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Antibody-Mediated Thrombotic Diseases
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Antibody-Mediated Thrombotic Diseases

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Hematology".

Deadline for manuscript submissions: closed (10 July 2024) | Viewed by 19290

Special Issue Editors

Prof. Dr. Tamam Bakchoul

E-Mail Website
Guest Editor
1. Institute for Clinical and Experimental Transfusion Medicine (IKET), University Hospital of Tuebingen, Tuebingen, Germany
2. Centre for Clinical Transfusion Medicine, University Hospital of Tuebingen, Tuebingen, Germany
Interests: platelet; thrombocytopenia; hematology; coagulation disorders; thrombosis; transfusion medicine
Dr. Günalp Uzun

E-Mail Website
Guest Editor
Centre for Clinical Transfusion Medicine, University Hospital of Tuebingen, 72076 Tuebingen, Germany
Interests: vaccine-induced thrombotic thrombocytopenia; immune thrombocytopenia; platelet immunology; diagnosis of platelet disorders

Special Issue Information

Dear colleagues,

In recent years, our knowledge of the interplay between adaptive immunity and hemostasis has increased considerably. One aspect of this connection is the antibody-mediated activation of the coagulation system. Antibody-mediated thrombotic diseases include thrombotic thrombocytopenic purpura (TTP), heparin-induced thrombocytopenia (HIT), and antiphospholipid syndrome (APS). Antibody-mediated platelet activation also plays a role in COVID-19-induced coagulatopathy, in which thrombotic complications are an important prognostic factor. Recently, vaccine-induced immune thrombotic thrombocytopenia (VITT), a prothrombotic side effect of adenoviral vector-based COVID-19 vaccines, was added to this list of conditions with antibody-mediated thrombosis. Remarkable progress has been made recently in the diagnosis and treatment of thrombotic diseases. Platelet count and thrombosis are important clinical signs. It is critical to identify the cause responsible for thrombocytopenia, but this often proves difficult due to the complex comorbidities. Anticoagulation is the mainstay of treatment for thrombotic diseases, and novel therapeutics targeting the underlying mechanisms of platelet activation and thrombus formation are under investigation.

This Special Issue aims to show the latest achievements in the field of antibody-mediated thrombotic diseases, including, but not restricted to, clinical presentations, pathophysiological studies, current treatment progress, and future therapeutic perspectives, in order to obtain a comprehensive view of the state of the art of new trends in this area.

Prof. Dr. Tamam Bakchoul
Dr. Günalp Uzun
Guest Editors

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • thrombotic diseases
  • thrombotic thrombocytopenic purpura
  • TTP
  • heparin-induced thrombocytopenia
  • HIT
  • vaccine-induced immune thrombotic thrombocytopenia
  • VITT
  • antiphopholipid syndrome
  • APS

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Published Papers (7 papers)

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Research

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12 pages, 5919 KiB  
Article
Subsequent Vaccination against SARS-CoV-2 after Vaccine-Induced Immune Thrombotic Thrombocytopenia
by Günalp Uzun, Theresa Ringelmann, Stefanie Hammer, Jan Zlamal, Beate Luz, Marc E. Wolf, Hans Henkes, Tamam Bakchoul and Karina Althaus
J. Clin. Med. 2024, 13(18), 5462; https://doi.org/10.3390/jcm13185462 - 14 Sep 2024
Cited by 1 | Viewed by 1045
Abstract
Background: Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare but severe complication following vaccination with adenovirus vector-based COVID-19 vaccines. Antibodies directed against platelet factor 4 (PF4) are thought to be responsible for platelet activation and subsequent thromboembolic events in these patients. Since a [...] Read more.
Background: Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare but severe complication following vaccination with adenovirus vector-based COVID-19 vaccines. Antibodies directed against platelet factor 4 (PF4) are thought to be responsible for platelet activation and subsequent thromboembolic events in these patients. Since a single vaccination does not lead to sufficient immunization, subsequent vaccinations against COVID-19 have been recommended. However, concerns exist regarding the possible development of a new thromboembolic episode after subsequent vaccinations in VITT patients. Methods: We prospectively analyzed follow-up data from four VITT patients (three women and one man; median age, 44 years [range, 22 to 62 years]) who subsequently received additional COVID-19 vaccines. Platelet counts, anti-PF4/heparin antibody level measurements, and a functional platelet activation assay were performed at each follow-up visit. Additionally, we conducted a literature review and summarized similar reports on the outcome of subsequent vaccinations in patients with VITT. Results: The patients had developed thrombocytopenia and thrombosis 4 to 17 days after the first vaccination with ChAdOx1 nCoV-19. The optical densities (ODs) of anti-PF4/heparin antibodies decreased with time, and three out of four patients tested negative within 4 months. One patient remained positive even after 10 months post first vaccination. All four patients received an mRNA-based vaccine as a second vaccination against SARS-CoV-2. No significant drop in platelet count or new thromboembolic complications were observed during follow-up. We identified seven publications reporting subsequent COVID-19 vaccination in VITT patients. None of the patients developed thrombocytopenia or thrombosis after the subsequent vaccination. Conclusion: Subsequent vaccination with an mRNA vaccine appears to be safe in VITT patients. Full article
(This article belongs to the Special Issue Antibody-Mediated Thrombotic Diseases)
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11 pages, 1175 KiB  
Article
Antiphospholipid Antibody Testing in a Maximum Care Hospital: Method-Dependent Differences
by Marija Kocijancic, Thomas Goj, Andreas Peter, Reinhild Klein and Sebastian Hörber
J. Clin. Med. 2024, 13(15), 4528; https://doi.org/10.3390/jcm13154528 - 2 Aug 2024
Viewed by 842
Abstract
Background: Antiphospholipid antibody (aPL) testing is critical for the classification of antiphospholipid syndrome. The 2023 ACR/EULAR classification criteria recommend the use of enzyme-linked immunosorbent assays (ELISAs) and specific thresholds for aPL positivity. Since non-ELISA methods are increasingly used, we compared and evaluated ELISA [...] Read more.
Background: Antiphospholipid antibody (aPL) testing is critical for the classification of antiphospholipid syndrome. The 2023 ACR/EULAR classification criteria recommend the use of enzyme-linked immunosorbent assays (ELISAs) and specific thresholds for aPL positivity. Since non-ELISA methods are increasingly used, we compared and evaluated ELISA and non-ELISA aPL assays in a real-world maximum care hospital setting. Methods: Between January 2021 and June 2024, anticardiolipin (aCL; IgG and IgM) and anti-beta2 glycoprotein I (aß2GPI; IgG and IgM) antibodies were measured using ELISA (n = 5115) and a chemiluminescence-based automated immunoassay (CLIA) (n = 3820). Results of parallel testing were compared, and associations with clinical and laboratory characteristics were evaluated. Results: A total of 946 samples were tested using ELISA and CLIA in parallel. A total of 136 (14%) specimens were positive for at least one aPL, and 55 (6%) specimens were from patients diagnosed with APS. Among the latter, 47 (85%) and 41 (75%) patients were positive when ELISA- or CLIA-based aPL assays were used, respectively. After applying the >40 units threshold of the new classification criteria, the number of aPL-positive specimens was significantly lower. In the entire cohort, the agreement between ELISA and CLIA aPL assays was acceptable only for aß2GPI IgG; the results from the two methods did not agree for aCL IgG/IgM and aß2GPI IgM. In APS patients, the agreement between ELISA and CLIA aPL assays was acceptable for aß2GPI IgG and IgM but poor for aCL IgG and IgM. Antibody levels in APS patients were significantly higher using CLIA compared to ELISA. Conclusions: The method-dependent discrepancies between ELISA- and CLIA-based aPL assays regarding the quantitative and qualitative results are substantial. Both methods are suitable for APS classification, but the choice of aPL assay may influence the classification, and therefore, aPL results should be interpreted carefully in the clinical context. Full article
(This article belongs to the Special Issue Antibody-Mediated Thrombotic Diseases)
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11 pages, 975 KiB  
Article
A Long-Term Follow-Up Study in Immune-Mediated Thrombotic Thrombocytopenic Purpura: What Are the Outcomes?
by Maria Addolorata Bonifacio, Daniele Roselli, Claudia Pia Schifone, Alessandra Ricco, Angelantonio Vitucci, Lara Aprile, Maria Addolorata Mariggiò and Prudenza Ranieri
J. Clin. Med. 2023, 12(23), 7305; https://doi.org/10.3390/jcm12237305 - 25 Nov 2023
Viewed by 1206
Abstract
Endothelium damage triggers the multimeric protein von Willebrand factor (VWF) release and subsequent binding to platelets, which are recruited at sites of vascular injury. A complex and fragile equilibrium between circulating levels of von Willebrand factor and its metalloprotease, ADAMTS13, is responsible for [...] Read more.
Endothelium damage triggers the multimeric protein von Willebrand factor (VWF) release and subsequent binding to platelets, which are recruited at sites of vascular injury. A complex and fragile equilibrium between circulating levels of von Willebrand factor and its metalloprotease, ADAMTS13, is responsible for the hemostatic balance. However, the presence of autoantibodies targeting ADAMTS13 results in an increase in von Willebrand factor, mainly in its ultra-large multimers. The latter lead to platelet aggregation, the formation of thrombi and microangiopathic hemolytic anemia. This pathologic condition, known as immune-mediated thrombotic thrombocytopenic purpura (iTTP), occurs with high morbidity and a high rate of relapses. In this work, the long-term follow-up of 40 patients with iTTP is reported. We assessed ADAMTS13 activity, plasmatic VWF levels and the ADAMTS13/VWF ratio, comparing iTTP relapsing patients with remitting ones. A decrease in the ADAMTS13/VWF ratio, along with a reduced ADAMTS13 activity, could serve as predictive and sensitive biomarkers of incoming relapses. Full article
(This article belongs to the Special Issue Antibody-Mediated Thrombotic Diseases)
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Review

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18 pages, 835 KiB  
Review
Management of Heparin-Induced Thrombocytopenia: A Contemporary Review
by Jun Yen Ng, Melanie D’Souza, Felanita Hutani and Philip Choi
J. Clin. Med. 2024, 13(16), 4686; https://doi.org/10.3390/jcm13164686 - 9 Aug 2024
Viewed by 2215
Abstract
Heparin-induced thrombocytopenia (HIT) is a life- and limb-threatening immune-mediated emergency classically associated with heparin therapy. This review focuses on type II HIT, characterized by the development of antibodies against platelet-factor 4 (PF4) bound to heparin after exposure, causing life-threatening thrombocytopenia, arterial thrombosis, and/or [...] Read more.
Heparin-induced thrombocytopenia (HIT) is a life- and limb-threatening immune-mediated emergency classically associated with heparin therapy. This review focuses on type II HIT, characterized by the development of antibodies against platelet-factor 4 (PF4) bound to heparin after exposure, causing life-threatening thrombocytopenia, arterial thrombosis, and/or venous thrombosis. The high morbidity and mortality rates emphasize the need for early recognition and urgent intervention with discontinuation of heparin and initiation of non-heparin anticoagulation. We discuss the management of HIT with an emphasis on recent developments: (i) incorporating the phases of HIT (i.e., suspected, acute, subacute A and B, and remote) into its management, categorized according to platelet count, immunoassay, and functional assay results and (ii) direct-acting oral anticoagulants (DOACs), which are increasingly used in appropriate cases of acute HIT (off-label). In comparison to parenteral options (e.g., bivalirudin and danaparoid), they are easier to administer, are more cost-effective, and obviate the need for transition to an oral anticoagulant after platelet recovery. We also identify the knowledge gaps and suggest areas for future research. Full article
(This article belongs to the Special Issue Antibody-Mediated Thrombotic Diseases)
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14 pages, 308 KiB  
Review
Vaccine-Induced Immune Thrombotic Thrombocytopenia: Clinicopathologic Features and New Perspectives on Anti-PF4 Antibody-Mediated Disorders
by Yi Zhang, Anna-Lise Bissola, Jared Treverton, Michael Hack, Mark Lychacz, Sarah Kwok, Addi Arnold and Ishac Nazy
J. Clin. Med. 2024, 13(4), 1012; https://doi.org/10.3390/jcm13041012 - 9 Feb 2024
Cited by 5 | Viewed by 2598
Abstract
Introduction: Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare yet severe adverse complication first identified during the global vaccination effort against SARS-CoV-2 infection, predominantly observed following administration of the ChAdOx1-S (Oxford-AstraZeneca) and Ad26.CoV2.S (Johnson & Johnson/Janssen) adenoviral vector-based vaccines. Unlike other anti-platelet factor [...] Read more.
Introduction: Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare yet severe adverse complication first identified during the global vaccination effort against SARS-CoV-2 infection, predominantly observed following administration of the ChAdOx1-S (Oxford-AstraZeneca) and Ad26.CoV2.S (Johnson & Johnson/Janssen) adenoviral vector-based vaccines. Unlike other anti-platelet factor 4 (PF4) antibody-mediated disorders, such as heparin-induced thrombocytopenia (HIT), VITT arises with the development of platelet-activating anti-PF4 antibodies 4–42 days post-vaccination, typically featuring thrombocytopenia and thrombosis at unusual sites. Aim: To explore the unique properties, pathogenic mechanisms, and long-term persistence of VITT antibodies in patients, in comparison with other anti-PF4 antibody-mediated disorders. Discussion: This review highlights the complexity of VITT as it differs in antibody behavior and clinical presentation from other anti-PF4-mediated disorders, including the high incidence rate of cerebral venous sinus thrombosis (CVST) and the persistence of anti-PF4 antibodies, necessitating a re-evaluation of long-term patient care strategies. The nature of VITT antibodies and the underlying mechanisms triggering their production remain largely unknown. Conclusion: The rise in awareness and subsequent prompt recognition of VITT is paramount in reducing mortality. As vaccination campaigns continue, understanding the role of adenoviral vector-based vaccines in VITT antibody production is crucial, not only for its immediate clinical implications, but also for developing safer vaccines in the future. Full article
(This article belongs to the Special Issue Antibody-Mediated Thrombotic Diseases)
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33 pages, 5438 KiB  
Review
Autoimmune Heparin-Induced Thrombocytopenia
by Theodore E. Warkentin
J. Clin. Med. 2023, 12(21), 6921; https://doi.org/10.3390/jcm12216921 - 3 Nov 2023
Cited by 11 | Viewed by 6998
Abstract
Autoimmune thrombocytopenia (aHIT) is a severe subtype of heparin-induced thrombocytopenia (HIT) with atypical clinical features caused by highly pathological IgG antibodies (“aHIT antibodies”) that activate platelets even in the absence of heparin. The clinical features of aHIT include: the onset or worsening of [...] Read more.
Autoimmune thrombocytopenia (aHIT) is a severe subtype of heparin-induced thrombocytopenia (HIT) with atypical clinical features caused by highly pathological IgG antibodies (“aHIT antibodies”) that activate platelets even in the absence of heparin. The clinical features of aHIT include: the onset or worsening of thrombocytopenia despite stopping heparin (“delayed-onset HIT”), thrombocytopenia persistence despite stopping heparin (“persisting” or “refractory HIT”), or triggered by small amounts of heparin (heparin “flush” HIT), most cases of fondaparinux-induced HIT, and patients with unusually severe HIT (e.g., multi-site or microvascular thrombosis, overt disseminated intravascular coagulation [DIC]). Special treatment approaches are required. For example, unlike classic HIT, heparin cessation does not result in de-escalation of antibody-induced hemostasis activation, and thus high-dose intravenous immunoglobulin (IVIG) may be indicated to interrupt aHIT-induced platelet activation; therapeutic plasma exchange may be required if high-dose IVIG is ineffective. Also, aHIT patients are at risk for treatment failure with (activated partial thromboplastin time [APTT]-adjusted) direct thrombin inhibitor (DTI) therapy (argatroban, bivalirudin), either because of APTT confounding (where aHIT-associated DIC and resulting APTT prolongation lead to systematic underdosing/interruption of DTI therapy) or because DTI inhibits thrombin-induced protein C activation. Most HIT laboratories do not test for aHIT antibodies, contributing to aHIT under-recognition. Full article
(This article belongs to the Special Issue Antibody-Mediated Thrombotic Diseases)
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20 pages, 6124 KiB  
Review
Vaccine-Induced Immune Thrombocytopenia and Thrombosis (VITT)—Insights from Clinical Cases, In Vitro Studies and Murine Models
by Venkata A. S. Dabbiru, Luisa Müller, Linda Schönborn and Andreas Greinacher
J. Clin. Med. 2023, 12(19), 6126; https://doi.org/10.3390/jcm12196126 - 22 Sep 2023
Cited by 2 | Viewed by 3466
Abstract
An effective worldwide vaccination campaign started and is still being carried out in the face of the coronavirus disease 2019 (COVID-19) pandemic. While vaccines are great tools to confront the pandemic, predominantly adenoviral vector-based vaccines can cause a rare severe adverse effect, termed [...] Read more.
An effective worldwide vaccination campaign started and is still being carried out in the face of the coronavirus disease 2019 (COVID-19) pandemic. While vaccines are great tools to confront the pandemic, predominantly adenoviral vector-based vaccines can cause a rare severe adverse effect, termed vaccine-induced immune thrombocytopenia and thrombosis (VITT), in about 1 in 100,000 vaccinated individuals. VITT is diagnosed 5–30 days post-vaccination and clinically characterized by thrombocytopenia, strongly elevated D-dimer levels, platelet-activating anti-platelet factor 4 (PF4) antibodies and thrombosis, especially at atypical sites such as the cerebral venous sinus and/or splanchnic veins. There are striking similarities between heparin-induced thrombocytopenia (HIT) and VITT. Both are caused by anti-PF4 antibodies, causing platelet and leukocyte activation which results in massive thrombo-inflammation. However, it is still to be determined why PF4 becomes immunogenic in VITT and which constituent of the vaccine triggers the immune response. As VITT-like syndromes are increasingly reported in patients shortly after viral infections, direct virus-PF4 interactions might be most relevant. Here we summarize the current information and hypotheses on the pathogenesis of VITT and address in vivo models, especially murine models for further studies on VITT. Full article
(This article belongs to the Special Issue Antibody-Mediated Thrombotic Diseases)
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