Congenital disorders associated with platelet dysfunctions

2008 ◽  
Vol 99 (02) ◽  
pp. 253-263 ◽  
Author(s):  
Paquita Nurden ◽  
Alan T. Nurden
Keyword(s):  
Bone Marrow ◽  
Blood Platelets ◽  
Severe Bleeding ◽  
Spontaneous Bleeding ◽  
Atp Production ◽  
Bleeding Management ◽  
Giant Platelet ◽  
Platelet Morphology ◽  
Vessel Injury ◽  
Adp Receptor

SummaryGenetic defects of the megakaryocyte lineage give rise to bleeding syndromes of varying severity. Blood platelets are unable to fulfill their hemostatic function of preventing blood loss on vessel injury. Spontaneous bleeding is mostly mucocutaneous in nature. Most studied are deficiencies of glycoprotein (GP) mediators of adhesion (Bernard-Soulier syndrome) and aggregation (Glanzmann thrombasthenia) which concern the GPIb-IX-V complex and the integrin αIIbβ3, respectively. Defects of primary receptors for stimuli include the P2Y12 ADP receptor pathology. Agonist-specific deficiencies in the platelet aggregation response and abnormalities of signaling pathways are common and lead to trauma-related bleeding. Inherited defects of secretion from storage organelles, of ATP production, and of the generation of procoagulant activity are also encountered. In some disorders, such as the Chediak-Higashi, Hermansky-Pudlak, Wiskott-Aldrich and Scott syndromes, the molecular lesion extends to other cells. In familial thrombocytopenia (FT), platelets are produced in insufficient numbers to assure haemostasis. Some of these disorders affect platelet morphology and give rise to the so-called ‘giant platelet’ syndromes (MYH9-related diseases) with changes in megakaryocyte maturation within the bone marrow and premature release of platelets. Diseases of platelet production may extend to other cells and in some cases interfere with development. Transfusion of platelets remains the most common treatment of severe bleeding, management with desmopressin is common for mild disorders. Substitute therapies are available including rFVIIa and the potential use of TPO analogues for FT. Stem cell or bone marrow transplanation is being used for severe diseases while gene therapy may be on the horizon.

Inherited Abnormalities of Platelets

1999 ◽  
Vol 82 (08) ◽  
pp. 468-480 ◽  
Author(s):  
Alan Nurden
Keyword(s):  
Molecular Basis ◽  
State Of The Art ◽  
New Drugs ◽  
Atp Production ◽  
Primary Hemostasis ◽  
Giant Platelet ◽  
Platelet Morphology ◽  
Platelet Adherence ◽  
Platelet Disorders ◽  
Granule Secretion

IntroductionGenetic defects of platelets give rise to bleeding syndromes of varying severity. Affected areas of platelet function include the glycoprotein (GP) effectors of adhesion and aggregation, primary receptors for agonists, signaling pathways where messages are transmitted to targets elsewhere in the membrane or within the platelet, dense- and α-granule secretion, ATP production, and the expression of procoagulant activity. Glanzmann thrombasthenia (GT) and Bernard-Soulier syndrome (BSS) are the best-characterized platelet diseases and will have a major place in this review. GT is caused by abnormalities of platelet membrane GP IIb-IIIa (integrin αIIbβ3), resulting in absent platelet aggregation. BSS is caused by abnormalities of the GP Ib-IX-V complex, resulting in a loss of platelet adherence to vessel wall subendothelium. The disorders affecting platelet morphology, which give rise to the so-called giant platelet syndromes, are also considered.Studies on platelet disorders are significant because the knowledge gained has provided a better understanding of the molecular basis of primary hemostasis and has helped in the development of new drugs for use in antithrombotic therapy. In 1987, this author gave the inaugural State-of-the-Art lecture at an International Society of Thrombosis and Haemostasis meeting.1 At that time, the application of molecular biology procedures to the study of platelet disorders was just beginning. Now, 12 years later, some of these data will be reviewed and the recent advances discussed.

scholarly journals The incredible journey: From megakaryocyte development to platelet formation

2013 ◽  
Vol 201 (6) ◽  
pp. 785-796 ◽  
Author(s):  
Kellie R. Machlus ◽  
Joseph E. Italiano
Keyword(s):  
Bone Marrow ◽  
Blood Vessel ◽  
Blood Vessels ◽  
Progenitor Cells ◽  
Branching Processes ◽  
Blood Platelets ◽  
Clinical Applications ◽  
Active Area ◽  
Vessel Injury ◽  
Platelet Formation

Circulating blood platelets are specialized cells that prevent bleeding and minimize blood vessel injury. Large progenitor cells in the bone marrow called megakaryocytes (MKs) are the source of platelets. MKs release platelets through a series of fascinating cell biological events. During maturation, they become polyploid and accumulate massive amounts of protein and membrane. Then, in a cytoskeletal-driven process, they extend long branching processes, designated proplatelets, into sinusoidal blood vessels where they undergo fission to release platelets. Given the need for platelets in many pathological situations, understanding how this process occurs is an active area of research with important clinical applications.

scholarly journals Factor XIII-A: An Indispensable “Factor” in Haemostasis and Wound Healing

2021 ◽  
Vol 22 (6) ◽  
pp. 3055
Author(s):  
Fahad S. M. Alshehri ◽  
Claire S. Whyte ◽  
Nicola J. Mutch
Keyword(s):  
Bone Marrow ◽  
Wound Healing ◽  
Crucial Role ◽  
Factor Xiii ◽  
Severe Bleeding ◽  
Bleeding Diathesis ◽  
Unknown Mechanism ◽  
Protein Substrates ◽  
Physiological Processes ◽  
Isopeptide Bonds

Factor XIII (FXIII) is a transglutaminase enzyme that catalyses the formation of ε-(γ-glutamyl)lysyl isopeptide bonds into protein substrates. The plasma form, FXIIIA2B2, has an established function in haemostasis, with fibrin being its principal substrate. A deficiency in FXIII manifests as a severe bleeding diathesis emphasising its crucial role in this pathway. The FXIII-A gene (F13A1) is expressed in cells of bone marrow and mesenchymal lineage. The cellular form, a homodimer of the A subunits denoted FXIII-A, was perceived to remain intracellular, due to the lack of a classical signal peptide for its release. It is now apparent that FXIII-A can be externalised from cells, by an as yet unknown mechanism. Thus, three pools of FXIII-A exist within the circulation: plasma where it circulates in complex with the inhibitory FXIII-B subunits, and the cellular form encased within platelets and monocytes/macrophages. The abundance of this transglutaminase in different forms and locations in the vasculature reflect the complex and crucial roles of this enzyme in physiological processes. Herein, we examine the significance of these pools of FXIII-A in different settings and the evidence to date to support their function in haemostasis and wound healing.

Platelet microparticles are released from blood platelets and bone marrow cells and stimulate endothelial invasion and neovascularisation

2006 ◽  
Vol 45 (3) ◽  
pp. e120-e121
Author(s):  
Lukasz Partyka ◽  
Joanna Grzybowska ◽  
Urszula Czech ◽  
Anna Polus ◽  
Lukasz Wator ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Cells ◽  
Blood Platelets ◽  
Platelet Microparticles ◽  
Marrow Cells

scholarly journals Abnormalities of Megakaryocytes in Sl/Sld Mice

Blood ◽  
1973 ◽  
Vol 42 (6) ◽  
pp. 865-871 ◽  
Author(s):  
Shirley Ebbe ◽  
Elizabeth Phalen ◽  
Frederick Stohlman
Keyword(s):  
Bone Marrow ◽  
Blood Platelets ◽  
Normal Concentration

Abstract Megakaryocytopoiesis was evaluated in Sl/Sld mice and their heterozygous and homozygous normal (+/+) littermates. Sl/Sld mice had a normal concentration of blood platelets which were of normal size. Numbers of megakaryocytes in bone marrow and spleen were reduced, but individual megakaryocytes were larger than normal.

Hyperfibrinolysis In A Patient With IgG-Paraproteinemia

1981 ◽  
Author(s):  
R Egbring ◽  
H G Klingemann ◽  
N Heimburger ◽  
H E Karges ◽  
K Havemann
Keyword(s):  
Bone Marrow ◽  
Male Patient ◽  
Plasma Cells ◽  
Normal Values ◽  
Simultaneous Increase ◽  
Bleeding Tendency ◽  
Spontaneous Bleeding ◽  
Significant Fall ◽  
Coagulation Status ◽  
Plasmin Inhibitor

In patients with various malignancies (prostata, thyreoid, gastric), a hyperfibrinolytic syndrome has been described. We would like to give a report on a 56 year-old male patient who became clinically apparent by his spontaneous bleeding tendencies with large haematoma. Analysis of the coagulation status revealed a primary hyperfibrinolysis characterized by a prolonged TT and PTT, decreased fibrinogen (F I) and a simultaneous increase of FDP, associated with the consumption of F I. There was also a significant fall of plasminogen(Pig) and an alpha2-plasmin-inhibitor α2PI) down to about 10% of the norm. However, a Pig activator as a trigger of hyperfibrinolysis could not be detected in plasma, a malignoma could not be diagnosed. However, a IgG-paraproteinemia and uria associated with a 20% infiltration of bone marrow with plasma cells was assessed. The bleeding tendency was treated successfully with aprotinin (AntagosanR). Under the infusion (1 Mio KIU/d) a normalization of the coagulation status was observed as measured by means of the TT and PTT; simultaneously an increase of F I and the disappearance of FDP was observed. Pig and α2PI also rised but did not reach normal values. Based on these observations an interrelationship between hyperfibrinolysis and paraproteinemia appears to be possible.

scholarly journals OBSERVATIONS ON THE INFLUENCE OF THE HYPOPHYSIS AND THE ADRENAL CORTEX ON BLOOD PLATELET LEVELS

Blood ◽  
1949 ◽  
Vol 4 (8) ◽  
pp. 936-946 ◽  
Author(s):  
ELIJAH ADAMS
Keyword(s):  
Bone Marrow ◽  
Adrenal Cortex ◽  
Blood Platelets ◽  
Blood Platelet ◽  
Distilled Water ◽  
Hypophysectomized Rats ◽  
Physiologic Saline ◽  
Maximum Rise ◽  
Adrenalectomized Rats ◽  
Intact Rats

Abstract Observations were made to investigate possible endocrine influences on blood platelets. Adrenal cortex extract failed to influence the platelet counts of mice, rats, or rabbits. Adrenalectomy and sham-adrenalectomy were followed by almost identical platelet increases in mice and rats. Administration of adrenal cortex extract, or physiologic saline, to adrenalectomized rats was followed by a consistent fall in platelets not observed in sham-adrenalectomized rats, or after administering distilled water to adrenalectomized rats. Platelet levels in hypophysectomized rats were significantly lower than in unoperated controls. Splenectomy in hypophysectomized rats was followed by a maximum rise in platelets markedly lower than following splenectomy in intact rats. Bone-marrow megakaryocytes in hypophysectomized rats were significantly fewer than in intact rats. No changes in megakaryocyte number or morphology appeared following splenectomy either in intact or hypophysectomized rats.

A Case of Acquired Amegakaryocytic Thrombocytopenia with Anti-c-mpl Autoantibody: Comparison with Idiopathic Thrombocytopenic Purpura

2019 ◽  
Vol 142 (4) ◽  
pp. 239-243
Author(s):  
Bora Son ◽  
Hee sue Park ◽  
Hye Sook Han ◽  
Hee Kyung Kim ◽  
Seung Woo Baek ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Platelet Count ◽  
Rare Disease ◽  
Idiopathic Thrombocytopenic Purpura ◽  
Immunosuppressive Treatment ◽  
Severe Bleeding ◽  
Severe Thrombocytopenia ◽  
Thrombocytopenic Purpura ◽  
Acquired Amegakaryocytic Thrombocytopenia

Acquired amegakaryocytic thrombocytopenia (AAMT) is a rare disease that causes severe bleeding. The pathogenesis and treatment of AAMT have not yet been defined. We report the case of a 60-year-old woman diagnosed with AAMT, who presented with severe thrombocytopenia, gastroin­testinal bleeding, and significantly reduced bone marrow megakaryocytes. The patient was treated with methylprednisolone, cyclosporin, and intravenous immunoglobulin. After 2 weeks of treatment, her platelet count started to increase, and her bone marrow megakaryocyte count had normalized 3 months after diagnosis. At the time of diagnosis, the patient was seropositive for anti-c-mpl antibody but was seen to be seronegative once the platelet count recovered. In contrast, anti-c-mpl antibodies were not detected in the serum of 3 patients with idiopathic thrombocytopenic purpura. This case study suggests that anti-c-mpl antibody plays an important role in the development of AAMT, and that intensive immunosuppressive treatment is required for autoantibody clearance and recovery of megakaryocyte count.

scholarly journals HISTOCHEMICAL DEMONSTRATION OF DEHYDROGENASE ACTIVITY IN THE CELLS OF NORMAL HUMAN BLOOD AND BONE MARROW

1960 ◽  
Vol 8 (1) ◽  
pp. 61-67 ◽  
Author(s):  
G. Adolph Ackerman
Keyword(s):  
Bone Marrow ◽  
Dehydrogenase Activity ◽  
Human Blood ◽  
Blood Platelets ◽  
Intracellular Localization ◽  
Succinic Dehydrogenase ◽  
Active Agent ◽  
Dehydrogenase Reaction ◽  
Normal Human ◽  
Normal Human Blood

Endogenous and succinic dehydrogenase activity was demonstrated in the living cells of normal human blood and bone marrow using a buffered nitro BT-succinate incubating solution. With this technique dehydrogenase activity was localized primarily in the granular leukocytes and the sites of enzymatic activity appeared to be non-mitochondrial. The addition of a non-ionic surface active agent to the incubating solution resulted in marked differences in the cellular and intracellular localization of dehydrogenase activity. With this method it was possible to demonstrate dehydrogenase activity in the mitochondria of most of the formed elements of the blood and bone marrow, including developing granulocytes and erythroid cells, agranulocytes, and blood platelets. Mature erythrocytes also exhibited a minimal dehydrogenase reaction with this procedure. This investigation indicated that in order adequately to demonstrate and evaluate dehydrogenase activity in the cells of the blood and bone marrow it was necessary to have increased cellular and mitochondrial permeability, as well as partially viable cells with an intact dehydrogenase system.

Morphological Distinction Unravels Mechanisms Of Platelet Biogenesis From Bone Marrow Megakaryocytes

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2428-2428
Author(s):  
Satoshi Nishimura ◽  
Koji Eto ◽  
Ryozo Nagai
Keyword(s):  
Bone Marrow ◽  
Fluorescent Protein ◽  
Conflicts Of Interest ◽  
Human Subjects ◽  
Blood Platelets ◽  
Serum Levels ◽  
Cytokine Balance ◽  
Green Fluorescent

Abstract Blood platelets are generated in the bone marrow (BM) from their precursors, megakaryocytes (MK). Although we know that MKs produce platelets throughout life, precisely how platelets are produced in vivo remains uncertain, largely because of the rarity of MKs in the BM and the lack an adequate visualization technique. In the present study, we were able to visualize MK dynamics leading to platelet release in living animals at high resolution. To clearly understand the nature of thrombopoiesis in BM MKs, we optimized an in vivo imaging technique based on two-photon microscopy that enabled us to visualize living BM in CAG- enhanced green fluorescent protein (eGFP) mice. By visualizing living bone marrow in vivo, we observed that two modes (fragmentation and proplatelet formation) can be ongoing simultaneously in the same mouse. We observed that these two modes detectable by different morphological behavior can be ongoing simultaneously in the same BM of mouse, and are regulated by specific cytokines. Short proplatelets from megakaryocytes predominated at steady state, and more elongated proplatelets were accelerated by thrombopoietin (TPO) with responding to chronic platelet needs including recovery form BM transplantations. In contrast, acute platelet needs by blood loss, 5-FU administration or pritoneal acute inflammation increased cytoplasmic fragmentation following rapid ‘rupture’. Observed two modes are both dependent on tubulin reorganization on platelet biogenesis. In addition, platelet increase at acute phase is independent of proliferation by MK progenitors and this factor might exert apoptosis machinery on already reserved mature type of MKs. This humoral factor was identified by combination of in vitro screening systems and in vivo MK visualization analysis. Factor serum levels were reduced independently of the thrombopoietin level in human subjects with low platelet counts. It thus appears the cytokine balance dynamically regulates the mode of thrombopoiesis and the cellular programming of MKs. Thus, these novel factor may be a novel therapeutic target in thrombocytopenic situations, especially when associated with acute loss of platelets or when platelet transfusion is limited or unsuccessful. Disclosures: No relevant conflicts of interest to declare.

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