The Medich giant platelet syndrome: Two new cases

The ultrastructure and contractile behavior of a new preparation of thrombin-activated human platelets is described. The preparation is referred to as the "platelet strip" because of its similarities to classical vascular smooth muscle strips. The platelet strip consists of a giant platelet aggregate 10 mm long, 4 mm wide, and 200 micron thick. To facilitate handling, the aggregate has a special high-compliance nylon mesh embedded in its mass. Each strip contains 7.3 X 10(8) platelets. Fibrin contamination is 150-fold lower than in platelet-rich plasma clots. Active isometric forces of up to 100 g/cm2 and 6-10 h viability are easily and reproducibly obtained. Platelet strips remain contracted after thrombin activation. The contraction is tonic and partial. Further small increases in force can be produced by depolarizing solutions or pharmacological agents, e.g., ADP, epinephrine, and endoperoxide analogues. These small increases are reversible on washout of the agents. Full relaxation is induced by agents such as prostaglandin E1 or papaverine, which increase adenosine 3',5'-cyclic monophosphate. However, after washout of these agents, recovery of tension is variable depending on the concentration of the drug and the degree of prestretching of the preparation.

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A Missense Mutation (Tyr88 to Cys) in the Platelet Membrane Glycoprotein Ibβ Gene Affects GPIb/IX Complex Expression

Thrombosis and Haemostasis ◽

10.1055/s-0037-1616058 ◽

2001 ◽

Vol 86 (11) ◽

pp. 1249-1256 ◽

Cited By ~ 22

Author(s):

Yumi Kurokawa ◽

Takehiko Kamijo ◽

Shinji Kunishima ◽

Dermot Kenny ◽

Kiyoshi Kitano ◽

...

Keyword(s):

Missense Mutation ◽

Dominant Negative ◽

Dominant Negative Effect ◽

Platelet Glycoprotein ◽

Homozygous Mutation ◽

Sequencing Analysis ◽

Giant Platelets ◽

Giant Platelet ◽

Negative Effect ◽

Dna Sequencing Analysis

SummaryThis study examined the molecular basis of a missense mutation of the platelet glycoprotein (GP) Ibβ gene in two families. In the propositus with a novel form of Bernard-Soulier syndrome (BSS) from Family I, only GPIbα was detectable in reduced amounts on platelet surfaces by flow cytometry. There were no GPIX or GPIbβ found by immunoblotting. DNA sequencing analysis showed a homozygous mutation in the GPIbβ gene which changed Tyr (TAC) to Cys (TGC) at residue 88. Her parents were heterozygous for Tyr88Cys in the GPIbβ gene. In transient transfection studies on 293T cells, both Tyr88Cys and Tyr88Ala mutations suppressed the expression of GPIb/IX complexes. In addition, Tyr88Cys GPIbβ mutation was found to exert a dominant negative effect on the GPIb expression.Five individuals from Family II, four of whom reported elsewhere as having giant platelet disorders with normal aggregation (BLOOD, 1997; 89: 2404) and one newly analyzed in this study, were heterozygous for Tyr88Cys in the GPIb gene. Microsatellite analysis of chromosome 22 showed a common haplotype in 8 of the individuals with Tyr88Cys mutations in Families I and II. Tyr88 in the GPIbβ gene plays a significant role in the GPIb/IX expression; the defect causes BSS in a homozygous form and possibly giant platelets in a heterozygous form.

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Inherited giant platelet disorders

European Journal Of Haematology ◽

10.1111/j.1600-0609.1994.tb00187.x ◽

2009 ◽

Vol 53 (4) ◽

pp. 191-196 ◽

Cited By ~ 27

Author(s):

Esa Jantunen

Keyword(s):

Giant Platelet ◽

Platelet Disorders

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Study of Bernard–Soulier Syndrome Megakaryocytes and Platelets Using Patient-Derived Induced Pluripotent Stem Cells

Thrombosis and Haemostasis ◽

10.1055/s-0039-1693409 ◽

2019 ◽

Vol 119 (09) ◽

pp. 1461-1470 ◽

Cited By ~ 3

Author(s):

Ponthip Mekchay ◽

Praewphan Ingrungruanglert ◽

Kanya Suphapeetiporn ◽

Darintr Sosothikul ◽

Wilawan Ji-au ◽

...

Keyword(s):

Electron Microscopy ◽

Stem Cells ◽

Induced Pluripotent Stem Cells ◽

Pluripotent Stem Cells ◽

Molecular Mechanisms ◽

Membrane System ◽

Giant Platelets ◽

Giant Platelet ◽

Induced Pluripotent ◽

Bernard Soulier Syndrome

AbstractBernard–Soulier syndrome (BSS) is a hereditary macrothrombocytopenia caused by defects in the glycoprotein (GP) Ib-IX-V complex. The mechanism of giant platelet formation remains undefined. Currently, megakaryocytes (MKs) can be generated from induced pluripotent stem cells (iPSCs) to study platelet production under pharmacological or genetic manipulations. Here, we generated iPSC lines from two BSS patients with mutations in different genes (GP1BA and GP1BB: termed BSS-A and BSS-B, respectively). The iPSC-derived MKs and platelets were examined under electron microscopy and stained by immunofluorescence to observe proplatelet formation and measure platelet diameters which were defined by circumferential tubulin. BSS-iPSCs produced abnormal proplatelets with thick shafts and tips. In addition, compared with the normal iPSCs, the diameters were larger in platelets derived from BSS-A and BSS-B with the means ± standard deviations of 4.34 ± 0.043 and 3.88 ± 0.045 µm, respectively (wild-type iPSCs 2.61 ± 0.025 µm, p < 0.001). Electron microscopy revealed giant platelets with the abnormal demarcation membrane system. Correction of BSS-A and BSS-B-iPSCs using lentiviral vectors containing respective GP1BA and GP1BB genes improved proplatelet structures and platelet ultrastructures as well as reduced platelets sizes. In conclusion, the iPSC model can be used to explore molecular mechanisms and potential therapy for BSS.

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ELECTRONMICROSCOPIC STUDIES ON PLATELETS AND MEGAKARYOCYTES IN GIANT PLATELET SYNDROME

10.1055/s-0038-1644560 ◽

1987 ◽

Author(s):

Sozo Suzuki ◽

Kazuo Mori ◽

Koji Sugai ◽

Yasuyuki Akutsu ◽

Masaaki Ishikawa ◽

...

Keyword(s):

Peripheral Blood ◽

Uranyl Acetate ◽

Ruthenium Red ◽

Membrane Systems ◽

Platelet Factor ◽

Giant Platelets ◽

Thin Sections ◽

Giant Platelet ◽

Dense Bodies ◽

Large Platelet

Giant platelet syndrome are characterized morphologically by many giant platelets associated with several functional abnormalities in the peripheral blood. However, the mechanism of large platelet production has not yet been clarified. In 1981, we reported acase with Bernard-Soulier syndrome(BSS) in whom giant platelets were considered to be formed by fusion of two or three platelets in the circulating blood. We examined the ultrastructure of platelets and megakaryocytes in another case with BSS (29 year-old female) and a case with May-Hegglin anomaly (31 year-old male). Whole blood and bone marrow specimens were fixed with glutaraldehyde-osmium solution. Thin sections were prepared and stained with uranyl acetate and lead cytrate. Membrane systems of platelets and megakaryocytes in a case with BSS was investigated by staining of surface coating with ruthenium red.In a case with BSS, most platelets were very large and similar in morphology to those in formerly reported case. Giant platelets contained several-fold increased number of α-granules and mitochondria. Typical dense bodies were also observed. Contents of ATP/ADP, platelet factor-4(PF-4), B-thromboglobulin(B-TG) and platelet factor-3 availability(PF-3) were increased. Disorganization of microtubules was recognized. Some giant platelet contained membrane systems similar to demarcation membranes(DM) in megakaryocytes, characteristically. In mature megakaryocytes, areas divided by DM similar in size to those in normal megakaryocytes were observed. Several of these areas appeared to fuse together to form the giant platelets containing many granules and remnants of DM. In a case with May-Hegglin anomaly, typical Dohle’s bodies were shown in neutrophilic granulocytes. Giant platelets in this case also contained large number of α-granules and some of them contained membrane systems similar to DM. Areas similar in morphology to these giant platelets were clearly noted in the cytoplasm of mature megakaryocytes.In these cases, most giant platelets in the peripheral blood may be formed in the cytoplasm of megakaryocytes by fusion of several areas divided by DM, each of which may become normal sized platelets in normal megakaryocytes.

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Platelet and Red Blood Cell Indices in Harris Platelet Syndrome.

Blood ◽

10.1182/blood.v108.11.3988.3988 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3988-3988 ◽

Cited By ~ 1

Author(s):

Harris V.K. Naina ◽

Samar Harris

Keyword(s):

Blood Cell ◽

Red Blood Cell ◽

Blood Donors ◽

Severe Thrombocytopenia ◽

Giant Platelets ◽

Giant Platelet ◽

Normal Platelet ◽

Platelet Disorder ◽

Significant Difference ◽

Blood Cell Morphology

Abstract Inherited giant platelet disorders are a group of rare disorders characterized by thrombocytopenia, giant platelets and variable bleeding symptoms. Naina et al., described a new giant platelet disorder called Harris Platelet Syndrome (HPS), the most common inherited giant platelet disorder occurring in up to one third of blood donors from north eastern part of Indian subcontinent. HPS is characterized by an autosomal dominant mode of inheritance with normal to severe thrombocytopenia (less than 50x109/L), giant platelets (mean platelet volume more than 10fL) and absent bleeding symptoms with normal platelet aggregation studies. Occasionally abnormalities in red blood cell morphology have been associated with certain giant platelet disorders such as stomatocytosis in Mediterranean Macrothrmboctopenia, dyserythropoiesis in GATA 1 associated macrothrombocytopenia and thalassemia, in X Linked Thrombocytopenia Thalassemia (XLTT). This study was undertaken to analyze the platelet and red blood cell indices in blood donors with Harris Platelet syndrome. A total of 203 blood donors were included in this study, 101 blood donors from northeaster part of India with MPV more than 12fl (normal 7–10fl) and 102 blood donors from southern part of India. Before blood donation, all donors were questioned about a history of bleeding conditions, in either themselves or their relatives. Blood samples were collected in ethylenediaminetetraacetic acid (EDTA). Automated platelet counts were performed using a Coulter STKS (Coulter, Hialeah, Florida) within 2 hours of collection. Peripheral blood smears were examined to confirm thrombocytopenia, giant platelets and red blood cell morphology. There was a significant difference between platelet count (Mean ±SD) 136± 40 Vs 262 ± 53 in southern India (p<0.000). Thirty three donors with HPS had a normal platelet count with MPV more than 12fL. MPV was 13.6±0.13 (range 12 to21.9fL) in donors with HPS and 7.3 ±0.6 (range 6–9.2fl) in southern Indian blood donors. The platelet distribution width (PDW) was 17.4±0.8 in donors with HPS and was 16.38±0.5 in southern India blood donors(p<0.000). Though there was a significant difference between hemoglobin, 13.8 ± 1.0 vs and 14.7± 1.1 (P<0.00), there was no significant difference between RDW, MCV, MCH, MCHC. Peripheral blood smear did not show any obvious red blood cell abnormality, but showed giant platelets and thrombocytopenia. Harris platelet syndrome is associated with normal to severe thrombocytopenia, giant platelets and significant platelet anisocytosis. There was no associated red blood cell abnormalities observed with HPS.

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