Materiały źródłowe

• #1 Thrombocytopenia pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Thrombocytopenia_pathophysiology

  Basically, thrombocytopenia is the result of one of these mechanisms or a combination of some of them: Reduced production of platelets due to bone marrow dysfunction, increased destruction of platelets in the body, iatrogenic, and entrapment of platelets in spleen. Several conditions, some of which mentioned below, can activate the mechanisms that ultimately lead to thrombocytopenia. […] It is thought that thrombocytopenia is the result of either of these four main mechanisms: […] Decreased production of platelets in the bone marrow. […] Destruction of platelets outside of bone marrow. […] Blood dilution from fluid resuscitation or massive transfusion. […] Sequestration of platelets in the spleen due to portal hypertension and/or splenomegaly. […] Some conditions cause thrombocytopenia through a combination of these mechanisms. For instance, primary ITP is associated with antibody-mediated platelet destruction, but it can also cause suppression of megakaryocytes, which is considered a bone marrow dysfunction.

• #2 Immune Thrombocytopenia: Pathogenesis and Treatment Approaches

  https://www.jscimedcentral.com/jounal-article-info/Journal-of-Hematology-and-Transfusion/Immune-Thrombocytopenia%3A-Pathogenesis-and-Treatment-Approaches-1547

  Immune thrombocytopenia (ITP) is a common hematologic disorder affecting both adult and pediatric patients. Pathogenesis of ITP involves 2 major mechanisms: increased platelet destruction by the immune system and abnormalities in megakaryocytopoiesis with impaired platelet production. […] As aforementioned, 2 major processes contribute to ITP: decreased platelet production and increased platelet destruction. […] Platelet production and platelet destruction must be in balance to maintain the size of the circulating platelet pool at normal range (150-400 Gi/L). In physiological conditions, each process can compensate for changes in the other to reestablish the balance; eg, platelet production increases if the platelet pool becomes smaller due to increased platelet destruction. However, in patients with ITP, this balance is disturbed by (1) decreased platelet production, (2) increased platelet destruction, or both, and therapeutic intervention may be needed to reestablish this balance before the decline in the platelet pool becomes life threatening.

• #3 Immune Thrombocytopenia: Pathogenesis and Treatment Approaches

  https://www.jscimedcentral.com/jounal-article-info/Journal-of-Hematology-and-Transfusion/Immune-Thrombocytopenia%3A-Pathogenesis-and-Treatment-Approaches-1547

  Immune thrombocytopenia (ITP) is a common hematologic disorder affecting both adult and pediatric patients. Pathogenesis of ITP involves 2 major mechanisms: increased platelet destruction by the immune system and abnormalities in megakaryocytopoiesis with impaired platelet production. […] As aforementioned, 2 major processes contribute to ITP: decreased platelet production and increased platelet destruction. […] Platelet production and platelet destruction must be in balance to maintain the size of the circulating platelet pool at normal range (150-400 Gi/L). In physiological conditions, each process can compensate for changes in the other to reestablish the balance; eg, platelet production increases if the platelet pool becomes smaller due to increased platelet destruction. However, in patients with ITP, this balance is disturbed by (1) decreased platelet production, (2) increased platelet destruction, or both, and therapeutic intervention may be needed to reestablish this balance before the decline in the platelet pool becomes life threatening.

• #4 Pathophysiological Mechanisms Leading to Low Platelet Count in Immune Thrombocytopenia

  https://www.immunologyresearchjournal.com/articles/pathophysiological-mechanisms-leading-to-low-platelet-count-in-immune-thrombocytopenia.html

  Primary immune thrombocytopenia (ITP) is an autoimmune disorder characterized by the decrease in peripheral blood platelet count below 100 x 10^9/L, and an increased bleeding risk when thrombocytopenia drops below 30 x 10^9/L. The mechanisms leading to ITP in adults, although not completely elucidated, involves an imbalance between effector and regulatory cells that results in a breakdown of the immune tolerance. Autoantibodies are considered the main responsible for thrombocytopenia, although direct T-cell cytotoxic effect and lysis by Complement attachment and activation could also contribute to platelet elimination from circulation. […] Therefore, humoral immunity has been classically considered the main cause of thrombocytopenia, although other mechanisms such as direct T-cell cytotoxic effect could contribute to platelet elimination as well. In addition, Complement activation/fixation capacity is enhanced in plasma samples from ITP. Indeed, Complement-mediated platelet destruction has been pointed as another mechanism of platelet elimination, mainly triggered by anti-platelet autoantibodies, but also observed in some ITP patients with no-detectable autoantibodies.

• #5 Q: What mechanisms contribute to the pathophysiology of ITP?

  https://expertperspectives.com/mechanisms-contributing-to-the-pathophysiology-of-immune-thrombocytopenia/

  Although the subject of multiple scientific studies and despite the emergence of novel treatment options that might help understand it, the pathogenesis of immune thrombocytopenia (ITP) remains poorly understood. […] Two major mechanisms known to be involved in the development of ITP are increased platelet destruction and insufficient platelet production. […] An insufficient level of thrombopoietin and impaired function of megakaryocytes are factors associated with decreased platelet production. […] Thrombopoietin is the main regulator of the process of new platelets being formed from megakaryocytes. […] Therefore, the superior efficacy of thrombopoietin receptor agonists in increasing platelet counts in patients with ITP supports the idea that platelet production is also insufficient in these patients.

• #6 Immune Thrombocytopenia: Pathogenesis and Treatment Approaches

  https://www.jscimedcentral.com/jounal-article-info/Journal-of-Hematology-and-Transfusion/Immune-Thrombocytopenia%3A-Pathogenesis-and-Treatment-Approaches-1547

  Increased platelet destruction: Abnormally accelerated platelet destruction is a characteristic of ITP. Current evidence suggests involvement of a 3-step mechanism. Firstly, immune tolerance is lost due to pathological regulatory and inflammatory T-cell function. Secondly, T-follicular helper cells located primarily in the spleen trigger differentiation of B cells to autoreactive cells that produce antiplatelet antibodies. Finally, antiplatelet antibodies target glycoproteins, primarily glycoprotein IIb/IIIa, on platelets and cause platelet destruction by macrophages or cytotoxic T cells. […] Decreased platelet production: In patients with ITP, platelet production may not be sufficient to replace the platelets that are destroyed. Since megakaryocytes and platelets share common surface antigens, most anti-platelet antibodies may also target megakaryocytes. Thus, decreased platelet production may be a secondary result of the factors leading to increased platelet destruction, which were discussed above. Other potential causes of decreased platelet production include impaired function of megakaryocytes, altered megakaryocyte morphology, or abnormal T-cell response in the bone marrow microenvironment. In addition, insufficient TPO levels are considered to be involved in pathogenesis of ITP because increased serum TPO, a typical compensatory response to thrombocytopenia, is not observed in ITP. […] Pathogenesis of ITP involves 2 major mechanisms: increased platelet destruction and decreased platelet production. The varying levels of contribution of these processes to ITP pathology in patients may be responsible for the heterogeneity of responses to different treatment strategies.

• #7 Current Understanding of Immune Thrombocytopenia: A Review of Pathogenesis and Treatment Options

  https://www.mdpi.com/1422-0067/25/4/2163

  Immune thrombocytopenia is an autoimmune disease with a very complex pathogenesis. Primary ITP arises from several different mechanisms, such as the peripheral destruction of platelets opsonized by antiplatelet antibodies, impaired thrombopoiesis, and the T-cell-mediated destruction of platelets; each pathogenic mechanism plays an independent role in generating thrombocytopenia. […] Peripheral destruction of platelets occurs in the blood, spleen, and liver and, together with impaired bone marrow production, results in an autoimmune response against megakaryocytes and peripheral thrombocytopenia. […] Persistence of this autoimmune response is favored by a loss of tolerance, which is supported by a deficiency of regulatory T cells (Tregs) in the spleen, blood, and bone marrow, with defects in the B and T cells, leading to both pathological autoantibody formation and abnormal T-cell responses.

• #8 Immune Thrombocytopenia: Pathogenesis and Treatment Approaches

  https://www.jscimedcentral.com/jounal-article-info/Journal-of-Hematology-and-Transfusion/Immune-Thrombocytopenia%3A-Pathogenesis-and-Treatment-Approaches-1547

  Increased platelet destruction: Abnormally accelerated platelet destruction is a characteristic of ITP. Current evidence suggests involvement of a 3-step mechanism. Firstly, immune tolerance is lost due to pathological regulatory and inflammatory T-cell function. Secondly, T-follicular helper cells located primarily in the spleen trigger differentiation of B cells to autoreactive cells that produce antiplatelet antibodies. Finally, antiplatelet antibodies target glycoproteins, primarily glycoprotein IIb/IIIa, on platelets and cause platelet destruction by macrophages or cytotoxic T cells. […] Decreased platelet production: In patients with ITP, platelet production may not be sufficient to replace the platelets that are destroyed. Since megakaryocytes and platelets share common surface antigens, most anti-platelet antibodies may also target megakaryocytes. Thus, decreased platelet production may be a secondary result of the factors leading to increased platelet destruction, which were discussed above. Other potential causes of decreased platelet production include impaired function of megakaryocytes, altered megakaryocyte morphology, or abnormal T-cell response in the bone marrow microenvironment. In addition, insufficient TPO levels are considered to be involved in pathogenesis of ITP because increased serum TPO, a typical compensatory response to thrombocytopenia, is not observed in ITP. […] Pathogenesis of ITP involves 2 major mechanisms: increased platelet destruction and decreased platelet production. The varying levels of contribution of these processes to ITP pathology in patients may be responsible for the heterogeneity of responses to different treatment strategies.

• #9 Immune Thrombocytopenia: Recent Advances in Pathogenesis and Treatments

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8171374/

  Immune thrombocytopenia (ITP) is a rare autoimmune disease due to both a peripheral destruction of platelets and an inappropriate bone marrow production. […] A loss of immune tolerance mostly represented by a regulatory T-cell defect allows T follicular helper cells to stimulate autoreactive splenic B cells that differentiate into antiplatelet antibody-producing plasma cells. Glycoprotein IIb/IIIa is the main target of antiplatelet antibodies leading to platelet phagocytosis by splenic macrophages, through interactions with Fc gamma receptors (FcRs) and complement receptors. This allows macrophages to activate autoreactive T cells by their antigen-presenting functions. Moreover, the activation of the classical complement pathway participates to platelet opsonization and also to their destruction by complement-dependent cytotoxicity. Platelet destruction is also mediated by a FcR-independent pathway, involving platelet desialylation that favors their binding to the Ashwell-Morell receptor and their clearance in the liver. Cytotoxic T cells also contribute to ITP pathogenesis by mediating cytotoxicity against megakaryocytes and peripheral platelets. The deficient megakaryopoiesis resulting from both the humoral and the cytotoxic immune responses is sustained by inappropriate levels of thrombopoietin, the major growth factor of megakaryocytes.

• #10 Immune Thrombocytopenia: Recent Advances in Pathogenesis and Treatments

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8171374/

  A major mechanism of peripheral platelet destruction is ADCP, mediated by splenic macrophages. […] During ITP, the inappropriate levels of TPO are linked to its physiological regulation. The production of TPO by hepatocytes is stimulated by the recognition of senescent desialylated platelets by the AMR. […] Overall, desialylation appears to be involved in both platelet destruction and production and is associated with a lower platelet count and a refractoriness to usual therapies. […] The role of CD4 T cells in ITP has been known for years, with clones recognizing GPIIb/IIIa detected in the spleen and the blood of ITP patients in the early 2000s. […] Similarly to most of autoimmune diseases, an imbalance between the proinflammatory and the anti-inflammatory responses is present during ITP, with a skewing of T cells to helper T cell (Th) polarizations, associated with a quantitative or functional deficiency of regulatory T cells (Treg).

• #11 Pathogenesis and Therapeutic Mechanisms in Immune Thrombocytopenia (ITP)

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5332920/

  Immune thrombocytopenia (ITP) is a complex autoimmune disease characterized by low platelet counts. The pathogenesis of ITP remains unclear although both antibody-mediated and/or T cell-mediated platelet destruction are key processes. […] In addition, impairment of T cells, cytokine imbalances, and the contribution of the bone marrow niche have now been recognized to be important. […] ITP is mainly due to IgG autoantibodies, which bind to platelets and MKs, targeting very abundant surface antigens such as glycoprotein (GP) IIb3 (GPIIbIIIA) and GPIb-IX-V. […] Platelets with bound autoantibodies are subsequently recognized by phagocytes bearing Fc-receptors (FcRs), which results in enhanced antibody-mediated platelet phagocytosis and destruction primarily in the spleen. […] Moreover, autoantibody binding to MKs can inhibit their maturation or can lead to their destruction, and thrombopoietin (TPO), a liver derived glycoprotein hormone that drives thrombopoiesis, cannot normalize the platelet count.

• #12 Pathogenesis and Therapeutic Mechanisms in Immune Thrombocytopenia (ITP)

  https://www.mdpi.com/2077-0383/6/2/16

  ITP is mainly due to IgG autoantibodies, which bind to platelets and MKs, targeting very abundant surface antigens such as glycoprotein (GP) αIIbβ3 (GPIIbIIIA) and GPIb-IX-V. […] Platelets with bound autoantibodies are subsequently recognized by phagocytes bearing Fcγ-receptors (FcγRs), which results in enhanced antibody-mediated platelet phagocytosis and destruction primarily in the spleen. […] Moreover, autoantibody binding to MKs can inhibit their maturation or can lead to their destruction, and thrombopoietin (TPO), a liver derived glycoprotein hormone that drives thrombopoiesis, cannot normalize the platelet count. […] In addition, autoreactive T cells are also involved in platelet and MK destruction, and, despite an increased MK number in the bone marrow of some patients, many present signs of morphological abnormalities including apoptotic ultrastructure as well as activation of Caspase-3.

• #13

  https://journals.lww.com/hemasphere/fulltext/2021/06000/immune_thrombocytopenia__recent_advances_in.6.aspx

  The deficient megakaryopoiesis resulting from both the humoral and the cytotoxic immune responses is sustained by inappropriate levels of thrombopoietin, the major growth factor of megakaryocytes. […] An integrative view of ITP pathogenesis is summarized in Figure 1 and Table 1. […] ITP results from a peripheral destruction of platelets that takes place in the blood, the spleen, and the liver, together with an inappropriate bone marrow production due to an autoimmune response against megakaryocytes and insufficient TPO levels. […] The involvement of the humoral response against platelets is known since the 1950s when Harrington et al observed that sera of ITP patients induced thrombocytopenia when infused to healthy volunteers. […] It was further shown that IgG were responsible for this effect by targeting various platelet GPs, notably GPIIb/IIIa (fibrinogen receptor), GPIb/IX (von Willebrand factor) and less frequently GPIa/IIa (collagen receptor) and GPIV.

• #14

  https://journals.lww.com/hemasphere/fulltext/2021/06000/immune_thrombocytopenia__recent_advances_in.6.aspx

  The deficient megakaryopoiesis resulting from both the humoral and the cytotoxic immune responses is sustained by inappropriate levels of thrombopoietin, the major growth factor of megakaryocytes. […] An integrative view of ITP pathogenesis is summarized in Figure 1 and Table 1. […] ITP results from a peripheral destruction of platelets that takes place in the blood, the spleen, and the liver, together with an inappropriate bone marrow production due to an autoimmune response against megakaryocytes and insufficient TPO levels. […] The involvement of the humoral response against platelets is known since the 1950s when Harrington et al observed that sera of ITP patients induced thrombocytopenia when infused to healthy volunteers. […] It was further shown that IgG were responsible for this effect by targeting various platelet GPs, notably GPIIb/IIIa (fibrinogen receptor), GPIb/IX (von Willebrand factor) and less frequently GPIa/IIa (collagen receptor) and GPIV.

• #15 Immune Thrombocytopenia (ITP): Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/202158-overview

  Immune thrombocytopenia (ITP) is a syndrome in which platelets become coated with autoantibodies to platelet membrane antigens, resulting in splenic sequestration and phagocytosis by mononuclear macrophages. The resulting shortened life span of platelets in the circulation, together with incomplete compensation by increased platelet production by bone marrow megakaryocytes, results in a decreased number of circulating platelets (thrombocytopenia; see the image below). […] In immune thrombocytopenia (ITP), an abnormal autoantibody, usually immunoglobulin G (IgG) with specificity for one or more platelet membrane glycoproteins, binds to circulating platelet membranes. […] Autoantibody-coated platelets induce Fc receptor-mediated phagocytosis by mononuclear macrophages, primarily but not exclusively in the spleen.

• #16 Pathogenesis and Therapeutic Mechanisms in Immune Thrombocytopenia (ITP)

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5332920/

  Immune thrombocytopenia (ITP) is a complex autoimmune disease characterized by low platelet counts. The pathogenesis of ITP remains unclear although both antibody-mediated and/or T cell-mediated platelet destruction are key processes. […] In addition, impairment of T cells, cytokine imbalances, and the contribution of the bone marrow niche have now been recognized to be important. […] ITP is mainly due to IgG autoantibodies, which bind to platelets and MKs, targeting very abundant surface antigens such as glycoprotein (GP) IIb3 (GPIIbIIIA) and GPIb-IX-V. […] Platelets with bound autoantibodies are subsequently recognized by phagocytes bearing Fc-receptors (FcRs), which results in enhanced antibody-mediated platelet phagocytosis and destruction primarily in the spleen. […] Moreover, autoantibody binding to MKs can inhibit their maturation or can lead to their destruction, and thrombopoietin (TPO), a liver derived glycoprotein hormone that drives thrombopoiesis, cannot normalize the platelet count.

• #17

  https://link.springer.com/article/10.1007/s44337-024-00040-8

  ITP is a disease caused by the immune system attacking platelets, and treatment options have been one of the hot topics of research. […] In recent years, significant progress has been made in understanding the complex pathogenesis of ITP, and the disease is becoming clearer, facilitating the development of new therapeutic approaches that target these pathways. […] The pathogenesis of ITP is intricate, and recent years have seen substantial advancements in uncovering different facets of ITP pathogenesis, there are ongoing investigations into new therapies that target these pathways. […] Initially, studies on the pathogenesis of ITP focused on humoral immunity, in which IgG-based platelet antibodies produced by B lymphocytes bind to platelets, leading to phagocytosis of platelets by the monocyte-macrophage system, resulting in increased platelet destruction and shortened lifespan, which is considered to be the most classical pathogenesis of ITP.

• #18

  https://journals.lww.com/hemasphere/fulltext/2021/06000/immune_thrombocytopenia__recent_advances_in.6.aspx

  Immune thrombocytopenia (ITP) is a rare autoimmune disease due to both a peripheral destruction of platelets and an inappropriate bone marrow production. […] A loss of immune tolerance mostly represented by a regulatory T-cell defect allows T follicular helper cells to stimulate autoreactive splenic B cells that differentiate into antiplatelet antibody-producing plasma cells. Glycoprotein IIb/IIIa is the main target of antiplatelet antibodies leading to platelet phagocytosis by splenic macrophages, through interactions with Fc gamma receptors (FcRs) and complement receptors. This allows macrophages to activate autoreactive T cells by their antigen-presenting functions. […] Moreover, the activation of the classical complement pathway participates to platelet opsonization and also to their destruction by complement-dependent cytotoxicity. Platelet destruction is also mediated by a FcR-independent pathway, involving platelet desialylation that favors their binding to the Ashwell-Morell receptor and their clearance in the liver. Cytotoxic T cells also contribute to ITP pathogenesis by mediating cytotoxicity against megakaryocytes and peripheral platelets.

• #19

  https://journals.lww.com/hemasphere/fulltext/2021/06000/immune_thrombocytopenia__recent_advances_in.6.aspx

  The spleen plays a major role in ITP pathogenesis, being the site of an intense autoimmune response with an expansion of germinal centers and the generation of mutated, high-affinity-antiplatelet antibody-secreting plasma cells. […] Various mechanisms support the cytotoxicity mediated by antibodies, such as complement-dependent cytotoxicity (CDC), causing the destruction of targeted cells by the formation of the membrane attack complex (MAC), but also facilitating their phagocytosis (antibody-dependent cellular phagocytosis [ADCP]) by macrophages expressing Fc gamma receptor (FcR) and complement receptor 1 that binds to the complement fraction C3b. […] Another mechanism, antibody-dependent cellular cytotoxicity (ADCC) mediated by natural killer (NK) cells, is probably less involved during ITP.

• #20 Desialylation is a mechanism of Fc-independent platelet clearance and a therapeutic target in immune thrombocytopenia | Nature Communications

  https://www.nature.com/articles/ncomms8737

  Immune thrombocytopenia (ITP) is a common bleeding disorder caused primarily by autoantibodies against platelet GPIIbIIIa and/or the GPIb complex. […] However, we and others have demonstrated that anti-GPIb (but not GPIIbIIIa)-mediated ITP is often refractory to therapies targeting FcR pathways. […] This leads to platelet clearance in the liver via hepatocyte AshwellMorell receptors, which is fundamentally different from the classical FcFcR-dependent macrophage phagocytosis. […] Importantly, sialidase inhibitors ameliorate anti-GPIb-mediated thrombocytopenia in mice. […] To date, there is no reliable measurement in the clinical setting to predict the success or failure of any ITP treatment. […] Unexpectedly, we and others have identified a novel mechanism of Fc-independent thrombocytopenia, in which antibodies against GPIb, but not those against GPIIbIIIa, can induce thrombocytopenia via their F(ab)2 (Fc independent) and in FcR-/ mice.

• #21 Desialylation is a mechanism of Fc-independent platelet clearance and a therapeutic target in immune thrombocytopenia | Nature Communications

  https://www.nature.com/articles/ncomms8737

  Immune thrombocytopenia (ITP) is a common bleeding disorder caused primarily by autoantibodies against platelet GPIIbIIIa and/or the GPIb complex. […] However, we and others have demonstrated that anti-GPIb (but not GPIIbIIIa)-mediated ITP is often refractory to therapies targeting FcR pathways. […] This leads to platelet clearance in the liver via hepatocyte AshwellMorell receptors, which is fundamentally different from the classical FcFcR-dependent macrophage phagocytosis. […] Importantly, sialidase inhibitors ameliorate anti-GPIb-mediated thrombocytopenia in mice. […] To date, there is no reliable measurement in the clinical setting to predict the success or failure of any ITP treatment. […] Unexpectedly, we and others have identified a novel mechanism of Fc-independent thrombocytopenia, in which antibodies against GPIb, but not those against GPIIbIIIa, can induce thrombocytopenia via their F(ab)2 (Fc independent) and in FcR-/ mice.

• #22 Pathophysiological Mechanisms Leading to Low Platelet Count in Immune Thrombocytopenia

  https://www.immunologyresearchjournal.com/articles/pathophysiological-mechanisms-leading-to-low-platelet-count-in-immune-thrombocytopenia.html

  This review summarizes mechanisms leading to thrombocytopenia in ITP with special focus on peripheral platelet destruction and impaired platelet production. […] The first and most commonly accepted mechanism of platelet clearance in ITP is the binding of anti-platelet autoantibodies to their antigenic glycoprotein targets that leads to platelet elimination by monocytes/macrophages of the reticuloendothelial system through FcRIIA and FcRIIIA-mediated recognition, mainly in the spleen and liver. However, additional pathological mechanisms including platelet apoptosis and loss of sialic acid from platelet membrane glycoproteins were described in recent years, that also contribute to platelet clearance from circulation. […] Several studies have demonstrated the contribution of platelet apoptosis to ITP pathogenesis.

• #23 Pathophysiological Mechanisms Leading to Low Platelet Count in Immune Thrombocytopenia

  https://www.immunologyresearchjournal.com/articles/pathophysiological-mechanisms-leading-to-low-platelet-count-in-immune-thrombocytopenia.html

  Cells expressing PS on their membrane are known to be cleared through scavenger receptors in macrophages, thus, apoptotic platelets would also be eliminated from circulation by this mechanism. […] In 2015, Li and col. described for the first time that plasma from ITP patients containing anti-GPIbIX autoantibodies induced loss of sialic acid capping carbohydrates from platelet glycoproteins. This mechanism is triggered by the ability of these autoantibodies to induce platelet activation, which promote neuraminidase externalization, the ultimate responsible for sialic acid cleavage from membrane glycoproteins. […] Overall, these studies demonstrate that ITP autoantibodies mainly affect specific and different intracellular pathways, depending on their target proteins, interfering with normal megakaryocytic functions within the bone marrow and leading to decreased platelet production.

• #24 Immune Thrombocytopenia: Recent Advances in Pathogenesis and Treatments

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8171374/

  A major mechanism of peripheral platelet destruction is ADCP, mediated by splenic macrophages. […] During ITP, the inappropriate levels of TPO are linked to its physiological regulation. The production of TPO by hepatocytes is stimulated by the recognition of senescent desialylated platelets by the AMR. […] Overall, desialylation appears to be involved in both platelet destruction and production and is associated with a lower platelet count and a refractoriness to usual therapies. […] The role of CD4 T cells in ITP has been known for years, with clones recognizing GPIIb/IIIa detected in the spleen and the blood of ITP patients in the early 2000s. […] Similarly to most of autoimmune diseases, an imbalance between the proinflammatory and the anti-inflammatory responses is present during ITP, with a skewing of T cells to helper T cell (Th) polarizations, associated with a quantitative or functional deficiency of regulatory T cells (Treg).

• #25 Desialylation is a mechanism of Fc-independent platelet clearance and a therapeutic target in immune thrombocytopenia | Nature Communications

  https://www.nature.com/articles/ncomms8737

  We further reported that most anti-GPIb antibody-mediated thrombocytopenia is resistant to IVIG treatment. […] These data indicate that anti-GPIb antibodies are able to uniquely induce platelet clearance in an Fc-independent manner in murine models, which may also be true in human ITP. […] In this study, by utilizing unique anti-GPIb and anti-GPIIbIIIa monoclonal antibodies (mAbs) as well as human ITP plasma samples, we show that significant platelet activation and desialylation occurs predominantly in the presence of anti-GPIb, but not anti-GPIIbIIIa antibodies in vitro and in vivo. […] Furthermore, anti-GPIb-mediated desialylation of platelets led to FcR-independent clearance via hepatocytes. […] Together these results confirm that increased sialidase activity resulting in desialylation directly follows from anti-GPIb antibody binding.

• #26 Current Understanding of Immune Thrombocytopenia: A Review of Pathogenesis and Treatment Options

  https://www.mdpi.com/1422-0067/25/4/2163

  The pathogenesis of secondary ITP may share similar mechanisms with primary ITP. However, unique mechanisms have been identified in some types of secondary ITP. For example, antigen mimicry, in which antibodies directed against a foreign protein cross-react with specific epitopes on platelet glycoproteins (GPs), has been observed in thrombocytopenia associated with hepatitis C, Helicobacter pylori, and HIV infections. […] Dysregulation of T cells plays a crucial role in the pathogenesis of ITP. […] Due to a breakdown of self-tolerance, the APC process is triggered and presents platelet autoantigens to autoreactive T cells, which initiates a cascade of events including the stimulation of autoantibody production and cytotoxic T-cell (CTL) activation and proliferation, along with an abnormal number and function of regulatory T cells (Tregs), the production of abnormal Th cells, and abnormal T-cell anergy.

• #27 Pathogenesis and Therapeutic Mechanisms in Immune Thrombocytopenia (ITP)

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5332920/

  In fact, approximately two-thirds of patients with ITP present with normal or decreased TPO plasma levels, adding a novel functional deficit of TPO to the pathophysiology of the disease. […] In addition, autoreactive T cells are also involved in platelet and MK destruction, and, despite an increased MK number in the bone marrow of some patients, many present signs of morphological abnormalities including apoptotic ultrastructure as well as activation of Caspase-3. […] Superimposed on these cellular impairments, the cytokine profile of patients with ITP is also imbalanced with, for example, higher serum levels of interleukin (IL)-2, interferon (IFN)-, and IL-17. […] In summary, T cells also play a crucial role in ITP. Indeed, abnormal T cell subsets, including lower Tregs and unbalanced Th17, Th0, and Th1 profiles, as well as the presence of cytotoxic CD8+ T cells constitute the cellular mechanisms of ITP pathogenesis.

• #28

  https://link.springer.com/article/10.1007/s44337-024-00040-8

  However, as the understanding of the pathogenesis of ITP has gradually increased, it has been found that humoral immunity can no longer fully explain the pathogenesis of ITP. […] More and more studies have shown that not only humoral immunity abnormalities but also cellular immunity abnormalities exist in the pathogenesis of ITP. […] In addition, with the rapid development in the field of pathophysiology, it is gradually revealed that apoptosis and epigenetics are also important parts of the pathogenesis of ITP. […] These studies suggest the presence of pathogenic B cells and abnormal levels of cytokines in ITP patients, leading to the production of platelet antibodies. […] All this evidence has confirmed that T-cell immunity is crucial for ITP. […] The cellular mechanism behind the pathophysiology of ITP consists of aberrant T-cell subsets, such as lower Tregs and an imbalance of Th17, Th2, and Th1 and cytotoxic CD8+T cells.

• #29 Pathogenesis and Therapeutic Mechanisms in Immune Thrombocytopenia (ITP)

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5332920/

  In fact, approximately two-thirds of patients with ITP present with normal or decreased TPO plasma levels, adding a novel functional deficit of TPO to the pathophysiology of the disease. […] In addition, autoreactive T cells are also involved in platelet and MK destruction, and, despite an increased MK number in the bone marrow of some patients, many present signs of morphological abnormalities including apoptotic ultrastructure as well as activation of Caspase-3. […] Superimposed on these cellular impairments, the cytokine profile of patients with ITP is also imbalanced with, for example, higher serum levels of interleukin (IL)-2, interferon (IFN)-, and IL-17. […] In summary, T cells also play a crucial role in ITP. Indeed, abnormal T cell subsets, including lower Tregs and unbalanced Th17, Th0, and Th1 profiles, as well as the presence of cytotoxic CD8+ T cells constitute the cellular mechanisms of ITP pathogenesis.

• #30

  https://journals.lww.com/hemasphere/fulltext/2021/06000/immune_thrombocytopenia__recent_advances_in.6.aspx

  A major mechanism of peripheral platelet destruction is ADCP, mediated by splenic macrophages. […] Recently confirmed in humans, the phagocytosis involved the ligation of opsonized platelets to FcRI and FcRIII, but not FcRII. […] Overall, desialylation appears to be involved in both platelet destruction and production and is associated with a lower platelet count and a refractoriness to usual therapies. […] The role of CD4 T cells in ITP has been known for years, with clones recognizing GPIIb/IIIa detected in the spleen and the blood of ITP patients in the early 2000s. […] Similarly to most of autoimmune diseases, an imbalance between the proinflammatory and the anti-inflammatory responses is present during ITP, with a skewing of T cells to helper T cell (Th) polarizations, associated with a quantitative or functional deficiency of regulatory T cells (Treg).

• #31 Immune Thrombocytopenia (ITP): Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/202158-overview

  The spleen is the key organ in the pathophysiology of ITP, not only because platelet autoantibodies are formed in the white pulp, but also because mononuclear macrophages in the red pulp destroy immunoglobulin-coated platelets. […] Malik et al have identified cytotoxic CD8+ T cells as an antibody-independent mechanism of platelet destruction in chronic ITP. These researchers demonstrated that adults with chronic ITP have clonal expansion of terminally differentiated effector memory CD8+ T cells (TEMRA), compared with age-matched controls. TEMRAs form aggregates with autologous platelets, release interferon gamma, and trigger platelet activation and apoptosis via the T-cell receptormediated release of cytotoxic granules. […] If bone marrow megakaryocytes cannot increase production and maintain a normal number of circulating platelets, thrombocytopenia and purpura develop. Impaired thrombopoiesis is attributed to failure of a compensatory increase in thrombopoietin and megakaryocyte apoptosis.

• #32 Q: What mechanisms contribute to the pathophysiology of ITP?

  https://expertperspectives.com/mechanisms-contributing-to-the-pathophysiology-of-immune-thrombocytopenia/

  Although the subject of multiple scientific studies and despite the emergence of novel treatment options that might help understand it, the pathogenesis of immune thrombocytopenia (ITP) remains poorly understood. […] Two major mechanisms known to be involved in the development of ITP are increased platelet destruction and insufficient platelet production. […] An insufficient level of thrombopoietin and impaired function of megakaryocytes are factors associated with decreased platelet production. […] Thrombopoietin is the main regulator of the process of new platelets being formed from megakaryocytes. […] Therefore, the superior efficacy of thrombopoietin receptor agonists in increasing platelet counts in patients with ITP supports the idea that platelet production is also insufficient in these patients.

• #33 Q: What mechanisms contribute to the pathophysiology of ITP?

  https://expertperspectives.com/mechanisms-contributing-to-the-pathophysiology-of-immune-thrombocytopenia/

  It has been proven that there are T-cell-mediated events involved that can lyse platelets, and they respond to the same antigens that are in megakaryocytes. […] The mechanisms are related to a loss of immune tolerance, and it is usually peripheral immune tolerance for the majority of cases. […] It has been shown that the best responders to anti-CD20 therapy, which kills the B cell lymphocyte, were individuals who reset the T cell repertoire. […] I think that the best you can say about the mechanisms that are associated with the pathophysiology of ITP is that it is a loss of immune tolerance and that there is a production and a destructive defect. […] What we have proven over the last 20 to 30 years is that there is also a production defect. […] Now, it is likely due to the same mechanism because I think that the megakaryocytes probably do, indeed, have the same targets as the platelets.

• #34 Current Understanding of Immune Thrombocytopenia: A Review of Pathogenesis and Treatment Options

  https://www.mdpi.com/1422-0067/25/4/2163

  The degree of Treg abnormalities is associated with disease severity. […] Impaired thrombopoiesis with an insufficient production of platelets is the result of an abnormal immune response against megakaryocytes (MKs), which is associated with a low TPO concentration. […] In ITP, since MKs express the same GP as platelets, they are clearly targeted by antiplatelet antibodies that bind to GPIb and GPIIb/IIIa, as well as by CTLs, which induces morphological and physiological changes or even apoptosis. […] Platelet production is correlated with the serum levels of TPO, a major megakaryocyte growth factor.

• #35 Immune Thrombocytopenia: Pathogenesis and Treatment Approaches

  https://www.jscimedcentral.com/jounal-article-info/Journal-of-Hematology-and-Transfusion/Immune-Thrombocytopenia%3A-Pathogenesis-and-Treatment-Approaches-1547

  Increased platelet destruction: Abnormally accelerated platelet destruction is a characteristic of ITP. Current evidence suggests involvement of a 3-step mechanism. Firstly, immune tolerance is lost due to pathological regulatory and inflammatory T-cell function. Secondly, T-follicular helper cells located primarily in the spleen trigger differentiation of B cells to autoreactive cells that produce antiplatelet antibodies. Finally, antiplatelet antibodies target glycoproteins, primarily glycoprotein IIb/IIIa, on platelets and cause platelet destruction by macrophages or cytotoxic T cells. […] Decreased platelet production: In patients with ITP, platelet production may not be sufficient to replace the platelets that are destroyed. Since megakaryocytes and platelets share common surface antigens, most anti-platelet antibodies may also target megakaryocytes. Thus, decreased platelet production may be a secondary result of the factors leading to increased platelet destruction, which were discussed above. Other potential causes of decreased platelet production include impaired function of megakaryocytes, altered megakaryocyte morphology, or abnormal T-cell response in the bone marrow microenvironment. In addition, insufficient TPO levels are considered to be involved in pathogenesis of ITP because increased serum TPO, a typical compensatory response to thrombocytopenia, is not observed in ITP. […] Pathogenesis of ITP involves 2 major mechanisms: increased platelet destruction and decreased platelet production. The varying levels of contribution of these processes to ITP pathology in patients may be responsible for the heterogeneity of responses to different treatment strategies.

• #36 Pathogenesis and Therapeutic Mechanisms in Immune Thrombocytopenia (ITP)

  https://www.mdpi.com/2077-0383/6/2/16

  ITP is mainly due to IgG autoantibodies, which bind to platelets and MKs, targeting very abundant surface antigens such as glycoprotein (GP) αIIbβ3 (GPIIbIIIA) and GPIb-IX-V. […] Platelets with bound autoantibodies are subsequently recognized by phagocytes bearing Fcγ-receptors (FcγRs), which results in enhanced antibody-mediated platelet phagocytosis and destruction primarily in the spleen. […] Moreover, autoantibody binding to MKs can inhibit their maturation or can lead to their destruction, and thrombopoietin (TPO), a liver derived glycoprotein hormone that drives thrombopoiesis, cannot normalize the platelet count. […] In addition, autoreactive T cells are also involved in platelet and MK destruction, and, despite an increased MK number in the bone marrow of some patients, many present signs of morphological abnormalities including apoptotic ultrastructure as well as activation of Caspase-3.

• #37 Immune Thrombocytopenia: Recent Advances in Pathogenesis and Treatments

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8171374/

  TFH are expanded within splenic germinal centers where they stimulate B cells to differentiate into plasma cells and to produce antiplatelet antibodies by a mechanism requiring the interaction between CD40, expressed by B cells, and CD154 expressed by TFH and the secretion of IL-21 by TFH. […] Besides peripheral destruction of platelets, CTL cytotoxicity also affects megakaryocytes, as supported by their higher recruitment in the bone marrow, driven by fractalkine, a chemokine that binds to CX3CR1 expressed by CTL, and their capability to interfere with the platelet production. […] Combined to the peripheral destruction of platelets, there is an inappropriate production in ITP resulting from both an immune response against megakaryocytes but also to inadequate level of TPO.

• #38 Pathogenesis and Therapeutic Mechanisms in Immune Thrombocytopenia (ITP)

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5332920/

  Immune thrombocytopenia (ITP) is a complex autoimmune disease characterized by low platelet counts. The pathogenesis of ITP remains unclear although both antibody-mediated and/or T cell-mediated platelet destruction are key processes. […] In addition, impairment of T cells, cytokine imbalances, and the contribution of the bone marrow niche have now been recognized to be important. […] ITP is mainly due to IgG autoantibodies, which bind to platelets and MKs, targeting very abundant surface antigens such as glycoprotein (GP) IIb3 (GPIIbIIIA) and GPIb-IX-V. […] Platelets with bound autoantibodies are subsequently recognized by phagocytes bearing Fc-receptors (FcRs), which results in enhanced antibody-mediated platelet phagocytosis and destruction primarily in the spleen. […] Moreover, autoantibody binding to MKs can inhibit their maturation or can lead to their destruction, and thrombopoietin (TPO), a liver derived glycoprotein hormone that drives thrombopoiesis, cannot normalize the platelet count.

• #39 Pathogenesis and Therapeutic Mechanisms in Immune Thrombocytopenia (ITP)

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5332920/

  In fact, approximately two-thirds of patients with ITP present with normal or decreased TPO plasma levels, adding a novel functional deficit of TPO to the pathophysiology of the disease. […] In addition, autoreactive T cells are also involved in platelet and MK destruction, and, despite an increased MK number in the bone marrow of some patients, many present signs of morphological abnormalities including apoptotic ultrastructure as well as activation of Caspase-3. […] Superimposed on these cellular impairments, the cytokine profile of patients with ITP is also imbalanced with, for example, higher serum levels of interleukin (IL)-2, interferon (IFN)-, and IL-17. […] In summary, T cells also play a crucial role in ITP. Indeed, abnormal T cell subsets, including lower Tregs and unbalanced Th17, Th0, and Th1 profiles, as well as the presence of cytotoxic CD8+ T cells constitute the cellular mechanisms of ITP pathogenesis.

• #40 Pathogenesis and Therapeutic Mechanisms in Immune Thrombocytopenia (ITP)

  https://www.mdpi.com/2077-0383/6/2/16

  ITP is mainly due to IgG autoantibodies, which bind to platelets and MKs, targeting very abundant surface antigens such as glycoprotein (GP) αIIbβ3 (GPIIbIIIA) and GPIb-IX-V. […] Platelets with bound autoantibodies are subsequently recognized by phagocytes bearing Fcγ-receptors (FcγRs), which results in enhanced antibody-mediated platelet phagocytosis and destruction primarily in the spleen. […] Moreover, autoantibody binding to MKs can inhibit their maturation or can lead to their destruction, and thrombopoietin (TPO), a liver derived glycoprotein hormone that drives thrombopoiesis, cannot normalize the platelet count. […] In addition, autoreactive T cells are also involved in platelet and MK destruction, and, despite an increased MK number in the bone marrow of some patients, many present signs of morphological abnormalities including apoptotic ultrastructure as well as activation of Caspase-3.

• #41 Immune Thrombocytopenia: Recent Advances in Pathogenesis and Treatments

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8171374/

  An integrative view of ITP pathogenesis is summarized in Figure 1 and Table 1. […] ITP results from a peripheral destruction of platelets that takes place in the blood, the spleen, and the liver, together with an inappropriate bone marrow production due to an autoimmune response against megakaryocytes and insufficient TPO levels. […] The involvement of the humoral response against platelets is known since the 1950s when Harrington et al observed that sera of ITP patients induced thrombocytopenia when infused to healthy volunteers. […] The spleen plays a major role in ITP pathogenesis, being the site of an intense autoimmune response with an expansion of germinal centers and the generation of mutated, high-affinity-antiplatelet antibody-secreting plasma cells. […] Various mechanisms support the cytotoxicity mediated by antibodies, such as complement-dependent cytotoxicity (CDC), causing the destruction of targeted cells by the formation of the membrane attack complex (MAC), but also facilitating their phagocytosis (antibody-dependent cellular phagocytosis [ADCP]) by macrophages expressing Fc gamma receptor (FcR) and complement receptor 1 that binds to the complement fraction C3b.

• #42

  https://journals.lww.com/hemasphere/fulltext/2021/06000/immune_thrombocytopenia__recent_advances_in.6.aspx

  The spleen plays a major role in ITP pathogenesis, being the site of an intense autoimmune response with an expansion of germinal centers and the generation of mutated, high-affinity-antiplatelet antibody-secreting plasma cells. […] Various mechanisms support the cytotoxicity mediated by antibodies, such as complement-dependent cytotoxicity (CDC), causing the destruction of targeted cells by the formation of the membrane attack complex (MAC), but also facilitating their phagocytosis (antibody-dependent cellular phagocytosis [ADCP]) by macrophages expressing Fc gamma receptor (FcR) and complement receptor 1 that binds to the complement fraction C3b. […] Another mechanism, antibody-dependent cellular cytotoxicity (ADCC) mediated by natural killer (NK) cells, is probably less involved during ITP.

• #43 Immune Thrombocytopenia (ITP): Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/202158-overview

  The spleen is the key organ in the pathophysiology of ITP, not only because platelet autoantibodies are formed in the white pulp, but also because mononuclear macrophages in the red pulp destroy immunoglobulin-coated platelets. […] Malik et al have identified cytotoxic CD8+ T cells as an antibody-independent mechanism of platelet destruction in chronic ITP. These researchers demonstrated that adults with chronic ITP have clonal expansion of terminally differentiated effector memory CD8+ T cells (TEMRA), compared with age-matched controls. TEMRAs form aggregates with autologous platelets, release interferon gamma, and trigger platelet activation and apoptosis via the T-cell receptormediated release of cytotoxic granules. […] If bone marrow megakaryocytes cannot increase production and maintain a normal number of circulating platelets, thrombocytopenia and purpura develop. Impaired thrombopoiesis is attributed to failure of a compensatory increase in thrombopoietin and megakaryocyte apoptosis.

• #44 Immune Thrombocytopenia: Recent Advances in Pathogenesis and Treatments

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8171374/

  An integrative view of ITP pathogenesis is summarized in Figure 1 and Table 1. […] ITP results from a peripheral destruction of platelets that takes place in the blood, the spleen, and the liver, together with an inappropriate bone marrow production due to an autoimmune response against megakaryocytes and insufficient TPO levels. […] The involvement of the humoral response against platelets is known since the 1950s when Harrington et al observed that sera of ITP patients induced thrombocytopenia when infused to healthy volunteers. […] The spleen plays a major role in ITP pathogenesis, being the site of an intense autoimmune response with an expansion of germinal centers and the generation of mutated, high-affinity-antiplatelet antibody-secreting plasma cells. […] Various mechanisms support the cytotoxicity mediated by antibodies, such as complement-dependent cytotoxicity (CDC), causing the destruction of targeted cells by the formation of the membrane attack complex (MAC), but also facilitating their phagocytosis (antibody-dependent cellular phagocytosis [ADCP]) by macrophages expressing Fc gamma receptor (FcR) and complement receptor 1 that binds to the complement fraction C3b.

• #45 Thrombocytopenia | AAFP

  https://www.aafp.org/pubs/afp/issues/2012/0315/p612.html

  Secondary immune thrombocytopenic purpura is associated with other underlying conditions, such as autoimmune disorders (e.g., systemic lupus erythematosus, antiphospholipid syndrome, Graves disease, sarcoidosis), lymphoproliferative disorders, and infections (e.g., human immunodeficiency virus, Epstein-Barr virus, cytomegalovirus, varicella-zoster virus, hepatitis C virus, Helicobacter pylori). […] The condition often is caused by the absence or deficiency of a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13. […] Thrombotic thrombocytopenic purpura occurs primarily in adults. […] Hemolytic uremic syndrome is thrombotic thrombocytopenic purpura found in children presenting with acute renal failure, bloody diarrhea, and/or abdominal pain.

• #46 Current Understanding of Immune Thrombocytopenia: A Review of Pathogenesis and Treatment Options

  https://www.mdpi.com/1422-0067/25/4/2163

  The pathogenesis of secondary ITP may share similar mechanisms with primary ITP. However, unique mechanisms have been identified in some types of secondary ITP. For example, antigen mimicry, in which antibodies directed against a foreign protein cross-react with specific epitopes on platelet glycoproteins (GPs), has been observed in thrombocytopenia associated with hepatitis C, Helicobacter pylori, and HIV infections. […] Dysregulation of T cells plays a crucial role in the pathogenesis of ITP. […] Due to a breakdown of self-tolerance, the APC process is triggered and presents platelet autoantigens to autoreactive T cells, which initiates a cascade of events including the stimulation of autoantibody production and cytotoxic T-cell (CTL) activation and proliferation, along with an abnormal number and function of regulatory T cells (Tregs), the production of abnormal Th cells, and abnormal T-cell anergy.

• #47 Current Understanding of Immune Thrombocytopenia: A Review of Pathogenesis and Treatment Options

  https://www.mdpi.com/1422-0067/25/4/2163

  The pathogenesis of secondary ITP may share similar mechanisms with primary ITP. However, unique mechanisms have been identified in some types of secondary ITP. For example, antigen mimicry, in which antibodies directed against a foreign protein cross-react with specific epitopes on platelet glycoproteins (GPs), has been observed in thrombocytopenia associated with hepatitis C, Helicobacter pylori, and HIV infections. […] Dysregulation of T cells plays a crucial role in the pathogenesis of ITP. […] Due to a breakdown of self-tolerance, the APC process is triggered and presents platelet autoantigens to autoreactive T cells, which initiates a cascade of events including the stimulation of autoantibody production and cytotoxic T-cell (CTL) activation and proliferation, along with an abnormal number and function of regulatory T cells (Tregs), the production of abnormal Th cells, and abnormal T-cell anergy.

• #48 Drug-induced immune thrombocytopenia – UpToDate

  https://www.uptodate.com/contents/drug-induced-immune-thrombocytopenia

  Unexplained thrombocytopenia is a common clinical problem, and the possibility of drug-induced thrombocytopenia must be considered, especially in hospitalized patients, in whom new drugs are commonly administered. […] Drugs can cause thrombocytopenia by several mechanisms including direct bone marrow or other organ toxicity. Many of the cytotoxic drugs used for cancer chemotherapy and other conditions produce dose-dependent reductions in platelet counts due to bone marrow suppression as a known effect of the drug. […] This topic review discusses drug-induced immune thrombocytopenia (DITP), in which the mechanism involves antibody-mediated platelet destruction caused by exposure to a drug that leads to isolated thrombocytopenia (without anemia or leukopenia). […] The „drug” in this context may be a prescribed medication (or its metabolite), over-the-counter medicine, vaccine, herbal supplement, food, beverage, or other substance.

• #49

  https://haematologica.org/article/view/haematol.2021.279484

  Several therapeutic agents can cause thrombocytopenia by either immune-mediated or non-immune-mediated mechanisms. […] Immune-mediated thrombocytopenia, on the other hand, involves the formation of antibodies that react to platelet-specific glycoprotein complexes, as in classic drug-induced immune thrombocytopenia (DITP), or to platelet factor 4, as in heparin-induced thrombocytopenia (HIT) and vaccine-induced immune thrombotic thrombocytopenia (VITT). […] According to the pathogenesis of the thrombocytopenia, two categories can be distinguished: immune-mediated and non-immune-mediated thrombocytopenia. […] In contrast, in drug-induced immune thrombocytopenia (DITP) a humoral immune response against platelet antigens causes increased platelet destruction/ consumption and/or impaired platelet production.

• #50

  https://haematologica.org/article/view/haematol.2021.279484

  Platelet specific glycoprotein (GP) complexes such as GPIIb/IIIa and GPIb/IX are most common target antigens in cases of DITP. […] The identification of the compound responsible for the reduced platelet count is essential to define the correct therapeutic approach in these patients. […] In DITP, IgG (less commonly IgM/A) antibodies bind to platelets leading to their destruction via either complement activation and/or phagocytosis. […] According to their binding mechanisms, at least six types of antibodies have been identified: 1) quinine-type drug-dependent antibodies (DDAbs); 2) hapten-dependent DDAbs; 3) fiban-type DDAbs; 4) drug-specific DDAbs (against chimeric antibodies); 5) autoantibody; and 6) immune complexes. […] Thrombocytopenia usually occurs approximately 5-10 days after initial drug administration and the median nadir platelet count is 20×10^9/L.

• #51

  https://haematologica.org/article/view/haematol.2021.279484

  Platelet specific glycoprotein (GP) complexes such as GPIIb/IIIa and GPIb/IX are most common target antigens in cases of DITP. […] The identification of the compound responsible for the reduced platelet count is essential to define the correct therapeutic approach in these patients. […] In DITP, IgG (less commonly IgM/A) antibodies bind to platelets leading to their destruction via either complement activation and/or phagocytosis. […] According to their binding mechanisms, at least six types of antibodies have been identified: 1) quinine-type drug-dependent antibodies (DDAbs); 2) hapten-dependent DDAbs; 3) fiban-type DDAbs; 4) drug-specific DDAbs (against chimeric antibodies); 5) autoantibody; and 6) immune complexes. […] Thrombocytopenia usually occurs approximately 5-10 days after initial drug administration and the median nadir platelet count is 20×10^9/L.

• #52

  https://haematologica.org/article/view/haematol.2021.279484

  Platelet specific glycoprotein (GP) complexes such as GPIIb/IIIa and GPIb/IX are most common target antigens in cases of DITP. […] The identification of the compound responsible for the reduced platelet count is essential to define the correct therapeutic approach in these patients. […] In DITP, IgG (less commonly IgM/A) antibodies bind to platelets leading to their destruction via either complement activation and/or phagocytosis. […] According to their binding mechanisms, at least six types of antibodies have been identified: 1) quinine-type drug-dependent antibodies (DDAbs); 2) hapten-dependent DDAbs; 3) fiban-type DDAbs; 4) drug-specific DDAbs (against chimeric antibodies); 5) autoantibody; and 6) immune complexes. […] Thrombocytopenia usually occurs approximately 5-10 days after initial drug administration and the median nadir platelet count is 20×10^9/L.

• #53

  https://haematologica.org/article/view/haematol.2021.279484

  Platelet specific glycoprotein (GP) complexes such as GPIIb/IIIa and GPIb/IX are most common target antigens in cases of DITP. […] The identification of the compound responsible for the reduced platelet count is essential to define the correct therapeutic approach in these patients. […] In DITP, IgG (less commonly IgM/A) antibodies bind to platelets leading to their destruction via either complement activation and/or phagocytosis. […] According to their binding mechanisms, at least six types of antibodies have been identified: 1) quinine-type drug-dependent antibodies (DDAbs); 2) hapten-dependent DDAbs; 3) fiban-type DDAbs; 4) drug-specific DDAbs (against chimeric antibodies); 5) autoantibody; and 6) immune complexes. […] Thrombocytopenia usually occurs approximately 5-10 days after initial drug administration and the median nadir platelet count is 20×10^9/L.

• #54 Heparin-induced thrombocytopenia: an update | Thrombosis Journal | Full Text

  https://thrombosisjournal.biomedcentral.com/articles/10.1186/1477-9560-3-14

  Heparin-induced thrombocytopenia is defined as a decrease in platelet count during or shortly following exposure to heparin. […] The mechanism underlying heparin-induced thrombocytopenia is an immune response. […] The principal antigen is a complex of heparin and platelet factor 4 (PF4). […] Because of opposite charges, heparin and other glycosaminoglycans bind to the PF4 molecules, exposing neoepitopes that act as immunogens leading to antibody production. […] In fact, patients who develop HIT produce an IgG antibody against the heparin-PF4 complex, which binds to the complex on platelet surface through the Fab region. […] The Fc portion of the HIT antibody can then bind to the platelet Fc receptor and this interaction triggers activation and aggregation of the platelets. […] Activated platelets release PF4, thus perpetuating the cycle of heparin-induced platelet activation.

• #55 Heparin-induced thrombocytopenia: an update | Thrombosis Journal | Full Text

  https://thrombosisjournal.biomedcentral.com/articles/10.1186/1477-9560-3-14

  Heparin-induced thrombocytopenia is defined as a decrease in platelet count during or shortly following exposure to heparin. […] The mechanism underlying heparin-induced thrombocytopenia is an immune response. […] The principal antigen is a complex of heparin and platelet factor 4 (PF4). […] Because of opposite charges, heparin and other glycosaminoglycans bind to the PF4 molecules, exposing neoepitopes that act as immunogens leading to antibody production. […] In fact, patients who develop HIT produce an IgG antibody against the heparin-PF4 complex, which binds to the complex on platelet surface through the Fab region. […] The Fc portion of the HIT antibody can then bind to the platelet Fc receptor and this interaction triggers activation and aggregation of the platelets. […] Activated platelets release PF4, thus perpetuating the cycle of heparin-induced platelet activation.

• #56 Heparin-induced thrombocytopenia mechanism | Student Doctor Network

  https://forums.studentdoctor.net/threads/heparin-induced-thrombocytopenia-mechanism.1173979/

  Heparin binds Platelet factor 4 (PF4) […] Heparin-PF4 complex is immunogenic, and causes IgG directed against it […] Heparin-PF4-IgG complex binds platelets via their Fc receptors. This causes activation of the platelets […] The severe maladaptive activation of platelets in HIT happens because 1) heparin binds PF4 exposing immune epitopes leading to the formation of IgG, 2) the platelets Fc receptor binds the exposed Fc region of IgG-heparin-PF4, 3) platelet activation leads to even more PF4 release creating a positive feedback loop of 1 2. This process is also mediated by a) the binding of heparin to PF4 which is dependent on the molecular characteristics of the specific sample of heparin you are administering, b) the ability to form anti heparin-PF4 antibody which varies based on the patient population, the type of heparin used (greater risk with bovine unfractionated), and even the setting of heparin administration (more common in post surgical cardiac patients), and c) the binding of antibody-heparin-PF4 to platelets which is influenced by the titer and type of antibody created. So yes, platelets can be activated through binding of other IgG-antigen to their Fc receptor. This response is just exaggerated in HIT with certain patients because of the circumstances.

• #57 Heparin-induced thrombocytopenia: an update | Thrombosis Journal | Full Text

  https://thrombosisjournal.biomedcentral.com/articles/10.1186/1477-9560-3-14

  In addition, the platelet activation leads to the production of prothrombotic platelet microparticles which promote coagulation. […] Finally, as a result of the presence of heparin-like molecules (heparan sulfate) on the surface of endothelial cells, the HIT antibody-PF4-heparan sulfate complexes formed on the endothelial surface may induce tissue factor expression with further activation of the coagulation cascade and thrombin generation. […] Thrombocytopenia in HIT is largely due to the clearance of activated platelets and antibody-coated platelets by the reticulo-endothelial system.

• #58 Overview of Thrombocytopenia – Blood Disorders – MSD Manual Consumer Version

  https://www.msdmanuals.com/home/blood-disorders/platelet-disorders/overview-of-thrombocytopenia

  Thrombocytopenia occurs when the bone marrow makes too few platelets or when too many platelets are destroyed or accumulate within an enlarged spleen. […] Thrombocytopenia can occur when the bone marrow does not produce enough platelets, as happens in leukemia or other bone marrow disorders. […] Finally, the body may use or destroy too many platelets, as occurs in many disorders. Three of the most notable of these disorders are immune thrombocytopenia, thrombotic thrombocytopenic purpura, and hemolytic-uremic syndrome. […] Decreased platelet production by the bone marrow (caused by bone marrow toxicity) […] Increased platelet destruction (immune-mediated thrombocytopenia). […] Treating the cause can often treat the thrombocytopenia. Thrombocytopenia caused by a medication usually is corrected when the person stops taking the medication. Thrombocytopenia caused by autoimmune destruction of platelets (as in immune thrombocytopenia) is treated with prednisone (a medication that suppresses the immune system to lessen platelet destruction), medications that stimulate the bone marrow to increase production of platelets, and sometimes removal of the spleen (splenectomy).

• #59 Thrombocytopenia pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Thrombocytopenia_pathophysiology

  Basically, thrombocytopenia is the result of one of these mechanisms or a combination of some of them: Reduced production of platelets due to bone marrow dysfunction, increased destruction of platelets in the body, iatrogenic, and entrapment of platelets in spleen. Several conditions, some of which mentioned below, can activate the mechanisms that ultimately lead to thrombocytopenia. […] It is thought that thrombocytopenia is the result of either of these four main mechanisms: […] Decreased production of platelets in the bone marrow. […] Destruction of platelets outside of bone marrow. […] Blood dilution from fluid resuscitation or massive transfusion. […] Sequestration of platelets in the spleen due to portal hypertension and/or splenomegaly. […] Some conditions cause thrombocytopenia through a combination of these mechanisms. For instance, primary ITP is associated with antibody-mediated platelet destruction, but it can also cause suppression of megakaryocytes, which is considered a bone marrow dysfunction.

• #60 Azthena logo with the word Azthena

  https://www.news-medical.net/health/What-is-Thrombocytopenia.aspx

  Thrombocytopenia is a condition in which the blood has an unusually low number of platelets. […] A variety of factors including different disorders can contribute to the development of thrombocytopenia. […] One such auto-immune condition known as ITP (immunological thrombocytopenia) is one of the most common causes of decreased platelets. […] When the bone marrow does not create enough platelets, for example with leukemia or with other bone marrow disorders, thrombocytopenia may develop. […] There are three major causes of insufficient platelets in thrombocytopenia. These include low platelet production in the bone marrow, increased platelet breakdown in the circulation, and increased platelet breakdown in the spleen or liver. […] Low production of platelets in the bone marrow can be caused due to a variety of factors like aplastic anemia, cancer (leukemia), folate deficiency, cirrhosis, and myelodysplastic syndrome.

• #61 Thrombocytopenia pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Thrombocytopenia_pathophysiology

  Bone marrow abnormalities that cause decreased platelet production commonly reduce the production of RBCs and WBCs as well, resulting in pancytopenia. […] Several mechanisms can accelerate the normal platelet degradation process in the body: Anti-platelet antibodies seen in both primary ITP and its secondary form (associated with systemic autoimmune disorders such as SLE) play a main role. […] Dilutional thrombocytopenia is an iatrogenic form of thrombocytopenia caused by massive fluid resuscitation or massive blood transfusion. […] In individuals with normal splenic function, approximately one-third of the platelet mass is found in the spleen, in equilibrium with the circulating platelet pool. Any condition resulting in splenomegaly and/or splenic congestion due to portal hypertension may lead to a reduced platelet count, while the total platelet mass in the body is intact.

• #62 Thrombocytopenia pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Thrombocytopenia_pathophysiology

  Bone marrow abnormalities that cause decreased platelet production commonly reduce the production of RBCs and WBCs as well, resulting in pancytopenia. […] Several mechanisms can accelerate the normal platelet degradation process in the body: Anti-platelet antibodies seen in both primary ITP and its secondary form (associated with systemic autoimmune disorders such as SLE) play a main role. […] Dilutional thrombocytopenia is an iatrogenic form of thrombocytopenia caused by massive fluid resuscitation or massive blood transfusion. […] In individuals with normal splenic function, approximately one-third of the platelet mass is found in the spleen, in equilibrium with the circulating platelet pool. Any condition resulting in splenomegaly and/or splenic congestion due to portal hypertension may lead to a reduced platelet count, while the total platelet mass in the body is intact.

• #63 Practical approach to thrombocytopenia in patients with sepsis: a narrative review | Thrombosis Journal | Full Text

  https://thrombosisjournal.biomedcentral.com/articles/10.1186/s12959-024-00637-0

  Thrombocytopenia is a common complication of chronic liver diseases such as liver cirrhosis. […] Multifactorial mechanisms contribute to the development of thrombocytopenia, including platelet sequestration commonly accompanied by hypersplenism and portal hypertension, viral-induced bone marrow suppression, autoantibodies, and decreased thrombopoietin (TPO) production. […] In patients with liver failure, it is necessary to differentiate DIC or detect its concurrence by assessing the coagulofibrinolytic activity.

• #64 Practical approach to thrombocytopenia in patients with sepsis: a narrative review | Thrombosis Journal | Full Text

  https://thrombosisjournal.biomedcentral.com/articles/10.1186/s12959-024-00637-0

  Thrombocytopenia is a common complication of chronic liver diseases such as liver cirrhosis. […] Multifactorial mechanisms contribute to the development of thrombocytopenia, including platelet sequestration commonly accompanied by hypersplenism and portal hypertension, viral-induced bone marrow suppression, autoantibodies, and decreased thrombopoietin (TPO) production. […] In patients with liver failure, it is necessary to differentiate DIC or detect its concurrence by assessing the coagulofibrinolytic activity.

• #65 Thrombocytopenia pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Thrombocytopenia_pathophysiology

  Bone marrow abnormalities that cause decreased platelet production commonly reduce the production of RBCs and WBCs as well, resulting in pancytopenia. […] Several mechanisms can accelerate the normal platelet degradation process in the body: Anti-platelet antibodies seen in both primary ITP and its secondary form (associated with systemic autoimmune disorders such as SLE) play a main role. […] Dilutional thrombocytopenia is an iatrogenic form of thrombocytopenia caused by massive fluid resuscitation or massive blood transfusion. […] In individuals with normal splenic function, approximately one-third of the platelet mass is found in the spleen, in equilibrium with the circulating platelet pool. Any condition resulting in splenomegaly and/or splenic congestion due to portal hypertension may lead to a reduced platelet count, while the total platelet mass in the body is intact.

• #66 Pathophysiology of Thrombotic Thrombocytopenia Purpura | American Society for Clinical Laboratory Science

  https://clsjournal.ascls.org/content/early/2023/04/10/ascls.2020002261

  1. Discuss the pathogenesis of acquired and congenital thrombotic thrombocytopenic purpura (TTP). […] 2. This review describes classic thrombotic thrombocytopenic purpura (TTP), discusses the pathogenesis of acquired and congenital TTP, describes clinical and laboratory manifestations observed in patients, and lists options for treating patients with TTP. […] 3. TTP involves the formation of microcvascular thrombi in arterioles, capillaries, and many organs. […] 4. The microvascular thrombi are composed of platelet aggregates primarily with very little fibrin. […] 5. In addition, there is neither perivascular inflammation nor overt endothelial cell (EC) damage. […] 6. This results in decreased blood flow to vital organs, such as the brain, heart, and kidney. […] 7. ADAMTS-13 is a metalloprotease found in plasma that is responsible for cleaving VWF in a shear dependent manner.

• #67 Pathophysiology of Thrombotic Thrombocytopenia Purpura | American Society for Clinical Laboratory Science

  https://clsjournal.ascls.org/content/early/2023/04/10/ascls.2020002261

  8. It plays a critical role in cleaving the unusually large multimers of VWF in plasma. […] 9. A severe deficiency of ADAMTS-13 protease results in persistence of the ULVWF multimers in plasma. […] 10. The uncleaved ULVWF multimers in the microcirculation cause the formation of platelet-rich thrombi that are responsible for fragmented erythrocytes in the circulation, one of the hallmarks of the TMAs. […] 11. About 5% of all TTP cases with a deficiency of ADAMTS-13 are congenital. […] 12. Patients present with symptoms at a very early age (around 5 years of age) and often experience relapsing episodes of TTP throughout life. […] 13. The most common form of TTP is acquired; incidences peak between ages 30 and 50. […] 14. Acquired TTP is more prevalent in women than men. […] 15. Autoantibodies (e.g., immunoglobulin G [IgG]) are directed against the enzyme activity of the protease, reducing its ability to cleave the ULVWF multimers.

• #68

  https://link.springer.com/article/10.1007/s44337-024-00040-8

  This may be related to abnormal cytokine secretion, abnormal expression of chemokines, and cytotoxic effects. […] Apoptosis is the most common form of programmed cell death (PCD) in physiology. […] Both megakaryocytes and platelets contain functional pathways for PCD, and genetic or induced (e.g., by autoantibodies) dysregulation of these PCD pathways may lead to thrombocytopenia or inefficient platelet production in ITP. […] These evidences suggest that abnormal apoptosis in megakaryocytes and platelets may contribute to the development of ITP. […] In recent years research on epigenetics in human diseases has been ongoing and several studies have revealed several major epigenetic mechanisms and their role in the etiology of ITP, including DNA methylation. […] This process can cause changes in chromatin structure, DNA conformation, and stability, thereby controlling gene expression. […] Several studies on ITP have identified abnormal DNA methylation.

• #69 Current Understanding of Immune Thrombocytopenia: A Review of Pathogenesis and Treatment Options

  https://www.mdpi.com/1422-0067/25/4/2163

  The degree of Treg abnormalities is associated with disease severity. […] Impaired thrombopoiesis with an insufficient production of platelets is the result of an abnormal immune response against megakaryocytes (MKs), which is associated with a low TPO concentration. […] In ITP, since MKs express the same GP as platelets, they are clearly targeted by antiplatelet antibodies that bind to GPIb and GPIIb/IIIa, as well as by CTLs, which induces morphological and physiological changes or even apoptosis. […] Platelet production is correlated with the serum levels of TPO, a major megakaryocyte growth factor.

• #70

  https://link.springer.com/article/10.1007/s44337-024-00040-8

  This may be related to abnormal cytokine secretion, abnormal expression of chemokines, and cytotoxic effects. […] Apoptosis is the most common form of programmed cell death (PCD) in physiology. […] Both megakaryocytes and platelets contain functional pathways for PCD, and genetic or induced (e.g., by autoantibodies) dysregulation of these PCD pathways may lead to thrombocytopenia or inefficient platelet production in ITP. […] These evidences suggest that abnormal apoptosis in megakaryocytes and platelets may contribute to the development of ITP. […] In recent years research on epigenetics in human diseases has been ongoing and several studies have revealed several major epigenetic mechanisms and their role in the etiology of ITP, including DNA methylation. […] This process can cause changes in chromatin structure, DNA conformation, and stability, thereby controlling gene expression. […] Several studies on ITP have identified abnormal DNA methylation.

• #71 Q: What mechanisms contribute to the pathophysiology of ITP?

  https://expertperspectives.com/mechanisms-contributing-to-the-pathophysiology-of-immune-thrombocytopenia/

  We are learning that the answer is multiple mechanisms. […] The traditional viewpoint about ITP was that it was a disease of accelerated platelet clearance, and the clearance was due to immunoglobulin G antibodies against antigens on the platelet surface that lead to their clearance in the spleen. […] That is clearly an important mechanism in ITP, but it is not the only mechanism and it is also more nuanced than that. […] We now know that antibodies in ITP are heterogeneous. […] There are antibodies to the glycoprotein IIBIIIA complex that do behave generally in that way, but then there are also antibodies to the glycoprotein IB-IX-V complex that seem to have a different pathophysiology. […] Therefore, we would not expect those patients to respond, for example, to splenectomy, corticosteroids, or anti-D.

• #72 Q: What mechanisms contribute to the pathophysiology of ITP?

  https://expertperspectives.com/mechanisms-contributing-to-the-pathophysiology-of-immune-thrombocytopenia/

  As far as cellular immunity, T cells are important in ITP, potentially as a means of platelet destruction, and the T cells can also attack the megakaryocytes and interfere with platelet production. […] What we are really learning is that ITP is a complicated disease. […] It is probably more than 1 disease, and the pathophysiologic mechanisms that operate in 1 patient may not be the same as those that operate in another patient.

• #73 Immune Thrombocytopenia: Pathogenesis and Treatment Approaches

  https://www.jscimedcentral.com/jounal-article-info/Journal-of-Hematology-and-Transfusion/Immune-Thrombocytopenia%3A-Pathogenesis-and-Treatment-Approaches-1547

  Increased platelet destruction: Abnormally accelerated platelet destruction is a characteristic of ITP. Current evidence suggests involvement of a 3-step mechanism. Firstly, immune tolerance is lost due to pathological regulatory and inflammatory T-cell function. Secondly, T-follicular helper cells located primarily in the spleen trigger differentiation of B cells to autoreactive cells that produce antiplatelet antibodies. Finally, antiplatelet antibodies target glycoproteins, primarily glycoprotein IIb/IIIa, on platelets and cause platelet destruction by macrophages or cytotoxic T cells. […] Decreased platelet production: In patients with ITP, platelet production may not be sufficient to replace the platelets that are destroyed. Since megakaryocytes and platelets share common surface antigens, most anti-platelet antibodies may also target megakaryocytes. Thus, decreased platelet production may be a secondary result of the factors leading to increased platelet destruction, which were discussed above. Other potential causes of decreased platelet production include impaired function of megakaryocytes, altered megakaryocyte morphology, or abnormal T-cell response in the bone marrow microenvironment. In addition, insufficient TPO levels are considered to be involved in pathogenesis of ITP because increased serum TPO, a typical compensatory response to thrombocytopenia, is not observed in ITP. […] Pathogenesis of ITP involves 2 major mechanisms: increased platelet destruction and decreased platelet production. The varying levels of contribution of these processes to ITP pathology in patients may be responsible for the heterogeneity of responses to different treatment strategies.

• #74 Q: What mechanisms contribute to the pathophysiology of ITP?

  https://expertperspectives.com/mechanisms-contributing-to-the-pathophysiology-of-immune-thrombocytopenia/

  As far as cellular immunity, T cells are important in ITP, potentially as a means of platelet destruction, and the T cells can also attack the megakaryocytes and interfere with platelet production. […] What we are really learning is that ITP is a complicated disease. […] It is probably more than 1 disease, and the pathophysiologic mechanisms that operate in 1 patient may not be the same as those that operate in another patient.

• #75 Desialylation is a mechanism of Fc-independent platelet clearance and a therapeutic target in immune thrombocytopenia | Nature Communications

  https://www.nature.com/articles/ncomms8737

  Thus, platelet desialylation may be an important biomarker for platelet activation and for anti-GPIb-mediated ITP. […] We describe herein a novel FcR-independent mechanism of platelet clearance in thrombocytopenia mediated predominantly by anti-GPIb antibodies, which is distinct from Fc-dependent ITP in both mechanism and therapeutic management. […] Our findings not only reveal a new mechanism of ITP, but also introduce a potential new diagnostic tool (for example, RCA-1 and NEU1 staining) and a novel therapeutic method (for example, sialidase inhibition), which will have a particularly significant impact on patients refractory to current ITP therapies.

• #76 Desialylation is a mechanism of Fc-independent platelet clearance and a therapeutic target in immune thrombocytopenia | Nature Communications

  https://www.nature.com/articles/ncomms8737

  Thus, platelet desialylation may be an important biomarker for platelet activation and for anti-GPIb-mediated ITP. […] We describe herein a novel FcR-independent mechanism of platelet clearance in thrombocytopenia mediated predominantly by anti-GPIb antibodies, which is distinct from Fc-dependent ITP in both mechanism and therapeutic management. […] Our findings not only reveal a new mechanism of ITP, but also introduce a potential new diagnostic tool (for example, RCA-1 and NEU1 staining) and a novel therapeutic method (for example, sialidase inhibition), which will have a particularly significant impact on patients refractory to current ITP therapies.

• #77 Desialylation is a mechanism of Fc-independent platelet clearance and a therapeutic target in immune thrombocytopenia | Nature Communications

  https://www.nature.com/articles/ncomms8737

  Thus, platelet desialylation may be an important biomarker for platelet activation and for anti-GPIb-mediated ITP. […] We describe herein a novel FcR-independent mechanism of platelet clearance in thrombocytopenia mediated predominantly by anti-GPIb antibodies, which is distinct from Fc-dependent ITP in both mechanism and therapeutic management. […] Our findings not only reveal a new mechanism of ITP, but also introduce a potential new diagnostic tool (for example, RCA-1 and NEU1 staining) and a novel therapeutic method (for example, sialidase inhibition), which will have a particularly significant impact on patients refractory to current ITP therapies.

• #78 Azthena logo with the word Azthena

  https://www.news-medical.net/health/What-is-Thrombocytopenia.aspx

  Conditions that lead to an increase in the breakdown of platelets are an enlarged spleen, drug-induced conditions, and serious illnesses during which the proteins involved in blood clotting become hyperactive. […] Thrombocytopenia can be caused by hepatitis C virus, HIV, Epstein-Barr virus, and a variety of other viruses. […] ITP is an autoimmune bleeding condition characterized by excessive reticuloendothelial platelet breakdown and insufficient compensatory platelet synthesis. […] Platelet autoantibodies opsonize platelets and promote megakaryocyte apoptosis, as well as direct T cell-mediated megakaryocyte and platelet destruction, resulting in ITP. […] However, during the last decade, therapy choices have significantly improved. […] While most previous treatments worked by reducing platelet destruction through a general immune system effect, newer medicines target the pathophysiology of ITP more precisely by increasing platelet production or decreasing platelet destruction.

• #79 Mechanism of Action (MOA) | Nplate® (romiplostim)

  https://www.nplatehcp.com/itp-and-nplate/mechanism-of-action

  Nplate Increases Platelet Production at a Rate That Outpaces Platelet Destruction1,2 […] Nplate Binds and Activates the Thrombopoietin (TPO) Receptor, a Mechanism Analogous to Endogenous TPO (eTPO)1 […] Nplate, a TPO mimetic, increases platelet production and can outpace platelet destruction in ITP.1,2 […] Nplate binds to the TPO receptor, activating the same signaling pathways as eTPO, resulting in megakaryocyte and platelet development.1 […] Nplate has no amino acid sequence homology to eTPO.1 […] Nplate administration may increase the risk for development or progression of reticulin fiber formation within the bone marrow.

• #80

  https://haematologica.org/article/view/haematol.2021.279484

  Immediate discontinuation of the drug responsible is the initial step for the treatment of DITP. […] Generally, after 4-5 half-lives of the offending drug or drug metabolite, the platelet count begins to recover once treatment has been stopped. […] Administration of high doses of IVIG (1 g/kg body weight) can be used to accelerate platelet recovery under two circumstances: in patients with severe thrombocytopenia and bleeding or in those at high risk of bleeding. […] In DITP, the therapeutic approach must take into account both the pathophysiologic mechanisms and the clinical characteristics of the individual patient. […] In vaccine-induced immune thrombotic thrombocytopenia, IgG antibodies reactive to PF4 are the drivers of the pathophysiology. […] Anti-PF4 antibodies bind to PF4 on the platelet surface and these complexes activate platelets by engaging their FcRIIA, thus causing the generation of procoagulant platelets and promoting thrombus formation.

• #81 Desialylation is a mechanism of Fc-independent platelet clearance and a therapeutic target in immune thrombocytopenia | Nature Communications

  https://www.nature.com/articles/ncomms8737

  Immune thrombocytopenia (ITP) is a common bleeding disorder caused primarily by autoantibodies against platelet GPIIbIIIa and/or the GPIb complex. […] However, we and others have demonstrated that anti-GPIb (but not GPIIbIIIa)-mediated ITP is often refractory to therapies targeting FcR pathways. […] This leads to platelet clearance in the liver via hepatocyte AshwellMorell receptors, which is fundamentally different from the classical FcFcR-dependent macrophage phagocytosis. […] Importantly, sialidase inhibitors ameliorate anti-GPIb-mediated thrombocytopenia in mice. […] To date, there is no reliable measurement in the clinical setting to predict the success or failure of any ITP treatment. […] Unexpectedly, we and others have identified a novel mechanism of Fc-independent thrombocytopenia, in which antibodies against GPIb, but not those against GPIIbIIIa, can induce thrombocytopenia via their F(ab)2 (Fc independent) and in FcR-/ mice.

• #82 Q: What mechanisms contribute to the pathophysiology of ITP?

  https://expertperspectives.com/mechanisms-contributing-to-the-pathophysiology-of-immune-thrombocytopenia/

  We are learning that the answer is multiple mechanisms. […] The traditional viewpoint about ITP was that it was a disease of accelerated platelet clearance, and the clearance was due to immunoglobulin G antibodies against antigens on the platelet surface that lead to their clearance in the spleen. […] That is clearly an important mechanism in ITP, but it is not the only mechanism and it is also more nuanced than that. […] We now know that antibodies in ITP are heterogeneous. […] There are antibodies to the glycoprotein IIBIIIA complex that do behave generally in that way, but then there are also antibodies to the glycoprotein IB-IX-V complex that seem to have a different pathophysiology. […] Therefore, we would not expect those patients to respond, for example, to splenectomy, corticosteroids, or anti-D.

• #83 Desialylation is a mechanism of Fc-independent platelet clearance and a therapeutic target in immune thrombocytopenia | Nature Communications

  https://www.nature.com/articles/ncomms8737

  Immune thrombocytopenia (ITP) is a common bleeding disorder caused primarily by autoantibodies against platelet GPIIbIIIa and/or the GPIb complex. […] However, we and others have demonstrated that anti-GPIb (but not GPIIbIIIa)-mediated ITP is often refractory to therapies targeting FcR pathways. […] This leads to platelet clearance in the liver via hepatocyte AshwellMorell receptors, which is fundamentally different from the classical FcFcR-dependent macrophage phagocytosis. […] Importantly, sialidase inhibitors ameliorate anti-GPIb-mediated thrombocytopenia in mice. […] To date, there is no reliable measurement in the clinical setting to predict the success or failure of any ITP treatment. […] Unexpectedly, we and others have identified a novel mechanism of Fc-independent thrombocytopenia, in which antibodies against GPIb, but not those against GPIIbIIIa, can induce thrombocytopenia via their F(ab)2 (Fc independent) and in FcR-/ mice.

• #84 Immune Thrombocytopenia: Pathogenesis and Treatment Approaches

  https://www.jscimedcentral.com/jounal-article-info/Journal-of-Hematology-and-Transfusion/Immune-Thrombocytopenia%3A-Pathogenesis-and-Treatment-Approaches-1547

  Increased platelet destruction: Abnormally accelerated platelet destruction is a characteristic of ITP. Current evidence suggests involvement of a 3-step mechanism. Firstly, immune tolerance is lost due to pathological regulatory and inflammatory T-cell function. Secondly, T-follicular helper cells located primarily in the spleen trigger differentiation of B cells to autoreactive cells that produce antiplatelet antibodies. Finally, antiplatelet antibodies target glycoproteins, primarily glycoprotein IIb/IIIa, on platelets and cause platelet destruction by macrophages or cytotoxic T cells. […] Decreased platelet production: In patients with ITP, platelet production may not be sufficient to replace the platelets that are destroyed. Since megakaryocytes and platelets share common surface antigens, most anti-platelet antibodies may also target megakaryocytes. Thus, decreased platelet production may be a secondary result of the factors leading to increased platelet destruction, which were discussed above. Other potential causes of decreased platelet production include impaired function of megakaryocytes, altered megakaryocyte morphology, or abnormal T-cell response in the bone marrow microenvironment. In addition, insufficient TPO levels are considered to be involved in pathogenesis of ITP because increased serum TPO, a typical compensatory response to thrombocytopenia, is not observed in ITP. […] Pathogenesis of ITP involves 2 major mechanisms: increased platelet destruction and decreased platelet production. The varying levels of contribution of these processes to ITP pathology in patients may be responsible for the heterogeneity of responses to different treatment strategies.

• #85 Q: What mechanisms contribute to the pathophysiology of ITP?

  https://expertperspectives.com/mechanisms-contributing-to-the-pathophysiology-of-immune-thrombocytopenia/

  As far as cellular immunity, T cells are important in ITP, potentially as a means of platelet destruction, and the T cells can also attack the megakaryocytes and interfere with platelet production. […] What we are really learning is that ITP is a complicated disease. […] It is probably more than 1 disease, and the pathophysiologic mechanisms that operate in 1 patient may not be the same as those that operate in another patient.

Zobacz więcej