Thrombotic risk in patients with immune thrombocytopenia and its association with antiphospholipid antibodies

Kim, Ki-Jo; Baek, In‐Cheol; Yoon, Chong‐Hyeon; Kim, Wan‐Uk; Cho, Chul-Soo

doi:10.1111/bjh.12318

Cited by 55 publications

(42 citation statements)

References 32 publications

(69 reference statements)

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“…‘Annualised’ cumulative incidence and risk . Following ITP diagnosis, the pooled ‘annualised’ cumulative risk for TE was 2.97%/yr (Fig. ) and the pooled ‘annualised’ cumulative incidence for TE was 1.29%/yr (Figure S2, Supporting information).…”

Section: Resultsmentioning

confidence: 99%

Thromboembolism in adults with primary immune thrombocytopenia: a systematic literature review and meta‐analysis

Doobaree

Nandigam

Bennett

et al. 2016

European J of Haematology

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Adults with primary immune thrombocytopenia (ITP) may be susceptible to thromboembolism (TE). The objective of this systematic review was to evaluate studies that reported the prevalence and risk of developing TE in the ITP population from ITP diagnosis and splenectomy. We searched several bibliographic databases and included 29 studies. Using meta-analytical techniques, the pooled prevalence of TE before ITP diagnosis was 7.84% (arterial 6.25%; venous 1.95%). The pooled 'annualised' cumulative incidence (without prior TE) and cumulative risk (irrespective of prior TE) were 1.29%/yr and 3.00%/yr, respectively. Splenectomised patients had pooled cumulative risk of arterial TE (ATE) and venous TE (VTE) of 0.19%/yr and 1.10%/yr, respectively. In cohorts, regardless of a history of TE, the pooled relative risk (RR) of any TE was 1.60 (1.34, 1.86) for ITP vs. ITP-free individuals [arterial: 1.52 (1.25, 1.80); venous: 1.70 (0.96, 2.43)]. Splenectomised patients were at higher risk of venous events, pooled RR 2.39 (1.61, 3.17). To conclude, we found an increased risk of TE (mainly ATE) among ITP individuals and a higher risk of VTEs after splenectomy. How intrinsic (ITP pathophysiology, age, gender) and extrinsic factors (treatment) contribute to this risk could not be investigated here but is a task for future studies. Primary immune thrombocytopenia (ITP) in adults is a rare heterogeneous blood disorder which is characterised by a reduced peripheral blood platelet count below 100 9 10 9 /L (1). Its underlying mechanisms are increasingly explained within an 'autoimmune' paradigm in which platelets are destroyed through antibody-mediated destruction and thrombocytopoiesis is reduced through immune-mediated megakaryocytic downregulation (2).Although bleeding is a prominent feature of the disease, patients often present with other comorbid conditions at ITP diagnosis or throughout the course of the disease (3, 4). Notably, there are studies that showed that the risk of thromboembolic events (TE) could be elevated among patients with ITP (4, 5) and also among patients who had ITP-related splenectomies (6). How such a paradoxical 'prothrombotic and thrombocytopenic' state coexists is not completely understood. One likely explanation for this heightened risk for TE is that the ITP pathophysiology promotes a prothrombotic state but the evidence is unclear and weak (7-9). On the other hand, the distribution and influence of typical prothrombotic risk factors, including obesity, smoking, family history of TE, and the impact of ITP-related treatments, such as long-term corticosteroid use or splenectomy, on the risk of TE in ITP have been not completely described and explained. Before engaging into investigative studies on the contributory factors of TE in ITP, it is important to review the published evidence to date to establish whether there is a heightened risk of TE in the ITP population.

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Section: Resultsmentioning

confidence: 99%

Thromboembolism in adults with primary immune thrombocytopenia: a systematic literature review and meta‐analysis

Doobaree

Nandigam

Bennett

et al. 2016

European J of Haematology

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“…41 One potential explanation for this difference may be that in HIT, monocytes, neutrophils, and endothelial cells are targeted for activation as well. 11,36,42,43 However, the involvement and mechanism by which these cells contribute to thrombosis has received far less attention than platelets.…”

Section: Discussionmentioning

confidence: 99%

Platelet transactivation by monocytes promotes thrombosis in heparin-induced thrombocytopenia

Tutwiler

Madeeva

Ahn

et al. 2016

Blood

125

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• The procoagulant nature of HIT can be simulated in a microfluidic model using human blood and its components.• PF4/glycosaminoglycans/ immunoglobulin G complexes activate monocytes through FcgRIIA to generate TF and thrombin, leading to coated platelets in HIT.Heparin-induced thrombocytopenia (HIT) is characterized by a high incidence of thrombosis, unlike other antibody-mediated causes of thrombocytopenia. We have shown that monocytes complexed with surface-bound platelet factor 4 (PF4) activated by HIT antibodies contribute to the prothrombotic state in vivo, but the mechanism by which this occurs and the relationship to the requirement for platelet activation via fragment crystallizable (Fc)gRIIA is uncertain. Using a microfluidic model and human or murine blood, we confirmed that activation of monocytes contributes to the prothrombotic state in HIT and showed that HIT antibodies bind to monocyte FcgRIIA, which activates spleen tyrosine kinase and leads to the generation of tissue factor (TF) and thrombin. The combination of direct platelet activation by HIT immune complexes through FcgRIIA and transactivation by monocyte-derived thrombin markedly increases Annexin V and factor Xa binding to platelets, consistent with the formation of procoagulant coated platelets. These data provide a model of HIT wherein a combination of direct FcgRIIA-mediated platelet activation and monocyte-derived thrombin contributes to thrombosis in HIT and identifies potential new targets for lessening this risk. (Blood. 2016;127(4):464-472) IntroductionHeparin-induced thrombocytopenia (HIT) is an iatrogenic, immunemediated disorder characterized by antibodies that recognize complexes between the platelet chemokine platelet factor 4 (PF4, CXCL4) and heparin or cell surface glycosaminoglycans (GAGs). 1,2 It is estimated that up to 50% of patients with HIT develop thrombosis that might be limb-and/or life-threatening. [3][4][5] Even with early recognition, cessation of heparin, and institution of alternative forms of anticoagulation, recurrent thromboembolic complications may occur and 10% to 20% of patients go on to amputation and/or death. 6 Thus, there is a need for a better understanding of the pathogenesis of HIT and to determine how this information can be used to mitigate the risk of thrombosis.Thrombocytopenia and thrombosis in HIT have been attributed to binding of PF4/heparin/immunoglobulin G (IgG) immune-complexes to the platelets through the IgG fragment crystallizable (Fc) region, which activates platelets through their immunoreceptor tyrosine-based activation motif (ITAM) receptor, FcgRIIA. 7,8 However, monocytes, endothelial cells, and other cell types might also be activated by these immune complexes and contribute to the underlying pathology, 9 but their contribution to the process is less well characterized. Indeed, recent evidence suggests that thrombosis in HIT is initiated by binding of pathogenic antibodies to antigenic complexes of PF4 and GAGs expressed by the endothelium as well as circulating cells, includi...

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“…102 APLA occurs in up to 40% of patients with ITP. 103 While these antibodies do not alter the course of ITP, several studies suggest that the presence of APLA, particularly the lupus anticoagulant, increase the risk of thrombosis, 103,104 with 5-year thrombosis free-survival of 39.9% and 97.7%, respectively, in patients with ITP and LA, versus ITP alone. A small study reported no significant increase in thrombotic events after splenectomy in patients with ITP and APLA, though there was a trend towards more arterial events.…”

Section: Systemic Lupus Erythematosus (Sle) and Antiphospholipid Antimentioning

confidence: 99%

Splenectomy for immune thrombocytopenia: down but not out

Chaturvedi

Arnold

McCrae

2018

Blood

158

154

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word count: 239Word count: 4298 ABSTRACTSplenectomy is an effective therapy for steroid-refractory or dependent immune thrombocytopenia (ITP). With the advent of medical alternatives such as rituximab and thrombopoietin receptor antagonists (TPO-RA), the use of splenectomy has declined and is generally reserved for patients that fail multiple medical therapies. Splenectomy removes the primary site of platelet clearance and autoantibody production, and offers the highest rate of durable response (50-70%) compared to other ITP therapies. However, there are no reliable predictors of splenectomy response, and long-term risks of infection and cardiovascular complications must be considered. Since the long-term efficacy of different second-line medical therapies for ITP have not been directly compared, treatment decisions must be made without supportive evidence. Splenectomy continues to be a reasonable treatment option for many patients, including those with an active lifestyle who desire freedom from medication and monitoring, and patients with fulminant ITP that does not respond well to medical therapy. We try to avoid splenectomy within the first 12 months after ITP diagnosis for most patients to allow for spontaneous or therapy-induced remissions, particularly in older patients who have increased surgical morbidity and lower rates of response, and in young children. Treatment decisions must be individualized based on patients' comorbidities, lifestyles and preferences. Future research should focus on comparing long-term outcomes of patients treated with different second line therapies, and on developing personalized medicine approaches to identify subsets of patients most likely to respond to splenectomy or other therapeutic approaches.

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Thrombotic risk in patients with immune thrombocytopenia and its association with antiphospholipid antibodies

Cited by 55 publications

References 32 publications

Thromboembolism in adults with primary immune thrombocytopenia: a systematic literature review and meta‐analysis

Thromboembolism in adults with primary immune thrombocytopenia: a systematic literature review and meta‐analysis

Platelet transactivation by monocytes promotes thrombosis in heparin-induced thrombocytopenia

Splenectomy for immune thrombocytopenia: down but not out

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