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Platelets Dec 2023Inherited thrombocytopenia (IT) is a group of hereditary disorders characterized by a reduced platelet count as the main clinical manifestation, and often with abnormal... (Review)
Review
Inherited thrombocytopenia (IT) is a group of hereditary disorders characterized by a reduced platelet count as the main clinical manifestation, and often with abnormal platelet function, which can subsequently lead to impaired hemostasis. In the past decades, humanized mouse models (HMMs), that are mice engrafted with human cells or genes, have been widely used in different research areas including immunology, oncology, and virology. With advances of the development of immunodeficient mice, the engraftment, and reconstitution of functional human platelets in HMM permit studies of occurrence and development of platelet disorders including IT and treatment strategies. This article mainly reviews the development of humanized mice models, the construction methods, research status, and problems of using humanized mice for the study of human thrombopoiesis.
Topics: Animals; Mice; Humans; Disease Models, Animal; Blood Platelets; Thrombopoiesis; Thrombocytopenia; Blood Platelet Disorders; Hematopoietic Stem Cell Transplantation
PubMed: 37849076
DOI: 10.1080/09537104.2023.2267676 -
Blood Dec 2023Platelet-activating anti-platelet factor 4 (PF4)/heparin antibodies and anti-PF4 antibodies cause heparin-induced thrombocytopenia (HIT) and vaccine-induced immune...
Platelet-activating anti-platelet factor 4 (PF4)/heparin antibodies and anti-PF4 antibodies cause heparin-induced thrombocytopenia (HIT) and vaccine-induced immune thrombocytopenia and thrombosis (VITT), respectively. Diagnostic and treatment considerations differ somewhat between HIT and VITT. We identified patients with thrombocytopenia and thrombosis without proximate heparin exposure or adenovirus-based vaccination who tested strongly positive by PF4/polyanion enzyme-immunoassays and negative/weakly positive by heparin-induced platelet activation (HIPA) test but strongly positive by PF4-induced platelet activation (PIPA) test (ie, VITT-like profile). We tested these patients by a standard chemiluminescence assay that detects anti-PF4/heparin antibodies found in HIT (HemosIL AcuStar HIT-IgG(PF4-H)) as well as a novel chemiluminescence assay for anti-PF4 antibodies found in VITT. Representative control sera included an exploratory anti-PF4 antibody-positive but HIPA-negative/weak cohort obtained before 2020 (n = 188). We identified 9 patients with a clinical-pathological profile of a VITT-like disorder in the absence of proximate heparin or vaccination, with a high frequency of stroke (arterial, n = 3; cerebral venous sinus thrombosis, n = 4), thrombocytopenia (median platelet count nadir, 49 × 109/L), and hypercoagulability (greatly elevated D-dimer levels). VITT-like serological features included strong reactivity by PIPA (aggregation <10 minutes in 9/9 sera) and positive testing in the novel anti-PF4 chemiluminescence assay (3/9 also tested positive in the anti-PF4/heparin chemiluminescence assay). Our exploratory cohort identified 13 additional patient sera obtained before 2020 with VITT-like anti-PF4 antibodies. Platelet-activating VITT-like anti-PF4 antibodies should be considered in patients with thrombocytopenia, thrombosis, and very high D-dimer levels, even without a proximate exposure to heparin or adenovirus vector vaccines.
Topics: Thrombocytopenia; Heparin; Vaccination; Humans; Platelet Factor 4; Antibodies; Male; Female; Child, Preschool; Child; Adult; Thrombosis
PubMed: 37883798
DOI: 10.1182/blood.2023022136 -
Haematologica Oct 2023Current immune thrombocytopenia (ITP) guidelines target children and adults, leading to oversimplification. Adolescents and young adults (AYAS) comprise a separate group...
Current immune thrombocytopenia (ITP) guidelines target children and adults, leading to oversimplification. Adolescents and young adults (AYAS) comprise a separate group with distinct health and psychosocial issues. This study aimed to describe the clinical presentation and therapeutic strategies of ITP among AYAS. We analyzed data from two large ITP registries (PARC-ITP; CARMEN-France) and included newly diagnosed ITP patients (aged 12-25 years) with an initial platelet counts of <100×109/L. Patients with secondary ITP or non-immune thrombocytopenia (n=57) and pregnant women (n=10) were excluded. Of the 656 cases of AYAS with primary ITP registered from 2004 up to 2021, 12-month follow-up data were available for 72%. The initial median platelet count was 12×109/L. In 109 patients (17%), the diagnosis was incidental, without documented bleeding. Apart from gynecological bleeding, the clinical and therapeutical characteristics of females and males were similar. Platelet-enhancing drugs were reported in 66%, 45%, and 30% of patients at diagnosis, 1-6 months, and 6-12 months after diagnosis, respectively. Corticosteroids were the preferred treatment at all time points. At 12 months, 50% of all patients developed chronic ITP. In the subgroup of patients with initial severe thrombocytopenia (<20×109/L), those receiving frontline treatment had a higher remission rate at 1 year than those who followed an initial watch-and-wait strategy (53% and 32%; P<0.05). Our analysis indicates that the remission rate at 1 year may be associated with the initial treatment strategy. This hypothesis must be confirmed in prospective studies.
Topics: Male; Child; Humans; Female; Adolescent; Young Adult; Pregnancy; Purpura, Thrombocytopenic, Idiopathic; Prospective Studies; Platelet Count; Thrombocytopenia; Hemorrhage
PubMed: 37051753
DOI: 10.3324/haematol.2022.282524 -
Blood Reviews Jan 2024Immune thrombocytopenia (ITP) is a rare autoimmune condition, due to peripheral platelet destruction through antibody-dependent cellular phagocytosis,... (Review)
Review
Immune thrombocytopenia (ITP) is a rare autoimmune condition, due to peripheral platelet destruction through antibody-dependent cellular phagocytosis, complement-dependent cytotoxicity, cytotoxic T lymphocyte-mediated cytotoxicity, and megakaryopoiesis alteration. This condition may be idiopathic or triggered by drugs, vaccines, infections, cancers, autoimmune disorders and systemic diseases. Recent advances in our understanding of ITP immunobiology support the idea that other forms of thrombocytopenia, for instance, occurring after immunotherapy or cellular therapies, may share a common pathophysiology with possible therapeutic implications. If a decent pipeline of old and new agents is currently deployed for classical ITP, in other more complex immune-mediated thrombocytopenic disorders, clinical management is less harmonized and would deserve further prospective investigations. Here, we seek to provide a fresh overview of pathophysiology and current therapeutical algorithms for adult patients affected by this disorder with specific insights into poorly codified scenarios, including refractory ITP and post-immunotherapy/cellular therapy immune-mediated thrombocytopenia.
Topics: Adult; Humans; Purpura, Thrombocytopenic, Idiopathic; Thrombocytopenia; Immunotherapy; Blood Platelets
PubMed: 37980261
DOI: 10.1016/j.blre.2023.101141 -
Platelets Dec 2023Platelets play a critical role in immune response. Coronavirus disease 2019 (COVID-19) patients with a severe course often show pathological coagulation parameters...
Platelets play a critical role in immune response. Coronavirus disease 2019 (COVID-19) patients with a severe course often show pathological coagulation parameters including thrombocytopenia, and at the same time the proportion of immature platelets increases. In this study, the platelet count and the immature platelet fraction (IPF) of hospitalized patients with different oxygenation requirements was investigated daily over a course of 40 days. In addition, the platelet function of COVID-19 patients was analyzed. It was found that the number of platelets in patients with the most severe course (intubation and extracorporeal membrane oxygenation (ECMO)) was significantly lower (111.5 ∙ 10 /mL) than in the other groups (mild (no intubation, no ECMO): 203.5 ∙ 10 /mL, < .0001, moderate (intubation, no ECMO): 208.0 ∙ 10 /mL, < .0001). IPF tended to be elevated (10.9%). Platelet function was reduced. Differentiation by outcome revealed that the deceased patients had a highly significant lower platelet count and higher IPF (97.3 ∙ 10 /mL, < .0001, 12.2%, = .0003).
Topics: Humans; COVID-19; Blood Platelets; Thrombocytopenia; Platelet Count; Blood Coagulation
PubMed: 36883692
DOI: 10.1080/09537104.2023.2184183 -
Archives of Pathology & Laboratory... Aug 2023Immune thrombotic thrombocytopenic purpura (iTTP) is a rare but potentially fatal blood disorder resulting from acquired deficiency of plasma ADAMTS13, a metalloprotease... (Review)
Review
CONTEXT.—
Immune thrombotic thrombocytopenic purpura (iTTP) is a rare but potentially fatal blood disorder resulting from acquired deficiency of plasma ADAMTS13, a metalloprotease that cleaves endothelium-derived ultralarge von Willebrand factor. Standard of care for iTTP including therapeutic plasma exchange, caplacizumab, and immunosuppressives, known as triple therapy, has led to a significant reduction in the disease-related mortality rate. The first International Society of Thrombosis and Haemostasis TTP guideline stresses the importance of having plasma ADAMTS13 activity testing in the algorithm for diagnosis and management of iTTP. However, the predictive role of assessing plasma ADAMTS13 activity and inhibitors or other ADAMTS13-related parameters in patients with acute iTTP and during remission has not been systematically evaluated.
OBJECTIVE.—
To review and assess the predictive values of testing plasma ADAMTS13 activity, antigen, and inhibitors or anti-ADAMTS13 immunoglobulin G at various stages of disease in outcomes of iTTP.
DATA SOURCES.—
Peer-reviewed publications and personal experience.
CONCLUSIONS.—
We conclude that assessing ADAMTS13 biomarkers is not only essential for establishing the initial diagnosis, but also crucial for risk stratification and the early detection of disease recurrence. This may guide therapeutic interventions during acute episodes and for long-term follow-up of iTTP patients.
Topics: Humans; ADAMTS13 Protein; Biomarkers; Immunosuppressive Agents; Purpura, Thrombotic Thrombocytopenic; Thrombosis; von Willebrand Factor
PubMed: 36223210
DOI: 10.5858/arpa.2022-0050-RA -
Journal of Thrombosis and Haemostasis :... Jun 2023Since the description of the first case with gray platelet syndrome (GPS) in 1971, this rare inherited platelet disorder has been the focus of extensive clinical and... (Review)
Review
Since the description of the first case with gray platelet syndrome (GPS) in 1971, this rare inherited platelet disorder has been the focus of extensive clinical and basic research. These studies have not only increased our knowledge about the clinical manifestations of GPS but also deepened our understanding of the biogenesis of platelet α-granules and their pathophysiology in hemostasis and thrombosis. The discovery of the causal gene, neurobeachin-like 2, in 2011 was a milestone in hematology. Following this was the rapid diagnosis and phenotyping of many new patients and the further development of experimental models to characterize the pathophysiological relevance of neurobeachin-like 2 in hemostasis and immunity. The impact of altered protein function on cells other than platelets became apparent, including defects in the granules of neutrophils and monocytes and changes in the transcriptomic and proteomic profiles of other immune cells such as T lymphocytes. Besides the previously recognized clinical manifestations of macrothrombocytopenia, splenomegaly, and early-onset bone marrow fibrosis, we now recognize that immunologic abnormalities, including autoimmune diseases and recurrent infections, affect a proportion of patients with GPS. There is a proinflammatory signature of the plasma in GPS, with quantitative alterations of multiple proteins, including many produced by the liver. This review will cover the classical features of GPS and then focus on additional clinical manifestations of immune dysregulation and cellular defects beyond platelets in patients with this rare disorder.
Topics: Humans; Megakaryocytes; Gray Platelet Syndrome; Autoimmunity; Proteomics; Blood Platelets; Autoimmune Diseases; Cytoplasmic Granules
PubMed: 37028650
DOI: 10.1016/j.jtha.2023.03.032 -
Frontiers in Public Health 2023In 2021, India contributed for ~79% of malaria cases and ~ 83% of deaths in the South East Asia region. Here, we systematically and critically analyzed data... (Review)
Review
INTRODUCTION
In 2021, India contributed for ~79% of malaria cases and ~ 83% of deaths in the South East Asia region. Here, we systematically and critically analyzed data published on malaria in pregnancy (MiP) in India.
METHODS
Epidemiological, clinical, parasitological, preventive and therapeutic aspects of MiP and its consequences on both mother and child were reviewed and critically analyzed. Knowledge gaps and solution ways are also presented and discussed. Several electronic databases including Google scholar, Google, PubMed, Scopus, Wiley Online library, the Malaria in Pregnancy Consortium library, the World Malaria Report, The WHO regional websites, and ClinicalTrials.gov were used to identify articles dealing with MiP in India. The archives of local scientific associations/journals and website of national programs were also consulted.
RESULTS
Malaria in pregnancy is mainly due to () and (), and on rare occasions to spp. and too. The overall prevalence of MiP is ~0.1-57.7% for peripheral malaria and ~ 0-29.3% for placental malaria. Peripheral infection at antenatal care (ANC) visits decreased from ~13% in 1991 to ~7% in 1995-1996 in Madhya Pradesh, while placental infection at delivery unit slightly decreased from ~1.5% in 2006-2007 to ~1% in 2012-2015 in Jharkhand. In contrast, the prevalence of peripheral infection at ANC increased from ~1% in 2006-2007 to ~5% in 2015 in Jharkhand, and from ~0.5% in 1984-1985 to ~1.5% in 2007-2008 in Chhattisgarh. Clinical presentation of MiP is diverse ranging from asymptomatic carriage of parasites to severe malaria, and associated with comorbidities and concurrent infections such as malnutrition, COVID-19, dengue, and cardiovascular disorders. Severe anemia, cerebral malaria, severe thrombocytopenia, and hypoglycemia are commonly seen in severe MiP, and are strongly associated with tragic consequences such as abortion and stillbirth. Congenital malaria is seen at prevalence of ~0-12.9%. Infected babies are generally small-for-gestational age, premature with low birthweight, and suffer mainly from anemia, thrombocytopenia, leucopenia and clinical jaundice. Main challenges and knowledge gaps to MiP control included diagnosis, relapsing malaria, mixed infection treatment, self-medication, low density infections and utility of artemisinin-based combination therapies.
CONCLUSION
All taken together, the findings could be immensely helpful to control MiP in malaria endemic areas.
Topics: Female; Humans; Infant, Newborn; Pregnancy; Abortion, Spontaneous; Anemia; India; Malaria; Malaria, Vivax; Placenta; Thrombocytopenia
PubMed: 37927870
DOI: 10.3389/fpubh.2023.1150466 -
Acta Bio-medica : Atenei Parmensis Jun 2023Vitamin A toxicity is uncommon, but when it occurs can be serious and even fatal. A case vitamin A intoxication with high levels in liver tests, thrombocytopenia and...
BACKGROUND AND AIM
Vitamin A toxicity is uncommon, but when it occurs can be serious and even fatal. A case vitamin A intoxication with high levels in liver tests, thrombocytopenia and appearance virosis. Laboratory testing is one of the most widely used diagnostic interventions supporting medical decisions of this phenomenon are necessary.
CASE REPORT
Here, we report a case vitamin A intoxication with high levels in liver tests, thrombocytopenia and appearance virosis. The patient showed several clinical signs abdominal pain, including mild anemia and thrombocytopenia.
CONCLUSIONS
We believe that Laboratory testing is one of the most widely used diagnostic interventions supporting medical decisions, and further investigations regarding the etiology and prevalence of this phenomenon are necessary. (www.actabiomedica.it).
Topics: Humans; Hypervitaminosis A; Vitamin A; Anemia; Thrombocytopenia
PubMed: 37326274
DOI: 10.23750/abm.v94i3.14041 -
International Journal of Biological... 2023Abnormal megakaryocyte maturation and platelet production lead to platelet-related diseases and impact the dynamic balance between hemostasis and bleeding. Cellular...
Abnormal megakaryocyte maturation and platelet production lead to platelet-related diseases and impact the dynamic balance between hemostasis and bleeding. Cellular repressor of E1A-stimulated gene 1 (CREG1) is a glycoprotein that promotes tissue differentiation. However, its role in megakaryocytes remains unclear. In this study, we found that CREG1 protein is expressed in platelets and megakaryocytes and was decreased in the platelets of patients with thrombocytopenia. A cytosine arabinoside-induced thrombocytopenia mouse model was established, and the mRNA and protein expression levels of CREG1 were found to be reduced in megakaryocytes. We established megakaryocyte/platelet conditional knockout () and transgenic mice (tg-). Compared to mice, mice exhibited thrombocytopenia, which was mainly caused by inefficient bone marrow (BM) thrombocytopoiesis, but not by apoptosis of circulating platelets. Cultured -megakaryocytes exhibited impairment of the actin cytoskeleton, with less filamentous actin, significantly fewer proplatelets, and lower ploidy. CREG1 directly interacts with MEK1/2 and promotes MEK1/2 phosphorylation. Thus, our study uncovered the role of CREG1 in the regulation of megakaryocyte maturation and thrombopoiesis, and it provides a possible theoretical basis for the prevention and treatment of thrombocytopenia.
Topics: Animals; Mice; Blood Platelets; Bone Marrow; Megakaryocytes; Mice, Transgenic; Thrombocytopenia; Thrombopoiesis; Humans
PubMed: 37496998
DOI: 10.7150/ijbs.78660