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.

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.

Clinical and molecular basis of transfusion-induced immunomodulation: Summary of the proceedings of a state-of-the-art conference

2001 ◽  
Vol 15 (2) ◽  
pp. 108-135 ◽  
Author(s):  
Morris A. Blajchman ◽  
Sunny Dzik ◽  
Eleftherios C. Vamvakas ◽  
Joseph Sweeney ◽  
Edward L. Snyder
Keyword(s):  
Molecular Basis ◽  
State Of The Art

scholarly journals My Life and Virus Research Journey

2018 ◽  
Vol 5 (1) ◽  
pp. 1-32 ◽  
Author(s):  
Said A. Ghabrial
Keyword(s):  
Molecular Basis ◽  
State Of The Art ◽  
Virus Disease ◽  
Pathogenic Fungus ◽  
Continuous Learning ◽  
Bean Pod Mottle Virus ◽  
Strain Diversity ◽  
Virus Research ◽  
Helminthosporium Victoriae ◽  
Transmissible Disease

My long career in virology has been a continuous learning exercise with a very modest start. Virology and related pertinent fields have changed significantly during my lifetime. Sometimes I wish that my career had just started and I could apply all available and state of the art technology to solving problems and explaining intriguing observations. I was always convinced that visiting growers’ fields is essential for researchers to get firsthand observations and knowledge of virus disease problems under field conditions. I never thought I would pursue so many avenues of research, yet it is true that research never ends. I enjoyed dissecting strain diversity in a very important plant pathogen like bean pod mottle virus (BPMV) and using BPMV-based vectors to address fundamental virology questions. Lastly, solving the enigma of the transmissible disease of Helminthosporium victoriae and attempting to gain an understanding of the molecular basis of disease in a plant pathogenic fungus were thrilling.

scholarly journals Diagnosing Inherited Platelet Disorders: Modalities and Consequences

2021 ◽  
Author(s):  
Carlo Zaninetti ◽  
Martina Wolff ◽  
Andreas Greinacher
Keyword(s):  
Hematological Malignancies ◽  
Ethical Issues ◽  
Diagnostic Delay ◽  
Bleeding Tendency ◽  
Platelet Morphology ◽  
Laboratory Characterization ◽  
Platelet Disorders ◽  
And Function ◽  
Generation Sequencing

AbstractInherited platelet disorders (IPDs) are a group of rare conditions featured by reduced circulating platelets and/or impaired platelet function causing variable bleeding tendency. Additional hematological or non hematological features, which can be congenital or acquired, distinctively mark the clinical picture of a subgroup of patients. Recognizing an IPD is challenging, and diagnostic delay or mistakes are frequent. Despite the increasing availability of next-generation sequencing, a careful phenotyping of suspected patients—concerning the general clinical features, platelet morphology, and function—is still demanded. The cornerstones of IPD diagnosis are clinical evaluation, laboratory characterization, and genetic testing. Achieving a diagnosis of IPD is desirable for several reasons, including the possibility of tailored therapeutic strategies and individual follow-up programs. However, detailed investigations can also open complex scenarios raising ethical issues in case of IPDs predisposing to hematological malignancies. This review offers an overview of IPD diagnostic workup, from the interview with the proband to the molecular confirmation of the suspected disorder. The main implications of an IPD diagnosis are also discussed.

scholarly journals Advanced Formulation Approaches for Ocular Drug Delivery: State-Of-The-Art and Recent Patents

Pharmaceutics ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 460 ◽  
Author(s):  
Eliana B. Souto ◽  
João Dias-Ferreira ◽  
Ana López-Machado ◽  
Miren Ettcheto ◽  
Amanda Cano ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Therapeutic Effect ◽  
State Of The Art ◽  
Circulatory System ◽  
Drug Action ◽  
New Drugs ◽  
Eye Drops ◽  
Target Segment ◽  
Different Types ◽  
A Current

The eye presents extensive perspectives and challenges for drug delivery, mainly because of the extraordinary capacity, intrinsic to this path, for drugs to permeate into the main circulatory system and also for the restrictions of the ocular barriers. Depending on the target segment of the eye, anterior or posterior, the specifications are different. The ocular route experienced in the last decades a lot of progresses related with the development of new drugs, improved formulations, specific-designed delivery and even new routes to administer a drug. Concomitantly, new categories of materials were developed and adapted to encapsulate drugs. With such advances, a multiplicity of parameters became possible to be optimized as the increase in bioavailability and decreased toxic effects of medicines. Also, the formulations were capable to easily adhere to specific tissues, increase the duration of the therapeutic effect and even target the delivery of the treatment. The ascending of new delivery systems for ocular targeting is a current focus, mainly because of the capacity to extend the normal time during which the drug exerts its therapeutic effect and, so, supplying the patients with a product which gives them fewer side effects, fewer number of applications and even more effective outcomes to their pathologies, surpassing the traditionally-used eye drops. Depending on the systems, some are capable of increasing the duration of the drug action as gels, emulsions, prodrugs, liposomes, and ocular inserts with hydrophilic properties, improving the absorption by the cornea. In parallel, other devices use as a strategy the capacity to sustain the release of the carried drugs by means of erodible and non-erodible matrices. This review discusses the different types of advanced formulations used for ocular delivery of therapeutics presenting the most recent patents according to the clinical applications.

scholarly journals Pharmacokinetics of Marine-Derived Drugs

Marine Drugs ◽  
2020 ◽  
Vol 18 (11) ◽  
pp. 557 ◽  
Author(s):  
Alexander N. Shikov ◽  
Elena V. Flisyuk ◽  
Ekaterina D. Obluchinskaya ◽  
Olga N. Pozharitskaya
Keyword(s):  
Molecular Basis ◽  
Sea Cucumber ◽  
Sea Urchins ◽  
Drug Application ◽  
New Drugs ◽  
Potential Contribution ◽  
Human Experiments ◽  
Near Future ◽  
Excellent Source ◽  
Selection Of

Marine organisms represent an excellent source of innovative compounds that have the potential for the development of new drugs. The pharmacokinetics of marine drugs has attracted increasing interest in recent decades due to its effective and potential contribution to the selection of rational dosage recommendations and the optimal use of the therapeutic arsenal. In general, pharmacokinetics studies how drugs change after administration via the processes of absorption, distribution, metabolism, and excretion (ADME). This review provides a summary of the pharmacokinetics studies of marine-derived active compounds, with a particular focus on their ADME. The pharmacokinetics of compounds derived from algae, crustaceans, sea cucumber, fungus, sea urchins, sponges, mollusks, tunicate, and bryozoan is discussed, and the pharmacokinetics data in human experiments are analyzed. In-depth characterization using pharmacokinetics is useful for obtaining information for understanding the molecular basis of pharmacological activity, for correct doses and treatment schemes selection, and for more effective drug application. Thus, an increase in pharmacokinetic research on marine-derived compounds is expected in the near future.

scholarly journals DDAVP enhances platelet adherence and platelet aggregate growth on human artery subendothelium

Blood ◽  
1984 ◽  
Vol 64 (1) ◽  
pp. 229-236 ◽  
Author(s):  
KS Sakariassen ◽  
M Cattaneo ◽  
A v.d. Berg ◽  
ZM Ruggeri ◽  
PM Mannucci ◽  
...  
Keyword(s):  
Bleeding Time ◽  
Close Association ◽  
Aggregate Formation ◽  
Human Artery ◽  
Primary Hemostasis ◽  
Platelet Adherence ◽  
Normal Individuals ◽  
Before And After ◽  
Platelet Aggregate ◽  
Aggregate Growth

Abstract The effect of intravenous 1-deamino (8-D-arginine)vasopressin (DDAVP) administration on platelet interaction with human artery subendothelium was investigated with flowing blood from five normal individuals and 12 patients with von Willebrand's disease (vWD). Three of the patients were diagnosed as vWD subtype I, four as subtype IIa, and five as subtype IIb. DDAVP administration to normals enhanced platelet adherence, in parallel with increasing plasma levels of factor VIII- related antigen ( FVIIIR :Ag) and ristocetin cofactor activity ( FVIIIR :RCF). Platelet aggregate formation was transiently increased within 90 minutes. Platelet adherence in patient blood before DDAVP infusion was subnormal. In patients with subtype I, administration of DDAVP normalized the bleeding time, enhanced the platelet adherence, and transiently improved the platelet aggregate formation. The platelet adherence was more corrected than would have been expected on the basis of the FVIIIR :Ag and FVIIIR :RCF levels. In patients with subtype IIa, infusion of DDAVP increased the FVIIIR :Ag levels approximately threefold, without affecting the FVIIIR :RCF levels, and in only two of four patients was a transiently enhanced platelet adherence with a corresponding shortening of the bleeding time observed. In patients with subtype IIb, administration of DDAVP increased the FVIIIR :Ag levels about threefold and the FVIIIR :RCF levels five to tenfold, but decreased the platelet adherence significantly. The bleeding time values were not normalized. A close association between the bleeding time values and corresponding platelet adherence values before and after DDAVP infusion was observed. Normalization of the bleeding time was paralleled with normalization of platelet adherence. We conclude that DDAVP improves the primary hemostasis by causing enhanced FVIII- vWF-mediated platelet adherence. DDAVP has little or no effect on the bleeding time in patients with subtype IIa and subtype IIb, because the platelet adherence is not normalized.

scholarly journals Asialo-von Willebrand factor inhibits platelet adherence to human arterial subendothelium: discrepancy between ristocetin cofactor activity and primary hemostatic function

Blood ◽  
1987 ◽  
Vol 70 (4) ◽  
pp. 1084-1089 ◽  
Author(s):  
JB Lawrence ◽  
HR Gralnick
Keyword(s):  
Von Willebrand Factor ◽  
Whole Blood ◽  
Specific Activity ◽  
Human Platelets ◽  
Primary Hemostasis ◽  
Platelet Adherence ◽  
Wall Shear ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Ristocetin Cofactor

Abstract Platelet adherence at high wall shear rates requires plasma von Willebrand factor (vWF). Clinically, the ristocetin cofactor (RCof) activity is the only widely available assay for vWF function. When purified vWF is treated with neuraminidase to yield asialo-vWF (AS- vWF), its RCof activity is increased by 20% to 40%. AS-vWF binds to normal human platelets independently of ristocetin and induces platelet aggregation in the presence of fibrinogen. To determine whether AS-vWF also shows an enhanced capacity to support platelet adherence to subendothelium, we used the Baumgartner technique. Intact vWF, AS-vWF, or AS-vWF treated with beta-galactosidase (asialo, agalacto-vWF; AS,AG- vWF) was added to normal citrated whole blood before perfusion over human umbilical artery segments (wall shear rate, 2,600 sec-1). Four micrograms per milliliter AS-vWF caused a 69% reduction in total platelet adherence compared with citrated whole blood (P less than .001), and 4 micrograms/mL AS,AG-vWF led to a 48% reduction (P less than .005). With 4 micrograms/mL intact vWF, the platelet adherence values were not significantly different from the controls. No significant differences in subendothelial platelet thrombi or postperfusion platelet counts were evident among any of the groups. In reconstituted afibrinogenemic perfusates, 4 micrograms/mL AS-vWF caused a 42% reduction in platelet adherence (P less than .05). Thus, AS-vWF is a potent inhibitor of platelet adherence, despite its enhanced RCof specific activity. Abnormalities in vWF carbohydrate may play a role in impaired primary hemostasis in some patients with von Willebrand's disease.

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