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__NOTOC__
__NOTOC__
{{ITP}}
{{ITP}}
{{CMG}}
increased platelet destruction{{CMG}}


==Overview==
==Overview==
AITP is characterized by the production of autoreactive antibodies against one's own platelets, resulting in increased platelet destruction by RES phagocytes
Auto-immune thrombocytopenic purpura is described by the increased platelet destruction due to production of auto-reactive antibodies against host platelets and suppression of platelet production in the bone marrow.


==Pathophysiology==
==Pathophysiology==
==Pathogenesis==
 
'''Increased platelet destruction:'''
=== '''Pathogenesis''' ===
* Autoantibody‐induced platelet destruction:
'''Acute ITP:'''  Mainly affects children and usually follows a viral or bacterial infection
** phagocytosis in the reticuloendothelial system
* Antigenic mimicry - Similar molecular structures on both host cells and infectious agents, inducing a self immune response which cross reacts with the host antigens.
** Platelet phagocytosis by splenic macrophages and peripheral blood neutrophils
** In acute ITP - anti-viral or anti-bacterial antibodies cross reacts against the patient's platelets.
** Abnormal IgG auto-antibody recognizes glycoprotein IIb/IIIa, glycoprotein Ib/IX complex, GP Ia/IIa, and GP VI etc
* Mostly acute ITP is self resolving as infectious agents and antibodies are cleared from the body, causing the loss of anti-platelet reactivity.
** IgG auto-antibody binds to the circulating platelet membranes through glycoproteins
* T cells are not involved in the parthenogenesis of acute ITP
** Autoantibody-coated platelets induce Fcg receptors and bind to antigen-presenting cells (Splenic macrophages or dendritic cells) where the platelets undergoes phagocytosis.
'''Chronic ITP:''' (platelet counts < 150,000 x 10<sup>9</sup> per liter x 6 months) usually in adults
**  
* '''Increased platelet destruction:'''
** '''Autoantibody‐induced platelet destruction'''
*** Abnormal IgG auto-antibody recognizes glyco-protein IIb/IIIa, glyco-protein Ib/IX complex, GP Ia/IIa, and GP VI etc<ref name="pmid15720967">{{cite journal |vauthors=McMillan R |title=The role of antiplatelet autoantibody assays in the diagnosis of immune thrombocytopenic purpura |journal=Curr. Hematol. Rep. |volume=4 |issue=2 |pages=160–5 |date=March 2005 |pmid=15720967 |doi= |url=}}</ref>
*** Predominantly IgG auto-antibodies constitute the majority of antibodies but IgM and IgA antibodies can also be found in some of ITP patients.<ref name="pmid157209672">{{cite journal |vauthors=McMillan R |title=The role of antiplatelet autoantibody assays in the diagnosis of immune thrombocytopenic purpura |journal=Curr. Hematol. Rep. |volume=4 |issue=2 |pages=160–5 |date=March 2005 |pmid=15720967 |doi= |url=}}</ref>
*** Auto-antibodies binds to the circulating platelet membranes through glyco-proteins
*** Auto-antibody-coated platelets induce Fcγ receptors and bind to antigen-presenting cells (Splenic macrophages or dendritic cells) in the reticulo-endothelial system<ref name="pmid2939345">{{cite journal |vauthors=Clarkson SB, Bussel JB, Kimberly RP, Valinsky JE, Nachman RL, Unkeless JC |title=Treatment of refractory immune thrombocytopenic purpura with an anti-Fc gamma-receptor antibody |journal=N. Engl. J. Med. |volume=314 |issue=19 |pages=1236–9 |date=May 1986 |pmid=2939345 |doi=10.1056/NEJM198605083141907 |url=}}</ref><ref name="pmid5214832">{{cite journal |vauthors=Shulman NR, Marder VJ, Weinrach RS |title=Similarities between known antiplatelet antibodies and the factor responsible for thrombocytopenia in idiopathic purpura. Physiologic, serologic and isotopic studies |journal=Ann. N. Y. Acad. Sci. |volume=124 |issue=2 |pages=499–542 |date=June 1965 |pmid=5214832 |doi= |url=}}</ref>
*** The auto-antibody-coated platelets undergo phagocytosis by splenic macrophages and peripheral blood neutrophils.<ref name="pmid5812817">{{cite journal |vauthors=Firkin BG, Wright R, Miller S, Stokes E |title=Splenic macrophages in thrombocytopenia |journal=Blood |volume=33 |issue=2 |pages=240–5 |date=February 1969 |pmid=5812817 |doi= |url=}}</ref>
** '''Autoreactive T lymphocyte‐mediated platelet lysis'''
*** Abnormal cytotoxic T cells defect leads to differentiation of direct autoreactive B cells further leading to secretion of IgG auto-antibodies<ref name="pmid12937414">{{cite journal |vauthors=Olsson B, Andersson PO, Jernås M, Jacobsson S, Carlsson B, Carlsson LM, Wadenvik H |title=T-cell-mediated cytotoxicity toward platelets in chronic idiopathic thrombocytopenic purpura |journal=Nat. Med. |volume=9 |issue=9 |pages=1123–4 |date=September 2003 |pmid=12937414 |doi=10.1038/nm921 |url=}}</ref>
*** Abnormal T cells includes cytotoxic T-lymphocyte (CD8+) and natural killer cells (CD3- CD16+ CD56+)<ref name="pmid16480433">{{cite journal |vauthors=Zhang F, Chu X, Wang L, Zhu Y, Li L, Ma D, Peng J, Hou M |title=Cell-mediated lysis of autologous platelets in chronic idiopathic thrombocytopenic purpura |journal=Eur. J. Haematol. |volume=76 |issue=5 |pages=427–31 |date=May 2006 |pmid=16480433 |doi=10.1111/j.1600-0609.2005.00622.x |url=}}</ref>
*** CD4-positive helper T cells react with platelet surface glycoproteins, through co-stimulation involving CD40:CD40L
*** T cells act directly on the megakaryocytes in the bone marrow
***
* '''Autoantibody‐mediated suppression of platelet production:'''
** Decreased platelet turnover<ref name="pmid3597777">{{cite journal |vauthors=Ballem PJ, Segal GM, Stratton JR, Gernsheimer T, Adamson JW, Slichter SJ |title=Mechanisms of thrombocytopenia in chronic autoimmune thrombocytopenic purpura. Evidence of both impaired platelet production and increased platelet clearance |journal=J. Clin. Invest. |volume=80 |issue=1 |pages=33–40 |date=July 1987 |pmid=3597777 |pmc=442198 |doi=10.1172/JCI113060 |url=}}</ref>
** Abnormal thrombopoiesis
** Autoantibody‐induced suppression of megakaryocytopoiesis<ref name="pmid12676790">{{cite journal |vauthors=Chang M, Nakagawa PA, Williams SA, Schwartz MR, Imfeld KL, Buzby JS, Nugent DJ |title=Immune thrombocytopenic purpura (ITP) plasma and purified ITP monoclonal autoantibodies inhibit megakaryocytopoiesis in vitro |journal=Blood |volume=102 |issue=3 |pages=887–95 |date=August 2003 |pmid=12676790 |doi=10.1182/blood-2002-05-1475 |url=}}</ref>
** Megakaryocitic nuclei and cytoplasm shows degenrative changes<ref name="pmid21013546">{{cite journal |vauthors=DAMESHEK W, MILLER EB |title=The megakaryocytes in idiopathic thrombocytopenic purpura, a form of hypersplenism |journal=Blood |volume=1 |issue= |pages=27–50 |date=January 1946 |pmid=21013546 |doi= |url=}}</ref>
**  
**  
** Antigen-presenting cells degrade glycoproteins and and not only degrade glycoprotein IIb/IIIa (light blue oval), thereby amplifying the initial immune response, but also may generate cryptic epitopes from other platelet glycoproteins
** Activated antigen-presenting cells
** express these novel peptides on the cell surface along with costimulatory help (represented in part by the interaction between CD154 and CD40) and the relevant cytokines that facilitate the proliferation of the initiating CD4-positive T-cell clones (T-cell clone 1) and those with additional specificities (T-cell clone 2)
** B-cell immunoglobulin receptors that recognize additional platelet antigens (B-cell clone 2) are thereby also induced to proliferate and synthesize anti–glycoprotein Ib/IX antibodies (green) in addition to amplifying the production of anti–glycoprotein IIb/IIIa antibodies (orange) by B-cell clone 1
* Autoreactive T lymphocyte‐mediated platelet lysis
** chronic AITP may be the result of an abnormal Th cell defect that could direct autoreactive B cells to differentiate and secrete IgG autoantibodies.
** act upon megakaryocytes in the bone marrow
** Antibody production in ITP appears to be driven by CD4-positive helper T cells reacting to platelet surface glycoproteins, possibly involving CD40:CD40L co-stimulation [32-34]. Splenic macrophages appear to be the major antigen-presenting cells [35]
*
'''immune‐mediated decreased platelet production:'''
* abnormal thrombopoiesis
* degenerative changes in both nuclei and cytoplasm
* reduced platelet turnover
* megakaryocyte damage
* autoantibody‐induced suppression of ''in vitro'' megakaryocytopoiesis
*
'''Acute AITP''' primarily affects children and often occurs after a viral or bacterial infection
* often follows an infectious event
* Antigenic mimicry (molecular structures on infectious or environmental agents that have similarities to host antigenic structures and stimulate an immune response that then cross-reacts with host antigens)
* T cells in this disorder are not necessarily directed at platelet antigens.
* antiplatelet antibodies are because of the antiviral antibodies cross-reacting with the patient's platelets.
* infectious agent is cleared and antibodies either disappear or affinity mature toward the infectious agent, the antiplatelet reactivity is lost
'''chronic AITP''' (platelet counts < 150 • 109]L for more than 6 months)) redominant in adults, with more women being affected than men
* true organ-specific autoimmune disorder
* no previous history of an infectious event and almost always requires some form of immunosuppressive therapy
* anti- 72 COOPAMAH ET AL body specificities are directed against several platelet glycoprotein epitopes
* associated with T-cellrelated and cytokine abnormalities
* '''Autoantibody‐induced platelet destruction:'''
** immune-targeted tissue abnormally expresses selfantigens that are then recognized by autoreactive Th cells.
**  
**  
*
*

Latest revision as of 18:27, 2 November 2018

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increased platelet destructionEditor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Auto-immune thrombocytopenic purpura is described by the increased platelet destruction due to production of auto-reactive antibodies against host platelets and suppression of platelet production in the bone marrow.

Pathophysiology

Pathogenesis

Acute ITP: Mainly affects children and usually follows a viral or bacterial infection

  • Antigenic mimicry - Similar molecular structures on both host cells and infectious agents, inducing a self immune response which cross reacts with the host antigens.
    • In acute ITP - anti-viral or anti-bacterial antibodies cross reacts against the patient's platelets.
  • Mostly acute ITP is self resolving as infectious agents and antibodies are cleared from the body, causing the loss of anti-platelet reactivity.
  • T cells are not involved in the parthenogenesis of acute ITP

Chronic ITP: (platelet counts < 150,000 x 109 per liter x 6 months) usually in adults

  • Increased platelet destruction:
    • Autoantibody‐induced platelet destruction
      • Abnormal IgG auto-antibody recognizes glyco-protein IIb/IIIa, glyco-protein Ib/IX complex, GP Ia/IIa, and GP VI etc[1]
      • Predominantly IgG auto-antibodies constitute the majority of antibodies but IgM and IgA antibodies can also be found in some of ITP patients.[2]
      • Auto-antibodies binds to the circulating platelet membranes through glyco-proteins
      • Auto-antibody-coated platelets induce Fcγ receptors and bind to antigen-presenting cells (Splenic macrophages or dendritic cells) in the reticulo-endothelial system[3][4]
      • The auto-antibody-coated platelets undergo phagocytosis by splenic macrophages and peripheral blood neutrophils.[5]
    • Autoreactive T lymphocyte‐mediated platelet lysis
      • Abnormal cytotoxic T cells defect leads to differentiation of direct autoreactive B cells further leading to secretion of IgG auto-antibodies[6]
      • Abnormal T cells includes cytotoxic T-lymphocyte (CD8+) and natural killer cells (CD3- CD16+ CD56+)[7]
      • CD4-positive helper T cells react with platelet surface glycoproteins, through co-stimulation involving CD40:CD40L
      • T cells act directly on the megakaryocytes in the bone marrow
  • Autoantibody‐mediated suppression of platelet production:
    • Decreased platelet turnover[8]
    • Abnormal thrombopoiesis
    • Autoantibody‐induced suppression of megakaryocytopoiesis[9]
    • Megakaryocitic nuclei and cytoplasm shows degenrative changes[10]

Genetics

Associated Conditions

Conditions associated with

Gross Pathology

On gross pathology, characteristic findings of itp include:

  • Acute
  • Chronic

Microscopic Pathology

On microscopic histopathological analysis, characteristic findings of itp include:

  • Acute
  • Chronic

References

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References

  1. ↑ McMillan R (March 2005). "The role of antiplatelet autoantibody assays in the diagnosis of immune thrombocytopenic purpura". Curr. Hematol. Rep. 4 (2): 160–5. PMID 15720967.
  2. ↑ McMillan R (March 2005). "The role of antiplatelet autoantibody assays in the diagnosis of immune thrombocytopenic purpura". Curr. Hematol. Rep. 4 (2): 160–5. PMID 15720967.
  3. ↑ Clarkson SB, Bussel JB, Kimberly RP, Valinsky JE, Nachman RL, Unkeless JC (May 1986). "Treatment of refractory immune thrombocytopenic purpura with an anti-Fc gamma-receptor antibody". N. Engl. J. Med. 314 (19): 1236–9. doi:10.1056/NEJM198605083141907. PMID 2939345.
  4. ↑ Shulman NR, Marder VJ, Weinrach RS (June 1965). "Similarities between known antiplatelet antibodies and the factor responsible for thrombocytopenia in idiopathic purpura. Physiologic, serologic and isotopic studies". Ann. N. Y. Acad. Sci. 124 (2): 499–542. PMID 5214832.
  5. ↑ Firkin BG, Wright R, Miller S, Stokes E (February 1969). "Splenic macrophages in thrombocytopenia". Blood. 33 (2): 240–5. PMID 5812817.
  6. ↑ Olsson B, Andersson PO, Jernås M, Jacobsson S, Carlsson B, Carlsson LM, Wadenvik H (September 2003). "T-cell-mediated cytotoxicity toward platelets in chronic idiopathic thrombocytopenic purpura". Nat. Med. 9 (9): 1123–4. doi:10.1038/nm921. PMID 12937414.
  7. ↑ Zhang F, Chu X, Wang L, Zhu Y, Li L, Ma D, Peng J, Hou M (May 2006). "Cell-mediated lysis of autologous platelets in chronic idiopathic thrombocytopenic purpura". Eur. J. Haematol. 76 (5): 427–31. doi:10.1111/j.1600-0609.2005.00622.x. PMID 16480433.
  8. ↑ Ballem PJ, Segal GM, Stratton JR, Gernsheimer T, Adamson JW, Slichter SJ (July 1987). "Mechanisms of thrombocytopenia in chronic autoimmune thrombocytopenic purpura. Evidence of both impaired platelet production and increased platelet clearance". J. Clin. Invest. 80 (1): 33–40. doi:10.1172/JCI113060. PMC 442198. PMID 3597777.
  9. ↑ Chang M, Nakagawa PA, Williams SA, Schwartz MR, Imfeld KL, Buzby JS, Nugent DJ (August 2003). "Immune thrombocytopenic purpura (ITP) plasma and purified ITP monoclonal autoantibodies inhibit megakaryocytopoiesis in vitro". Blood. 102 (3): 887–95. doi:10.1182/blood-2002-05-1475. PMID 12676790.
  10. ↑ DAMESHEK W, MILLER EB (January 1946). "The megakaryocytes in idiopathic thrombocytopenic purpura, a form of hypersplenism". Blood. 1: 27–50. PMID 21013546.

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