VPAC1 Receptor-Mediated Regulation of Megakaryopoiesis.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 735-735
Author(s):  
Kathleen Freson ◽  
Chantal Thys ◽  
Christine Wittevrongel ◽  
Rita De Vos ◽  
Jos Vermylen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Examination ◽  
T Test ◽  
Bleeding Complications ◽  
Bleeding Tendency ◽  
Regulatory Pathways ◽  
Normal Platelet ◽  
Vpac1 Receptor ◽  
Life Threatening ◽  
Antibodies Monoclonal

Abstract Identification of the regulatory pathways that direct megakaryopoiesis and platelet production is essential for the development of novel strategies to treat life threatening bleeding complications in bone marrow suppressed patients. We demonstrated that megakaryocytes and platelets express the Gs-coupled VPAC1 receptor, for which both PACAP and VIP are specific agonists. We have further identified a bleeding tendency and found three copies of the PACAP gene in two related patients with severe mental retardation, responsible for elevated PACAP plasma levels and associated increased platelet cAMP concentrations, resulting in strongly reduced platelet aggregation (JCI, 2004, 113, 905). In this study, we have further demonstrated a fundamental role for the VPAC1 signalling pathway during megakaryocyte maturation and platelet formation. Patients with PACAP overexpression have mild thrombocytopenia, a normal platelet survival and relatively small platelets with an MPV of 8.2 fL (normal MPV 9-13 fL). FACS analysis of the patients’ platelets showed reduced expression of GPIX and GPIIIa. Electron microscopy of bone marrow of patients and of mice, specifically overexpressing PACAP in megakaryocytes revealed the presence of early megakaryocyte progenitors but almost not of mature megakaryocytes. Immature megakaryoblasts seemed to have reduced levels of rough endoplasmic reticulum cisternae and free ribosomes. To further study the modulating role of VPAC1 in thrombopoiesis, control mice were therefore subcutaneously injected with neutralizing polyclonal or monoclonal anti-PACAP, anti-VIP or anti-VPAC1 antibodies. Injection of these antibodies in all cases led to increased platelet counts, compared to control antibodies (monoclonal anti-PACAP antibody: 1194 ± 237 x 109 plt/L; control antibody: 722 ± 178 x 109 plt/L; p=0.01, unpaired t-test at day 7 after injection). This strategy was also capable of reducing the drop in platelet count in busulfan treated mice (polyclonal anti-PACAP antibody: 561 ± 121 x 109 plt/L; control antibody: 349 ± 65 x 109 plt/L; p=0.033, unpaired t-test at day 29 or day 18 after respectively antibody and busulfan injection). In addition, bone marrow examination of mice injected with monoclonal anti-PACAP or anti-VPAC1 antibodies revealed an increase in megakaryocyte numbers and showed a marked expansion and mobilization of megakaryocyte progenitor cells. Mice injected with a monoclonal anti-VPAC1 antibody showed an increase of about 50% in bone marrow CFU-MK. In conclusion, we provide evidence that the VPAC1 pathway modulates normal megakaryopoiesis. Further studies are needed to evaluate whether this pathway can be safely manipulated in man in the treatment of thrombocytopenia.

Pancytopenia: A Challenging Problem for Treating Physician

2018 ◽  
Vol 2 (01) ◽  
pp. 22-28
Author(s):  
Md. Rezaul Karim Chowdhury ◽  
Amina Begum ◽  
Md. Haroon Ur Rashid ◽  
Md. Kamrul Hasan
Keyword(s):  
Bone Marrow ◽  
Physical Examination ◽  
Blood Smear ◽  
Peripheral Blood Smear ◽  
Bone Marrow Examination ◽  
Challenging Problem ◽  
Trephine Biopsy ◽  
Life Threatening ◽  
Underlying Pathology ◽  
Careful History

Pancytopenia is an important clinico-haematological entity and striking feature of many serious and life-threatening illnesses. Many haematological and non-haematological diseases involve the bone marrow primarily or secondarily and cause pancytopenia. Decrease in haemopoietic cell production, ineffective haemopoiesis and peripheral sequestration or destruction of the cells are the main pathophysiology of pancytopenia. The cause of pancytopenia thus may be lying in the bone marrow or in the periphery or both. Careful history, physical examination, simple blood work, review of the peripheral blood smear, sometimes bone marrow examination and trephine biopsy are required for diagnosis. Treatment and prognosis depend on the severity of pancytopenia and underlying pathology.

scholarly journals Plasmodium in the bone marrow: case series from a hospital in Pakistan, 2007–2015

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Muhammad Shariq Shaikh ◽  
Basim Ali ◽  
Mahin Janjua ◽  
Ayesha Akbar ◽  
Syed Arish Haider ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Incidental Finding ◽  
Case Series ◽  
Unknown Origin ◽  
Bone Marrow Examination ◽  
Reticuloendothelial System ◽  
University Hospital ◽  
Multisystem Disease ◽  
Body Tissues ◽  
Life Threatening

Abstract Background Malaria is a life-threatening, multisystem disease caused by the plasmodial parasite with a global incidence of approximately 229 million annually. The parasites are known to have unique and crucial interactions with various body tissues during its life cycle, notably the liver, spleen, and recent work has shown the bone marrow to be a reservoir of infection. Methods This study is a case series of patients in whom examination of bone marrow revealed malarial parasites. A retrospective record review of 35 parasite-positive bone marrow specimens examined at Aga Khan University Hospital (AKUH), Karachi, Pakistan, over the years 2007 to 2015 was conducted. Bone marrow aspirates were collected as per International Council for Standardization in Haematology (ICSH) guidelines. Results The median age of patients was 22 years (range 1–75), and 60 % (n = 21) were male. 22 patients had evidence of Plasmodium falciparum, 12 had evidence of Plasmodium vivax and 1 patient had a mixed infection. Gametocytes and trophozoites were the most common stages identified on both peripheral blood and bone marrow examinations. Indications for bone marrow examination included fever of unknown origin and the workup of cytopenias and malignancies. Conclusions The incidental finding of Plasmodium in samples of bone marrow suggests the reticuloendothelial system may be regularly harbour these parasites, be the infection acute or chronic in character.

scholarly journals Clinical and Experimental Studies on the Bleeding Tendency During Defibrinogenation Therapy

1977 ◽  
Author(s):  
S. Ishimaru ◽  
K. Furukawa ◽  
M. Takahashi ◽  
M. Fujimaki ◽  
K. Fukutake
Keyword(s):  
Platelet Aggregation ◽  
Platelet Function ◽  
Surgical Procedure ◽  
Postoperative Bleeding ◽  
Experimental Studies ◽  
Bleeding Complications ◽  
Fibrinogen Concentration ◽  
Bleeding Tendency ◽  
Normal Platelet ◽  
Normal Limits

Defibrinogenation with thrombin-like enzyme is expected to be a new type of anticoagulant therapy without serious bleeding complications. However, it appears to be dangerous to perform surgical procedure in defibrinogenated state. In order to investigate the causes of the bleeding tendency which occurs during defibrinogenation therapy, the following clinical and experimental studies were undertaken. Ten mongrel dogs were used, the superior caval vein was replaced by expanded polytetrafluoroethylene graft. 50 to 100 μl/kg of batroxobin was administered 2 days prior to the operation. 5 out of 10 dogs died due to bleeding postoperativelly, and the causes of the bleeding seemed to be the decreased fibrinogen concentration and the reduced platelet function. Fifteen patients suffering from peripheral vascular thrombosis were treated with 30 to 60 μl/kg of batroxobin. In 9 patients, urokinase was administered combined with batroxobin. No bleeding complications were observed in these patients. In another 6 patients, surgical procedure was performed after batroxobin administration. Postoperative bleeding was observed in one out of these 6 patients. This patient was operated on after the initial administration of batroxobin. FDP level was 512 μg/ml and ADP induced platelet aggregation was within normal limits, but fibrinogen concentration was unmeasurable at the time of operation. The cause of the bleeding seemed to be the decreased fibrinogen concentration. From these clinical experiences, it is suggested that platelet adhesion to glass and ADP induced platelet aggregation are not influenced by the decreased fibrinogen concentration nor the increased level of FDP during the defibrinogenation therapy with batroxobin. These results indicate that an adequate level of fibrinogen is needed for certain hemostasis besides normal platelet function.

scholarly journals Etiological and Clinical Spectrum of Pancytopenia Based on Peripheral Blood Smear and Bone Marrow Examination: A Cross-sectional Study

2021 ◽  
pp. 26-32
Author(s):  
Vipin Porwal ◽  
Rajesh Deshpande ◽  
Rohit Modi
Keyword(s):  
Bone Marrow ◽  
Peripheral Blood ◽  
General Medicine ◽  
Peripheral Blood Smear ◽  
Bone Marrow Examination ◽  
Cross Sectional Study ◽  
Megaloblastic Anaemia ◽  
Bleeding Tendency ◽  
Cross Sectional ◽  
Common Clinical Finding

Aims: Pancytopenia is a common clinic-haematological problem suspected in patients with anaemia, prolonged fever, and a bleeding tendency.  This study was performed to find the prevalence of pancytopenia and to determine the common causes of pancytopenia. Study Design:  Cross-sectional observational study. Place and Duration of Study: department of general medicine at R. D. Gardi Medical College, Ujjain, India between November 2017 toAugust 2019. Methodology: The study was conducted among patients with pancytopenia during a two-year period. The etiological pattern was assessed through routine blood tests to determine their clinical features, peripheral blood pictures, and bone marrow morphologies. Results: Out of 100 patients with pancytopenia, the majority (64.0%) were men. A total of 34 patients were aged between the 21 and 30 years and 28 were aged between 31 and 40 years. Generalized weakness was the most common (88%) presentation and the most common clinical finding was pallor (94.0%), followed by splenomegaly (40.0%) and hepatomegaly (30.0%). Megaloblastic anaemia was the most common cause of pancytopenia that was observed in 58 patients, followed by aplastic anaemia (n=12), cirrhosis of the liver (n=8), leukaemia (n=6), dengue, myelodysplastic syndrome, and malaria (n=4 each), paroxysmal nocturnal haemoglobinuria and acquired immunodeficiency syndrome (n=2 each). A total of 28.0% patients had normocellular bone marrow and 72.0% had cellular marrow. Conclusion: Megaloblastic anaemia was the most common aetiology of pancytopenia.

scholarly journals Plasmodia in bone marrow examinations: Case series from a hospital in Pakistan 2007-2015

2021 ◽  
Author(s):  
Muhammad Shariq Shaikh ◽  
Basim Ali ◽  
Mahin Janjua ◽  
Ayesha Akbar ◽  
Syed Arish Haider ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Incidental Finding ◽  
Case Series ◽  
Unknown Origin ◽  
Bone Marrow Examination ◽  
Reticuloendothelial System ◽  
University Hospital ◽  
Multisystem Disease ◽  
Body Tissues ◽  
Life Threatening

Abstract Background Malaria is a life-threatening, multisystem disease caused by the protozoan plasmodia with a global incidence of approximately 212 million annually. The parasite is known to have unique and crucial interactions with various body tissues during its life cycle, notably the liver, spleen, and recent work has shown the bone marrow as reservoir of infection.Methods This study is a case series of patients in whom examination of bone marrow revealed malaria parasites. We conducted a retrospective record review of 35 malaria-positive bone marrow specimens examined at Aga Khan University Hospital (AKUH), Karachi, Pakistan, over the years 2007 to 2015. Bone marrow aspirates were collected as per International Council for Standardization in Haematology (ICSH) guidelines.Results The median age of patients was 22 years (range 1–75), and 60% (n = 21) were male. 22 patients had evidence of P. falciparum, 12 had evidence of P. vivax and 1 patient had a mixed infection. Gametocytes and trophozoites were the most common stages identified on both peripheral blood and bone marrow examinations. Indications for bone marrow examination included fever of unknown origin and the workup of cytopenias and malignancies.Conclusions The incidental finding of plasmodia in samples of bone marrow from our patients suggests the reticuloendothelial system may be regularly infected by these parasites, be it acute or chronic in character.

Study of Albinism in Relation to Hermanský-Pudlák Syndrome

1975 ◽  
Author(s):  
F. Hermanský ◽  
P. Cieslar ◽  
O. Matousová ◽  
K. Smetana
Keyword(s):  
Bone Marrow ◽  
Oculocutaneous Albinism ◽  
Bleeding Tendency ◽  
Normal Platelet ◽  
Dense Bodies ◽  
Ultrathin Sections ◽  
Hermansky Pudlak Syndrome ◽  
Platelet Defects ◽  
Disorder Type ◽  
Platelet Functions

Up to now 24 patients with oculocutaneous albinism have been investigated in this study to find out the frequency of characteristic signs of HPS. Seven of them suffered from mild bleeding tendency. Platelet defects of storage pool disorder type have been revealed at a varying degree in all these cases. (Aggregation abnormalities, decrease of total platelet ADP contents and of its release, lower serotonin uptake with the lack of very dense bodies in ultrathin sections). This thrombocytophathy has been regularly associated with the storage of pigment typical for HPS in their bone marrow. In 7 of 17 remaining albinos with normal platelet functions some increase in the accumulation of non-specific cytochemically different lipopigments was noted.Our results demonstrate a rather frequent occurence of HPS in albinos and suggest a mutation of one common gene or of closely linked genes as a cause of complete HPS.

Fundamentals of Bone Marrow Examination

1994 ◽  
Vol 8 (4) ◽  
pp. 651-663 ◽  
Author(s):  
Bong H. Hyun ◽  
Alan J. Stevenson ◽  
Cheryl A. Hanau
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Examination

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.”

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.

Ion Channel Remodelling in Atrial Fibrillation

2011 ◽  
Vol 7 (2) ◽  
pp. 97 ◽  
Author(s):  
Niels Voigt ◽  
Dobromir Dobrev ◽  
◽  
Keyword(s):  
Atrial Fibrillation ◽  
Ion Channel ◽  
Antiarrhythmic Drugs ◽  
Current Knowledge ◽  
Bleeding Complications ◽  
Large Size ◽  
Cardiovascular Morbidity And Mortality ◽  
Number Of Patients ◽  
Life Threatening ◽  
Underlying Mechanisms

Atrial fibrillation (AF) is the most common arrhythmia and is associated with substantial cardiovascular morbidity and mortality, with stroke being the most critical complication. Present drugs used for the therapy of AF (antiarrhythmics and anticoagulants) have major limitations, including incomplete efficacy, risks of life-threatening proarrhythmic events and bleeding complications. Non-pharmacological ablation procedures are efficient and apparently safe, but the very large size of the patient population allows ablation treatment of only a small number of patients. These limitations largely result from limited knowledge about the underlying mechanisms of AF and there is a hope that a better understanding of the molecular basis of AF may lead to the discovery of safer and more effective therapeutic targets. This article reviews the current knowledge about AF-related ion-channel remodelling and discusses how these alterations might affect the efficacy of antiarrhythmic drugs.

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