Platelet lifespan and mechanisms for clearance.

PURPOSE OF REVIEW: Activated or aged platelets are removed from circulation under (patho)physiologic conditions, the exact mechanism of platelet clearance under such conditions remains unclear and are currently being investigated. This review focuses on recent findings and controversies regarding platelet clearance and the disruption of platelet life cycle. RECENT FINDINGS: The platelet life span is determined by glycosylation of platelet surface receptors with sialic acid. Recently, it was shown that platelet activation and granule release leads to desialylation of glycans and accelerated clearance of platelets under pathological conditions. This phenomenon was demonstrated to be a main reason for thrombocytopenia being a complication in several infections and immune disorders. SUMMARY: Although we have recently gained some insight into how aged platelets are cleared from circulation, we are still not seeing the full picture. Further investigations of the platelet clearance pathways under pathophysiologic conditions are needed as well as studies to unravel the connection between platelet clearance and platelet production.

Platelets in dengue infection: more than a numbers game.

Dengue virus (DENV) infection is responsible for the development of dengue illness, which can be either asymptomatic, present mild manifestations or evolve to severe dengue. Thrombocytopenia is an important characteristic during DENV infection, being observed both in mild and severe dengue, although the lowest platelet counts are encountered during severe cases. This review gathers information regarding several mechanisms that have been related to alterations in platelet number and function, leading to thrombocytopenia but also platelet-mediated immune and inflammatory response. On this regard, we highlight that the decrease in platelet counts may be due to bone marrow suppression or consumption of platelets at the periphery. We discuss the infection of hematopoietic progenitors and stromal cells as mechanisms involved in bone marrow suppression. Concerning peripheral consumption of platelets, we addressed the direct infection of platelets by DENV, adhesion of platelets to leukocytes and vascular endothelium and platelet clearance mediated by anti-platelet antibodies. We also focused on platelet involvement on the dengue immunity and pathogenesis through translation and secretion of viral and host factors and through platelet-leukocyte aggregates formation. Hence, the present review highlights important findings related to platelet activation and thrombocytopenia during dengue infection, and also exhibits different mechanisms associated with decreased platelet counts.Graphical abstract:Schematic mechanistic representation of platelet-mediated immune responses and thrombocytopenia during dengue infection. (A) DENV-infected platelets secrete cytokines and chemokines and also adhere to activated vascular endothelium. Platelets aggregate with leukocytes, inducing the secretion of NETs and inflammatory mediators by neutrophils and monocytes, respectively. (B) DENV directly infects stromal cells and hematopoietic precursors, including megakaryocytes, which compromises megakaryopoiesis. Both central and peripheric mechanisms contribute to DENV-associated thrombocytopenia.

Heparin-induced thrombocytopenia: An update for the COVID-19 era.

The increased use of heparin during the current COVID-19 pandemic has highlighted the risk of a rare but potentially serious complication of heparin therapy, viz. heparin-induced thrombocytopenia (HIT). This is a short review on the pharmacology of heparin and its derivatives, and the pathophysiology of HIT. Guidance on laboratory testing for and clinical management of HIT is presented in accordance with international guidelines. There are important similarities and differences between HIT and the new entity of vaccine-induced immune thrombotic thrombocytopenia, also known as thrombosis with thrombocytopenia syndrome, which clinicians need to be aware of.

Entecavir-associated thrombocytopenia.

Entecavir (ETV) is widely used in the treatment of hepatitis B, but there are only a few reports about entecavir-associated thrombocytopenia, and it is considered as an immediate response and inappropriate to continue the treatment with other nucleoside analogues. Now, we report the third case, and this case was delayed response and we switched to treatment with tenofovir (TDF). There was a 66-year-old female who was infected with hepatitis B virus (HBV). Her platelet count decreased from 111*109/L to 3*109/L and was prone to gum bleeding and skin ecchymosis after she received ETV treatment for 88 days. As a treatment option, ETV was replaced by TDF immediately, frequent platelets transfusions and thrombopoietin were applied for several days, daily prednisone of 50 mg was concomitantly taken, and then platelet count improved after 10 days. She was diagnosed with entecavir-associated thrombocytopenia after analysis of the temporal relationship and exclusion of other causes of thrombocytopenia by blood and bone marrow examinations. Our case suggested that the platelet count should be monitored regularly in patients during ETV treatment, and it may be a feasible option to choose TDF to maintain antiviral treatment when entecavir-associated thrombocytopenia occurs.

[Step by step - A diagnostic approach to bleeding disorders]. / Abklärung erhöhter Blutungsneigung ­ Schritt für Schritt.

The main symptom of hemorrhagic diathesis is an increased bleeding tendency. Due to the subjectivity of various features of the bleeding history, unclarity of the family history, and an individualization of the extent of diagnostic the evaluation of a suspected bleeding disorder represents a challenging endeavour in hematology. Hemorrhagic diathesis can be divided into the following sub-categories: disorders in primary hemostasis (e. g. von Willebrand disease, different causes of thrombocytopenia), secondary hemostasis (e. g. hemophilia A and B, Vitamin K deficiency) and fibrinolysis, and in connective tissue or vascular formation. This article reviews available diagnostic methods for bleeding disorders, from structured patient history to highly specialized laboratory diagnosis.

Right heart thrombus-in-transit in a patient with Evans syndrome: A case report.

INTRODUCTION: Right heart free-floating thrombus in the absence of structural heart disease or atrial fibrillation is rare. When it travels to the heart into the lung, called thrombus-in-transit, may cause cardiopulmonary collapse and sudden death. The clinical presentation varies from mild respiratory symptoms to sudden death; however, there are few clinical case reports of giant, free-floating thrombus in the right heart in an asymptomatic patient, and the optimal management options have not been established. PATIENT CONCERNS: A 36-year-old Asian woman presented to the emergency department with complaints of worsening swelling of the left lower extremity over 12 hours. DIAGNOSIS: Left leg deep vein thrombosis accompanied by an asymptomatic giant right atrial thrombus and pulmonary embolism with a rare autoimmune disease of Evans syndrome. INTERVENTIONS: Emergent surgical thrombectomy under cardiopulmonary bypass for right atrial thrombus. OUTCOMES: The postoperative course was uneventful, and she was discharged on the eighth postoperative day with normal heart function and mild tricuspid regurgitation. CONCLUSION: An additional diagnostic workup in cases of deep vein thrombosis is necessary for the rapid diagnosis of right heart thrombus and pulmonary embolism without delay. This case report illustrates that early recognition of venous thromboembolism and emergent thrombectomy of right heart thrombus-in-transit is crucial to prevent mortality.

Platelets in the perspective of COVID-19; pathophysiology of thrombocytopenia and its implication as prognostic and therapeutic opportunity.

Despite endorsed and exponential research to improve diagnostic and therapeutic strategies, efforts have not yet converted into a better prospect for patients infected with the novel coronavirus (2019nCoV), and still, the name of SARS-CoV-2 is coupled with numerous unanswered questions. One of these questions is concerning how this respiratory virus reduces the number of platelets (PLTs)? The results of laboratory examinations showed that about a quarter of COVID-19 cases experience thrombocytopenia, and more remarkably, about half of these patients succumb to the infection due to coagulopathy. These findings have positioned PLTs as a pillar in the management as well as stratifying COVID-19 patients; however, not all the physicians came into a consensus about the prognostic value of these cells. The current review aims to unravel the contributory role of PLTs s in COVID-19; and alsoto summarize the original data obtained from international research laboratories on the association between COVID-19 and PLT production, activation, and clearance. In addition, we provide a special focus on the prognostic value of PLTs and their related parameters in COVID-19. Questions on how SARS-CoV-2 induces thrombocytopenia are also responded to. The last section provides a general overview of the most recent PLT- or thrombocytopenia-related therapeutic approaches. In conclusion, since SARS-CoV-2 reduces the number of PLTs by eliciting different mechanisms, treatment of thrombocytopenia in COVID-19 patients is not as simple as it appears and serious cautions should be considered to deal with the problem through scrutiny awareness of the causal mechanisms.

Diagnosis of Evans syndrome.

This manuscript concerns the case of a patient hospitalized and diagnosed with Evans syndrome. She was hospitalized with signs of thrombocytopenia induced purpura, petechiae, ecchymosis and anemia. She was successfully treated with corticoids and blood transfusions. Our purpose is to explain her clinical presentation and the exams, we used in order to make the diagnosis of Evans syndrome, which requires great suspicion. Moreover, other diseases causing hemolytic anemia and thrombocytopenia must be excluded. We used laboratory tests (blood samples, Coombs examination and virologic test). Bone marrow examination took place twice. Evans syndrome is an autoimmune disease which is characterized by the coexistence of hemolytic anemia and immune-mediated thrombocytopenia. There is no typical clinical presentation. Its etiology is unknown and its therapy is generally poor. Diagnosis of Evans syndrome is very difficult and requires the exclusion of other diseases causing anemia and thrombocytopenia.

Vaccine-induced thrombotic thrombocytopenia: the elusive link between thrombosis and adenovirus-based SARS-CoV-2 vaccines.

The amazing effort of vaccination against COVID-19, with more than 2 billion vaccine doses administered all around the world as of 16 June 2021, has changed the history of this pandemic, drastically reducing the number of severe cases or deaths in countries were mass vaccination campaign have been carried out. However, the people's rising enthusiasm has been blunted in late February 2021 by the report of several cases of unusual thrombotic events in combination with thrombocytopenia after vaccination with ChAdOx1 nCov-19 (Vaxzevria), and a few months later also after Ad26.COV2. S vaccines. Of note, both products used an Adenovirus-based (AdV) platform to deliver the mRNA molecule - coding for the spike protein of SARS-CoV-2. A clinical entity characterized by cerebral and/or splanchnic vein thrombosis, often associated with multiple thromboses, with thrombocytopenia and bleeding, and sometimes disseminated intravascular coagulation (DIC), was soon recognized as a new syndrome, named vaccine-induced immune thrombotic thrombocytopenia (VITT) or thrombosis with thrombocytopenia syndrome (TTS). VITT was mainly observed in females under 55 years of age, between 4 and 16 days after receiving only Adenovirus-based vaccine and displayed a seriously high fatality rate. This prompted the Medicine Regulatory Agencies of various countries to enforce the pharmacovigilance programs, and to provide some advices to restrict the use of AdV-based vaccines to some age groups. This point-of view is aimed at providing a comprehensive review of epidemiological issues, pathogenetic hypothesis and treatment strategies of this rare but compelling syndrome, thus helping physicians to offer an up-to dated and evidence-based counseling to their often alarmed patients.

Research on clinical characteristics and prognostic analysis of heparin-induced thrombocytopenia after surgery for acute type a aortic dissection.

PURPOSE: The present study aimed to explore the clinical characteristics of heparin-induced thrombocytopenia (HIT) after surgery for acute type A aortic dissection and perform a relevant prognostic analysis. METHODS: After continuous observation and analysis of 204 patients who underwent acute type A aortic dissection, we found that blood platelets decreased significantly after surgery and that these patients can be suspected to suffer HIT based on relevant 4Ts scores. For these suspected HIT patients, a latex particle-enhanced immunoturbidimetric assay was conducted to detect heparin-induced antibodies. Perioperative clinical data of patients in HIT and non-HIT groups were recorded as were blood platelet counts, HIT antibody test results, 4Ts scores, thromboembolic complications, clinical prognosis and outcomes. RESULTS: In the present study, 38 suspected HIT patients, 16 HIT patients and 188 non-HIT patients were selected in the clinical setting. Among them, HIT patients were found to have prolonged cardiopulmonary bypass time (223 min on average vs. 164 min) and delayed aortic cross-clamp time (128 min on average vs. 107 min), and these differences between HIT patients and non-HIT patients were significant (P < 0.05). Additionally, the HIT group required longer operation time and higher dose of heparin, but showing no statistical differences (P > 0.05). The transfusions of blood platelets in the HIT group and non-HIT group were 18.7 ± 5.0u and 15.6 ± 7.34 u, respectively. In the HIT group, the mechanic ventilation time and the length of ICU stay were longer comparing the non-HIT group(P < 0.05), though no significant differences in total length of stay or In-hospital mortality were observed (P > 0.05). The incidence of continuous renal replacement therapy in HIT group was higher than the non-HIT group (P < 0.05). Additionally,there were no significant differences in 24-h postoperative drainage or reoperation for bleeding in both group(P > 0.05). However, the HIT antibody titer in the HIT group was significantly higher than that in the Suspected HIT group (2.7 ± 0.8 U/mL vs. 0.3 ± 0.2 U/mL) (P < 0.05). Among patients diagnosed with HIT, the incidence of thromboembolism reached 31.5%.For example, two HIT patients newly developed thromboembolism in both lower extremities,and three patients experienced cerebral infarction. CONCLUSIONS: After surgery for acute type A aortic dissection, HIT patients developed postoperative complications, the duration of ventilatory support and length of ICU stay were extended, and the incidence of thromboembolism increased. HIT antibody detection and risk classification should be implemented for high-risk patients showing early clinical characteristics.

Diversity, localization, and (patho)physiology of mature lymphocyte populations in the bone marrow.

The bone marrow (BM) is responsible for generating and maintaining lifelong output of blood and immune cells. In addition to its key hematopoietic function, the BM acts as an important lymphoid organ, hosting a large variety of mature lymphocyte populations, including B cells, T cells, natural killer T cells, and innate lymphoid cells. Many of these cell types are thought to visit the BM only transiently, but for others, like plasma cells and memory T cells, the BM provides supportive niches that promote their long-term survival. Interestingly, accumulating evidence points toward an important role for mature lymphocytes in the regulation of hematopoietic stem cells (HSCs) and hematopoiesis in health and disease. In this review, we describe the diversity, migration, localization, and function of mature lymphocyte populations in murine and human BM, focusing on their role in immunity and hematopoiesis. We also address how various BM lymphocyte subsets contribute to the development of aplastic anemia and immune thrombocytopenia, illustrating the complexity of these BM disorders and the underlying similarities and differences in their disease pathophysiology. Finally, we summarize the interactions between mature lymphocytes and BM resident cells in HSC transplantation and graft-versus-host disease. A better understanding of the mechanisms by which mature lymphocyte populations regulate BM function will likely improve future therapies for patients with benign and malignant hematologic disorders.

Mild thrombocytopenia indicating maternal organ damage in pre-eclampsia: a cross-sectional study.

BACKGROUND: Currently, there is a disagreement between guidelines regarding platelet count cut-off values as a sign of maternal organ damage in pre-eclampsia; the American College of Obstetricians and Gynecologists guidelines state a cut-off value of < 100 × 109/L; however, the International Society for the Study of Hypertension in Pregnancy guidelines specify a cut-off of < 150 × 109/L. We evaluated the effect of mild thrombocytopenia: platelet count < 150 × 109/L and ≥ 100 × 109/L on clinical features of pre-eclampsia to examine whether mild thrombocytopenia reflects maternal organ damage in pre-eclampsia. METHODS: A total of 264 women were enrolled in this study. Participants were divided into three groups based on platelet count levels at delivery: normal, ≥ 150 × 109/L; mild thrombocytopenia, < 150 × 109/L and ≥ 100 × 109/L; and severe thrombocytopenia, < 100 × 109/L. Risk of severe hypertension, utero-placental dysfunction, maternal organ damage, preterm delivery, and neonatal intensive care unit admission were analyzed based on platelet count levels. Estimated relative risk was calculated with a Poisson regression analysis with a robust error. RESULTS: Platelet counts indicated normal levels in 189 patients, mild thrombocytopenia in 51 patients, and severe thrombocytopenia in 24 patients. The estimated relative risks of severe thrombocytopenia were 4.46 [95 % confidence interval, 2.59-7.68] for maternal organ damage except for thrombocytopenia, 1.61 [1.06-2.45] for preterm delivery < 34 gestational weeks, and 1.35 [1.06-1.73] for neonatal intensive care unit admission. On the other hand, the estimated relative risks of mild thrombocytopenia were 0.97 [0.41-2.26] for maternal organ damage except for thrombocytopenia, 0.91 [0.62-1.35] for preterm delivery < 34 gestational weeks, and 0.97 [0.76-1.24] for neonatal intensive care unit admission. CONCLUSIONS: Mild thrombocytopenia was not associated with severe features of pre-eclampsia and would not be suitable as a sign of maternal organ damage.

Low arterial oxygen partial pressure induces pulmonary thrombocytopenia in patients and a mouse model.

BACKGROUND: Recent basic studies demonstrate that the lung is a primary organ of platelet biogenesis. However, whether the pathophysiological state of the lung affect the platelets is little known. We aim to investigate the incidence of thrombocytopenia in patients with pulmonary infection (PIN) and risk factors associated with pulmonary thrombocytopenia. METHODS: In total, 11,941 patients with pulmonary infection (PIN) were enrolled, and patients with other three infectious diseases were collected as controls. The incidence of thrombocytopenia was compared, and the risk factors associated with thrombocytopenia in PIN patients were investigated by multivariate analysis. To explore the mechanism of thrombocytopenia, hypoxic model was constructed. Blood platelet counts from the angular vein (PLTs), left ventricle (PLTpost) and right ventricle (PLTpre) were determined. Megakaryocytes identified by anti-CD41 antibody were detected through flow cytometry and immunofluorescence. RESULTS: The incidence of thrombocytopenia in PIN was higher than that in other three infectious diseases (9.8% vs. 6.4% ~ 5.0%, P < 0.001). Low arterial oxygen partial pressure (PaO2) was an important risk factor for thrombocytopenia (OR = 0.88; P < 0.001). In a hypoxic mouse model, PLTs decreased (518.38 ± 127.92 vs 840.75 ± 77.30, P < 0.05), which showed that low PaO2 induced thrombocytopenia. The difference between the PLTpost and PLTpre (∆PLTpost-pre), representing the production of platelets in the lungs, was significantly attenuated in hypoxic mice when compared with normoxic mice (F = 25.47, P < 0.05). Additionally, proportions of CD41-positive megakaryocytes in the lungs, marrow, spleen all decreased in hypoxic mice. CONCLUSION: There is a high incidence for thrombocytopenia in PIN patients. Low PaO2-induced thrombocytopenia is associated with impaired generation of platelet in the lungs.

The Thrombopoietin Receptor Agonist Lusutrombopag Is Effective for Patients with Chronic Liver Disease and Impaired Renal Function.

BACKGROUND: The thrombopoietin (TPO) receptor agonist lusutrombopag was developed to treat thrombocytopenia in chronic liver disease (CLD). However, its effectiveness remains unclear. The purpose of this study was to assess the efficacy of lusutrombopag and identify predictors associated with increase in platelet count. METHODS: Eighty CLD patients with thrombocytopenia were enrolled. The primary endpoint was a satisfactory increase in platelets (greater than 1.0 × 104/µL from baseline) in the absence of platelet transfusion. The secondary endpoints were response rate (an increase of greater than 1.0 × 104/µL from baseline), independent predictors of increase in platelets, and the superiority of lusutrombopag over platelet transfusion. RESULTS: The primary endpoint was achieved in 93.8% (75 of 80) patients. The response rate was 96.2% (77 of 80). Renal function parameters (blood urea nitrogen, creatinine, eGFR) were significantly negatively associated with platelet count (p = 0.033, 0.049, and 0.0014, respectively) and were identified as independent predictors by multiple regression analysis (p = 0.049, 0.0023, and 0.0016, respectively). The median increase in platelet count was significantly higher after lusutrombopag than after platelet transfusion (41,000 vs. 12,000/µL, p = 0.015). CONCLUSION: Lusutrombopag was more effective than platelet transfusion for CLD patients, and renal function independently predicted increase in platelet count. Renal function parameters were significantly associated with platelet count.

Platelet aggregates, a marker of severe COVID-19 disease.

Thrombocytopenia is common in an intensive care unit (ICU) setting due to endogenous and iatrogenic factors. Despite that, thrombocytopenia in patients with severe COVID-19 infections is surprisingly uncommon. By examining the blood film of 20 ICU patients with COVID-19, we observed the presence of platelet aggregates and macrothrombocytes indicating increased platelet activity. We compared these findings with 20 blood films of non-severe COVID-19 cases where these findings were absent. These morphology features could be consistent with severe COVID-19 infection and is further evidence of the important role that platelets play when COVID-19 manifests with thrombotic complications or respiratory failure.

A novel homozygous GFI1B variant in 2 sisters with thrombocytopenia and severe bleeding tendency.

Genetic variants in growth factor-independent 1B (GFI1B), encoding transcription factor GFI1B, are causative of platelet-type bleeding disorder-17. Presently, 53 cases of GFI1B associated inherited thrombocytopenia (IT) have been published, however only three were homozygous. The bleeding- and platelet phenotypes of these patients depend on location and inheritance pattern of the GFI1B variant. We report a novel homozygous GFI1B (Thr174Ile) variant located in the first Zinc finger domain of GFI1B in two sisters of Palestinian ancestry born to consanguineous parents. They experienced severe bleeding tendency at moderately reduced platelet counts. Flow cytometry and immunofluorescent microscopy confirmed the diagnostic features of GFI1B associated IT: a reduced content of alpha granules and aberrant expression of the stem cell marker CD34 on platelets. Transcription factor GFI1B is differentially expressed during hemato- and lymphopoiesis. In addition, to platelet function investigations, we present results of lymphoid subgroup analyses and deformability of red cells measured by ektacytometry.