There were two different types of organelles developing in megakaryocytes from our patients unrelated to the formed organelles in the large cells. No relationship could be identified between the aberrant structures and alpha granules, lysosomes or dense bodies. One of the large organelles was intensely electron opaque and appeared to arise from small dense fragments forming in segments of endoplasmic reticulum. The second, target-like organelle also appeared to develop in the endoplasmic reticulum. Its smallest precursors were hexagonal fragments with a granular layer inside a more electron-dense outer layer. Fusion of these elements resulted in formation of typical target-like organelles. Ultimately the target-like organelles became electron opaque and difficult to distinguish from the large dense bodies. Other features of these unusual structures were identified in platelets from the two patients and will be discussed in a subsequent report.

Adult↗
PubMed2003

Giant electron-dense chains, clusters and granules in megakaryocytes and platelets with normal dense bodies: an inherited thrombocytopenic disorder.

A woman and her male child were referred because of life-long thrombocytopenia, moderately increased platelet size, and absence of laboratory findings suggesting immune thrombocytopenia or defective platelet function. Evaluation of their platelets in the electron microscope revealed the presence of large organelles never seen before in human platelets. Examination of bone marrow from the mother and her son in an earlier study revealed that the giant platelet organelles originated in megakaryocytes. The present study has focused on the continuing development of the aberrant organelles in circulating platelets. The smallest subunits were electron-dense fragments and hollow-cored bodies observed in the dense tubular system (DTS). The dense fragments formed chains that became thicker, resulting in clusters, and clusters formed the large electron opaque bodies. Hollow-cored, almost hexagonal subunits also formed chains that interacted with each other to form target-like organelles. The multi-layered target organelles tended to become completely electron dense and difficult to distinguish from the opaque bodies. How two different types of aberrant organelles can develop in the same megakaryocyte/platelet system and both originate from channels of the DTS is unknown. Partial clarification stemming from analytical electron microscopy and ultrastructural cytochemistry will be presented in a subsequent report.

Adenine Nucleotides↗
PubMed2003

Giant electron dense chains, clusters and granules in megakaryocytes and platelets with normal dense bodies: an inherited thrombocytopenic disorder III. Platelet analytical electron microscopy.

A woman and her son were referred because of prolonged thrombocytopenia. Ultrastructural studies revealed the presence of giant organelles in their cells never observed previously in human platelets. Our initial reports described the evolution of two types of giant organelles in patient megakaryocytes and platelets. The last report also demonstrated that the large organelles in platelet whole mount preparations were inherently electron opaque like serotonin-rich dense bodies in normal and patient platelets. In the present study analytical electron microscopy of whole mount preparations from the patients and controls revealed that the inherently electron opaque dense and hexagonal precursor fragments, chains, clusters and giant organelles contained high concentrations of calcium and phosphorous, the major elements in normal dense bodies. The ratio of calcium to phosphorous in patient giant organelles was nearly the same as in normal platelet dense bodies. However, as shown in the previous study, levels of serotonin and adenine nucleotides were normal in patient platelets, and giant organelles and their contents were not secreted following activation of platelets with thrombin. Thus, despite the similarity in mineral content responsible for electron density, the giant organelles in patient platelets do no appear to be aberrant serotonin storage organelles.

Adenine Nucleotides↗
PubMed2003

Giant electron dense chains, clusters and granules in megakaryocytes and platelets with normal dense bodies: an inherited thrombocytopenic disorder IV. Ultrastructural cytochemistry and analytical electron microscopy.

Platelets from a mother and son with prolonged thrombocytopenia were shown in previous studies to contain giant organelles that developed in megakaryocytes and continued to evolve in circulating cells. Whole mount platelet preparations revealed that the large organelles were electron opaque like the serotonin-rich dense bodies in normal and patient platelets, and analytical electron microscopy revealed they contained large amounts of calcium and phosphorous in a ratio close to that found in normal platelet dense bodies. However, differences in physiology, biochemistry and morphology indicated the large opaque bodies and target-organelles in patient platelets were not aberrant dense bodies. The present study has shown that the giant organelles contain peroxidase activity like primary lysosomes in polymorphonuclear (PMN) leukocytes. Further, the giant organelles in patient platelets contain acid phosphatase activity. Analytical electron microscopy demonstrated that cerium, the capture ion for the acid phosphatase reaction product, was present in the opaque organelles with calcium and phosphorous, but not present in their normal dense bodies. Since normal sized lysosomes appeared to be reduced in patient platelets, it was concluded that the large structures were abnormal lysosomes, or fused with normal platelet lysosomes during their development. Similar giant lysosomes were not present in other patient blood cells. As a result the disorder can be considered a unique lysosomal disease of platelets.

Acid Phosphatase↗