Antiplatelet autoantibody-related microparticles in patients with idiopathic (autoimmune) thrombocytopenic purpura

Nomura, Shosaku; Yanabu, Mutsumasa; Kakemoto, Hirofumi; Fukuroi, Tsutomu; Yamaguchi, Kazuyuki; Soga, Tetsuji; Nagata, Hirokazu; Kokawa, Terutoshi; Yasunaga, Kōjirō

doi:10.1007/bf01702922

Cited by 35 publications

(18 citation statements)

References 27 publications

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“…Also in ITP, a paradoxically increased risk of thrombosis has been described [25]. In-vivo platelet activation, circulating platelet-leukocyte-monocyte aggregates, platelet-derived microparticles, and immature reticulated platelets have all been implicated in the mechanism of a prothrombotic state in patients with ITP [26,27]. Reticulated platelets are immature platelets with increased mass and a greater prothrombotic potential compared with mature platelets [28–30].…”

Section: Discussionmentioning

confidence: 99%

Platelet count kinetics following interruption of antiretroviral treatment

Zetterberg

Neuhaus

Baker

et al. 2013

Aids

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Objectives To investigate the mechanisms of platelet kinetics in the Strategies for Management of Antiretroviral Therapy (SMART) study that demonstrated excess mortality with CD4 guided episodic antiretroviral therapy (ART) drug conservation compared with continuous treatment viral suppression. Follow-up analyses of stored plasma samples demonstrated increased activation of both inflammatory and coagulation pathways after stopping ART. Design SMART patients from sites that determined platelets routinely. Methods Platelet counts were retrospectively collected from 2206 patients from visits at study entry, and during follow-up. D-dimer levels were measured at study entry, month 1, and 2. Results Platelet levels decreased in the drug conservation group following randomization, but remained stable in the viral suppression group [median (IQR) decline from study entry to month 4: −24 000/µl (−54 000 to 4000) vs. 3000 (−22 000 to 24 000), respectively, P < 0.0001)] and the rate of developing thrombocytopenia (<100 000/µl) was significantly higher in the drug conservation vs. the viral suppression arm (unadjusted drug conservation/viral suppression [HR (95%CI) = 1.8 (1.2–2.7)]. The decline in platelet count among drug conservation participants on fully suppressive ART correlated with the rise in D-dimer from study entry to either month 1 or 2 (r = −0.41; P = 0.02). Among drug conservation participants who resumed ART 74% recovered to their study entry platelet levels. Conclusion Interrupting ART increases the risk of thrombocytopenia, but reinitiation of ART typically reverses it. Factors contributing to declines in platelets after interrupting ART may include activation of coagulation pathways or HIV-1 replication itself. The contribution of platelets in HIV-related procoagulant activity requires further study.

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Section: Discussionmentioning

confidence: 99%

Platelet count kinetics following interruption of antiretroviral treatment

Zetterberg

Neuhaus

Baker

et al. 2013

Aids

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“…17 PMPs generally express phosphatidylserine and are therefore considered to be procoagulant. 17 Increased numbers of circulating PMPs are also seen in other autoimmune thrombocytopenias, such as idiopathic thrombocytopenic purpura, 18 which is a disorder that is generally associated with an increased risk of bleeding. We posit that platelet activation and release of PMPs alone is unlikely to account for the increased thrombotic risk in patients with HIT.…”

Section: Introductionmentioning

confidence: 99%

PF4/heparin-antibody complex induces monocyte tissue factor expression and release of tissue factor positive microparticles by activation of FcγRI

Kasthuri

Glover

Jonas

et al. 2012

Blood

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Heparin-induced thrombocytopenia (HIT) is IntroductionHeparin-induced thrombocytopenia (HIT) is a well-recognized complication of heparin therapy and is one of the most common and potentially devastating causes of drug-induced thrombocytopenia. 1 Millions of Americans are exposed to heparin each year, resulting in thousands of cases of HIT annually. 2 Platelet factor 4 (PF4), a strongly cationic chemokine expressed by megakaryocytes and packaged into the ␣ granules of platelets, is released on platelet activation. 3 PF4 binds with high affinity to highly anionic molecules, such as heparin and endogenous heparin-like glycosaminoglycans (GAGs). 4 The precise physiologic role of PF4 in the regulation of coagulation is not known. 5 A subset of patients exposed to heparin develop autoantibodies (so called HIT Abs) against PF4/heparin complexes. 6,7 These Abs bind to specific epitopes on PF4, leading to the formation of trimeric complexes of PF4/heparin-IgG, which are referred to as HIT Ab complexes. 8,9 These complexes bind to platelets, resulting in platelet activation and the development of thrombocytopenia. 10 Immune complexes exert their effects on cells via engagement of specific Fc receptors. IgG Abs bind to Fc␥ receptors. In humans, 3 different classes of Fc␥Rs have been identified: Fc␥Rs I, II, and III. Fc␥RI is a high-affinity receptor and as such can also bind monomeric IgG as opposed to the low-affinity Fc␥Rs, Fc␥RII and Fc␥RIII, that only bind aggregated immunoglobulins or Ag-Ab complexes. 11 Fc␥RI is expressed on monocytes/macrophages, neutrophils, eosinophils, and dendritic cells. Fc␥RII is further subclassified into Fc␥RIIa and Fc␥RIIb. Fc␥RIIa is an activating receptor and is expressed on monocytes/macrophages, neutrophils, eosinophils, platelets, and Langerhans cells, whereas Fc␥RIIb is expressed on B lymphocytes and mast cells. In terms of function, Fc␥RIIb is the only inhibitory Fc␥R, and all the other Fc␥Rs result in activation of cells. 12 Fc␥RIII is subdivided into Fc␥RIIIa, which is expressed on natural killer cells and macrophages, and Fc␥RIIIb, which is expressed on eosinophils, neutrophils, macrophages, mast cells, and follicular dendritic cells. Binding of immune complexes to the activating Fc␥Rs leads to phosphorylation of the cytoplasmic immunoreceptor tyrosine-based activation motif by src-kinases, leading to activation of downstream signaling. 12 It has been found that platelet activation by HIT Ab complexes is mediated by engagement of the Fc␥RIIa receptor. 10 Most thrombocytopenias are associated with an increased risk of bleeding. However, the most-feared complication in HIT is the development of arterial and venous thrombosis. 13,14 The precise mechanism leading to thrombosis in HIT is unknown. It has been proposed that platelet activation and the release of platelet-derived microparticles (PMPs) may be responsible for thrombosis. 15,16 Microparticles (MPs) are sub-micron-sized membrane vesicles released on cell activation or apoptosis. 17 PMPs generally express phosphatidylserine a...

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“…A modification of the previously reported method was used [2][3][4], Gel-filtered platelets were stimulated with 10 gg/ml collagen plus 1.0 U/ml thrombin. Then unstimulated platelets or platelets stimulated with col lagen plus thrombin were fixed by incubation in 1 % paraformaldehyde at room temperature for 30 min.…”

Section: Flow Cytometry Assay O F Platelet Microparticlesmentioning

confidence: 99%

“…The functional significance o f these plateletderived microparticles is o f considerable in terest because they are rich in membrane receptors for coagulation factor Va and pro vide a catalytic surface for the prothrombinase reaction [2], Microparticles have been detected in various clinical situations associ ated with platelet activation, including im mune thrombocytopenic purpura [3][4][5], thrombotic diseases [6,7] and cardiopulmo nary bypass [8]. These observations suggest that microparticles may play a role in modu lating hemostasis and thrombosis, but the mechanism o f their production remains un resolved.…”

Section: Introductionmentioning

confidence: 99%

Participation of α<sub>IIb</sub>β<sub>3</sub> in Platelet Microparticle Generation by Collagen plus Thrombin

Nomura¹,

Komiyama

Matsuura

et al. 1996

Pathophysiol Haemos Thromb

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We investigated the role of α_IIbβ₃ in microparticle generation by normal and thrombasthenic platelets stimulated with collagen plus thrombin. Microparticle generation by normal platelets was scarcely inhibited by monoclonal antibodies for glyco-protein lb and glycoprotein IX. Although one monoclonal anti-α α_IIbβ₃ antibody (NNKY1-32) partly inhibited microparticle generation, 3 other monoclonal anti-α α_IIbβ₃ antibodies had little effect. However, the combination of 4 monoclonal anti- α_IIbβ₃ antibodies or treatment with a polyclonal anti- α_IIbβ₃ antibody significantly inhibited microparticle generation (p < 0.05). Microparticle generation by thrombasthenic platelets also occurred after stimulation with collagen plus thrombin, although at a significantly lower level compared with normal platelets. Monoclonal antibodies for resting α_IIbβ₃, P-selectin, activated α_IIbβ₃ and β₂-glycoprotein I bound to microparticles from healthy platelets. In contrast, only a monoclonal antibody for β₂-glycoprotein I bound to thrombasthenic microparticles. These results suggest that microparticle generation by collagen plus thrombin occurs via two different mechanisms which are dependent and independent of α_IIbβ₃, respectively. The α_IIbβ₃-dependent mechanism appears to require activation of α_IIbβ₃·

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Antiplatelet autoantibody-related microparticles in patients with idiopathic (autoimmune) thrombocytopenic purpura

Cited by 35 publications

References 27 publications

Platelet count kinetics following interruption of antiretroviral treatment

Platelet count kinetics following interruption of antiretroviral treatment

PF4/heparin-antibody complex induces monocyte tissue factor expression and release of tissue factor positive microparticles by activation of FcγRI

Participation of α<sub>IIb</sub>β<sub>3</sub> in Platelet Microparticle Generation by Collagen plus Thrombin

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