scholarly journals Reduced platelet forces underlie impaired hemostasis in mouse models of MYH9-related disease

2021 ◽  
Author(s):  
Juliane Baumann ◽  
Laura Sachs ◽  
Oliver Otto ◽  
Ingmar Schoen ◽  
Peter Nestler ◽  
...  
Keyword(s):  
Tranexamic Acid ◽  
Mouse Models ◽  
Myosin Light Chain ◽  
Bleeding Risk ◽  
Bleeding Tendency ◽  
Myosin Light Chain Phosphorylation ◽  
Clot Retraction ◽  
Related Disease ◽  
Muscle Myosin ◽  
Mouse Lines

MYH9-related disease patients with mutations in the contractile protein non-muscle myosin heavy chain IIA display, among others, macrothrombocytopenia and a mild to moderate bleeding tendency. In this study, we used three mouse lines, each with one point mutation in the Myh9 gene at positions 702, 1424, or 1841, to investigate mechanisms underlying the increased bleeding risk. Agonist-induced activation of Myh9 mutant platelets was comparable to controls. However, myosin light chain phosphorylation after activation was reduced in mutant platelets, which displayed altered biophysical characteristics and generated lower adhesion, interaction, and traction forces. Treatment with tranexamic acid restored clot retraction and reduced bleeding. We verified our findings from the mutant mice with platelets from patients with the respective mutation. These data suggest that reduced platelet forces lead to an increased bleeding tendency in MYH9-related disease patients, and treatment with tranexamic acid can improve the hemostatic function.

Combination of FXI Antisense Oligonucleotide and Plavix® Treatment Results in Enhanced Antithrombotic Activity without Increased Risk of Bleeding in Mouse Models of Thrombosis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4173-4173
Author(s):  
Dacao Gao ◽  
Jeff Crosby ◽  
Robert MacLeod ◽  
Gourab Bhattacharjee ◽  
Ester C Lowenberg ◽  
...  
Keyword(s):  
Mouse Models ◽  
Antisense Oligonucleotide ◽  
Factor Xa ◽  
Bleeding Risk ◽  
Fibrin Clot ◽  
Bleeding Tendency ◽  
Loss Of Function ◽  
Factor Xi ◽  
Antithrombotic Activity ◽  
Increased Risk

Abstract Abstract 4173 Factor XI (FXI) is a serine protease produced in the liver that contributes to thrombin generation via the intrinsic coagulation pathway. Also, it is a key component of an amplification pathway that is thought to sustain thrombin production at a wound site to maintain fibrin clot integrity. Loss of function mutations in the human FXI gene results in FXI deficiency, a disorder which is associated with only mild bleeding. In addition, high levels of FXI are a risk factor for thrombosis. We have previously presented the antithrombotic efficacy and safety of antisense oligonucleotide (ASO) mediated FXI depletion in various animal models of thrombosis. We have demonstrated that in combination with Lovenox®, FXI ASO treatment increases antithrombotic activity but does not increase bleeding risk. The purpose of the current study was to evaluate the relative risk/benefit of ASO mediated Factor XI depletion in combination with the platelet antagonist Plavix®. The “risk” component was bleeding tendency as measured by blood volume loss following tail nick, and the “benefit” component was antithrombotic effect in arterial and venous mouse models of thrombosis. Our study investigated a 20 mg/kg dose of FXI ASO in combination with a dose response of Plavix® and indicates that antisense mediated FXI depletion provides enhanced antithrombotic protection when given in combination with Plavix®. The combination of FXI ASO and Plavix® did not result in increased bleeding tendency. In contrast, treatment with a small molecule inhibitor of factor Xa in combination with Plavix® significantly increased bleeding. The approach used in this study is being used to define the ability of FXI ASO to combine with standard of care agents for the treatment of thrombosis. Disclosures: Gao: Isis Pharmaceuticals, Inc.: Employment. Crosby:Isis Pharmaceuticals, Inc.: Employment. MacLeod:Isis Pharmaceuticals: Employment. Bhattacharjee:Isis Pharmaceuticals, Inc.: Employment. Lowenberg:Isis Pharmaceuticals, Inc.: Consultancy. Levi:Isis Pharmaceuticals, Inc.: Consultancy. Monia:Isis Pharmaceuticals, Inc.: Employment.

scholarly journals An Alternatively Spliced Isoform of Non-muscle Myosin II-C Is Not Regulated by Myosin Light Chain Phosphorylation

2009 ◽  
Vol 284 (17) ◽  
pp. 11563-11571 ◽  
Author(s):  
Siddhartha S. Jana ◽  
Kye-Young Kim ◽  
Jian Mao ◽  
Sachiyo Kawamoto ◽  
James R. Sellers ◽  
...  
Keyword(s):  
Light Chain ◽  
Myosin Light Chain ◽  
Myosin Ii ◽  
Myosin Light Chain Phosphorylation ◽  
Alternatively Spliced ◽  
Muscle Myosin

Changes in cardiac muscle myosin light-chain phosphorylation associated with varying inotropic states

1981 ◽  
Vol 25 (3) ◽  
pp. 298-308 ◽  
Author(s):  
Arnold B. Meshkov ◽  
Rita A. Carey ◽  
Alfred A. Bove ◽  
William P. Santamore ◽  
James F. Spann
Keyword(s):  
Cardiac Muscle ◽  
Light Chain ◽  
Myosin Light Chain ◽  
Myosin Light Chain Phosphorylation ◽  
Muscle Myosin

Essential Athrombia

1975 ◽  
Vol 33 (02) ◽  
pp. 278-285 ◽  
Author(s):  
Şeref Inceman ◽  
Yücel Tangün
Keyword(s):  
Platelet Aggregation ◽  
Bleeding Time ◽  
Bleeding Tendency ◽  
Clot Retraction ◽  
Platelet Factor ◽  
Prolonged Bleeding Time ◽  
Normal Platelet ◽  
Aggregation Response ◽  
Platelet Disorder ◽  
Fibrinogen Content

SummaryA constitutional platelet function disorder in a twelve-year-old girl characterized by a lifelong bleeding tendency, prolonged bleeding time, normal platelet count, normal clot retraction, normal platelet factor 3 activity and impaired platelet aggregation was reported.Platelet aggregation, studied turbidimetrically, was absent in the presence of usual doses of ADP (1–4 μM), although a small wave of primary aggregation was obtained by very large ADP concentrations (25–50 μM). The platelets were also unresponsive to epinephrine, thrombin and diluted collagen suspensions. But an almost normal aggregation response occurred with strong collagen suspensions. The platelets responded to Ristocetin. Pelease of platelet ADP was found to be normal by collagen and thrombin, but impaired by kaolin. Platelet fibrinogen content was normal.The present case, investigated with recent methods, confirms the existence of a type of primary functional platelet disorder characterized solely by an aggregation defect, described in 1955 and 1962 under the name of “essential athrombia.”

Studies on the Haemostatic Defect in a Complicated Syndrome

1995 ◽  
Vol 74 (05) ◽  
pp. 1244-1251 ◽  
Author(s):  
H Stormorken ◽  
H Holmsen ◽  
R Sund ◽  
K S Sakariassen ◽  
T Hovig ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Bleeding Tendency ◽  
Clot Retraction ◽  
Abnormal Finding ◽  
Shear Rates ◽  
Perfusion Chamber ◽  
Coagulant Activity ◽  
5 Ht Uptake ◽  
And Storage

SummaryThe Stormorken syndrome is a multifacetted syndrome including a bleeding tendency. No deviations were found in the coagulation- or fibrinolytic systems. Platelet number was low normal, and size abnormal, whereas EM findings were unremarkable. Survival time was half normal. Clot retraction was initially rapid, but clearly decreased, whereas prothrombin consumption was also initially rapid, but complete. Membrane GP’s were normal, so was AA metabolism, PI-cycle, granule storage and secretion, and c-AMP function, whereas 5-HT uptake and storage was decreased. Optical platelet aggregation was low normal with all physiological agonists. The only clearly abnormal finding was that coagulant activity was present on non stimulated platelets at the same level as kaolin-stimulated normal platelets. This indicated a platelet abnormality which should lead to a thrombogenic, not to a haemorrhagic trait. This paradox may have its origin in rheology, because when challenged with in vivo shear rates in an ex vivo perfusion chamber, platelet cohesion was abnormally low. Further studies to better delineate the membrane abnormality are underway.

Determination and Treatment of Disorders of Primary Haemostasis

1999 ◽  
Vol 19 (04) ◽  
pp. 168-175 ◽  
Author(s):  
M. Weippert-Kretschmer ◽  
V. Kretschmer
Keyword(s):  
Platelet Function ◽  
Bleeding Risk ◽  
Bleeding Complications ◽  
Bleeding Tendency ◽  
Platelet Counts ◽  
Platelet Function Disorders ◽  
Perioperative Bleeding ◽  
Before And After ◽  
Low Sensitivity

SummaryPerioperative bleeding complications due to disorders of primary haemostasis are often underestimated. Routine determination of primary haemostasis is still problematic. The in vivo bleeding time (BT) shows low sensitivity and high variability. In this contribution the results and experiences with the IVBT having been obtained in various studies and during 10 years of routine use are reported. Patients and Methods: Blood donors before and after ASA ingestion, patients with thrombocytopenia as well as congenital and acquired platelet function disorders. Monitoring of desmopressin efficacy. IVBT with Thrombostat 4000 (tests with CaCl2 = TST-CaCl2 and ADP = TST-ADP) and PFA-100 (test cartridges with epinephrine = PFA-EPI and ADP = PFA-ADP). Results and Conclusions: IVBT becomes abnormal with platelet counts <100,000/μl. With platelet counts <50,000/μl the results are mostly outside the methodical range. IVBT proved clearly superior to BT in von Willebrand syndrome (vWS). All 16 patients with vWS were detected by PFA-EPI, whereas with BT 7 of 10 patients with moderate and 1 of 6 patients with mild forms of vWS were spotted. The majority of acquired and congenital platelet function disorders with relevant bleeding tendency were detectable by IVBT. Sometimes diagnostic problems arose in case of storage pool defect. Four to 12 h after ingestion of a single dose of 100 mg ASA the TST-CaCl2 became abnormal in all cases, the PFA-EPI only in 80%. However, the ASA sensitivity of TST-CaCl2 proved even too high when looking for perioperative bleeding complications in an urological study. Therefore, the lower ASS sensitivity of the PFA-100 seems to be rather advantageous for the estimation of a real bleeding risk. The good efficacy of desmopressin in the majority of cases with mild thrombocytopenia, congenital and acquired platelet function disorders and even ASS-induced platelet dysfunction could be proven by means of the IVBT. Thus IVBT may help to increase the reliability of the therapy. However, the IVBT with the PFA-100 is not yet fully developed. Nevertheless, routine use can be recommended when special methodical guidelines are followed.

scholarly journals Characterization of the calmodulin-binding and catalytic domains in skeletal muscle myosin light chain kinase.

1985 ◽  
Vol 260 (20) ◽  
pp. 11275-11285 ◽  
Author(s):  
A M Edelman ◽  
K Takio ◽  
D K Blumenthal ◽  
R S Hansen ◽  
K A Walsh ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Light Chain ◽  
Myosin Light Chain Kinase ◽  
Myosin Light Chain ◽  
Skeletal Muscle Myosin ◽  
Calmodulin Binding ◽  
Catalytic Domains ◽  
Muscle Myosin
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