Massive image-based single-cell profiling reveals high levels of circulating platelet aggregates in patients with COVID-19

Nishikawa, Masako; Kanno, Hiroshi; Zhou, Yuqi; Xiao, Ting‐Hui; Suzuki, Takaya; Ibayashi, Yuma; Harmon, Jeffrey; Takizawa, Shigeo; Hiramatsu, Kazumasa; Nitta, Nao; Kameyama, Risako; Peterson, Walker; Takiguchi, Jun; Shifat‐E‐Rabbi, Mohammad; Zhuang, Yan; Yin, Xuwang; Rubaiyat, Abu Hasnat Mohammad; Deng, Yunjie; Zhang, Hongqian; Miyata, Shigeki; Rohde, Gustavo K.; Iwasaki, Wataru; Yatomi, Yutaka; Goda, Keisuke

doi:10.1038/s41467-021-27378-2

Cited by 50 publications

(59 citation statements)

References 53 publications

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“…An important component of severe acute COVID-19 disease accompanying pathological clotting, is virus-induced endotheliopathy resulting in systemic endotheliitis [111,[231][232][233][234][235]. Endotheliitis is central to initiating a state of failing normal clotting physiology and it is also known to be significantly linked to coagulopathies, as it activates microthrombotic pathways and initiates endotheliopathy-associated intravascular microthrombi [236].…”

Section: Endotheliopathymentioning

confidence: 99%

A central role for amyloid fibrin microclots in long COVID/PASC: origins and therapeutic implications

Kell

Laubscher

Pretorius

2022

Biochemical Journal

185

212

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Post-acute sequelae of COVID (PASC), usually referred to as ‘Long COVID’ (a phenotype of COVID-19), is a relatively frequent consequence of SARS-CoV-2 infection, in which symptoms such as breathlessness, fatigue, ‘brain fog’, tissue damage, inflammation, and coagulopathies (dysfunctions of the blood coagulation system) persist long after the initial infection. It bears similarities to other post-viral syndromes, and to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Many regulatory health bodies still do not recognize this syndrome as a separate disease entity, and refer to it under the broad terminology of ‘COVID’, although its demographics are quite different from those of acute COVID-19. A few years ago, we discovered that fibrinogen in blood can clot into an anomalous ‘amyloid’ form of fibrin that (like other β-rich amyloids and prions) is relatively resistant to proteolysis (fibrinolysis). The result, as is strongly manifested in platelet-poor plasma (PPP) of individuals with Long COVID, is extensive fibrin amyloid microclots that can persist, can entrap other proteins, and that may lead to the production of various autoantibodies. These microclots are more-or-less easily measured in PPP with the stain thioflavin T and a simple fluorescence microscope. Although the symptoms of Long COVID are multifarious, we here argue that the ability of these fibrin amyloid microclots (fibrinaloids) to block up capillaries, and thus to limit the passage of red blood cells and hence O2 exchange, can actually underpin the majority of these symptoms. Consistent with this, in a preliminary report, it has been shown that suitable and closely monitored ‘triple’ anticoagulant therapy that leads to the removal of the microclots also removes the other symptoms. Fibrin amyloid microclots represent a novel and potentially important target for both the understanding and treatment of Long COVID and related disorders.

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Section: Endotheliopathymentioning

confidence: 99%

A central role for amyloid fibrin microclots in long COVID/PASC: origins and therapeutic implications

Kell

Laubscher

Pretorius

2022

Biochemical Journal

185

212

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“…134 ). A remarkable application of the latest imaging technology for platelets in COVID-19 used large-scale single-cell platelet imaging by intelligent platelet morphometry 135 ; the investigators analyzed whole-blood samples to identify platelet aggregates in nearly 90% of all patients with COVID-19. TEM demonstrated uptake of SARS-CoV-2 through attachment to microparticles, independent of angiotensin-converting enzyme 2 (ACE2) (ref.…”

Section: Investigating Platelets In Covid-19mentioning

confidence: 99%

A guide to molecular and functional investigations of platelets to bridge basic and clinical sciences

Tyagi

Jain

et al. 2022

Nat Cardiovasc Res

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any studies in the past decade have elaborated the emerging functions of platelets beyond hemostasis and thrombosis. Molecular and functional studies have shown diverse roles of platelets in vascular integrity and remodeling, immunoregulation and tissue regeneration (Fig. 1). Although the function of platelets in the development and progression of cardiovascular diseases is well established, platelets were also demonstrated to be critical players in the pathophysiology of cancer, inflammatory diseases and infections such as that with severe acute respiratory syndrome coronavirus (SARS-CoV)-2, giving rise to COVID-19. Investigations of platelets and their heterogeneous states, platelet releasates and other target cells in various diseases have provided important mechanistic insights for diagnosis, prognosis and therapeutics. In this Review, we discuss the pathophysiological role of platelets and the latest developments in basic and clinical platelet methodologies. We also provide new insights into the development of guidelines for platelet investigation in which knowledge of underlying mechanisms might be important for diagnosis.

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“…Platelet-related markers such as the presence of platelet aggregates [ 76 ], platelet activation (high mean platelet volume (MPV) and high immature platelet fraction (IPF)) [ 77 ], and high immature platelet count (IPC) [ 78 ] have also recently been considered as predictors of poor prognosis. As platelets mature, their volume and MPV both decrease.…”

Section: Covid-19-associated Coagulopathymentioning

confidence: 99%

“…In COVID-19, low platelet count [ 59 , 60 ] and platelet hyperfunction [ 76 , 77 , 78 ] are important predictors of poor prognosis. Conditions with marked platelet activation and high consumption are thought to be associated with poor prognosis.…”

Section: Covid-19-associated Coagulopathymentioning

confidence: 99%

Coagulopathy and Fibrinolytic Pathophysiology in COVID-19 and SARS-CoV-2 Vaccination

Yamada

Asakura

2022

IJMS

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Coronavirus Disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is frequently complicated by thrombosis. In some cases of severe COVID-19, fibrinolysis may be markedly enhanced within a few days, resulting in fatal bleeding. In the treatment of COVID-19, attention should be paid to both coagulation activation and fibrinolytic activation. Various thromboses are known to occur after vaccination with SARS-CoV-2 vaccines. Vaccine-induced immune thrombotic thrombocytopenia (VITT) can occur after adenovirus-vectored vaccination, and is characterized by the detection of anti-platelet factor 4 antibodies by enzyme-linked immunosorbent assay and thrombosis in unusual locations such as cerebral venous sinuses and visceral veins. Treatment comprises high-dose immunoglobulin, argatroban, and fondaparinux. Some VITT cases show marked decreases in fibrinogen and platelets and marked increases in D-dimer, suggesting the presence of enhanced-fibrinolytic-type disseminated intravascular coagulation with a high risk of bleeding. In the treatment of VITT, evaluation of both coagulation activation and fibrinolytic activation is important, adjusting treatments accordingly to improve outcomes.

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Massive image-based single-cell profiling reveals high levels of circulating platelet aggregates in patients with COVID-19

Cited by 50 publications

References 53 publications

A central role for amyloid fibrin microclots in long COVID/PASC: origins and therapeutic implications

A central role for amyloid fibrin microclots in long COVID/PASC: origins and therapeutic implications

A guide to molecular and functional investigations of platelets to bridge basic and clinical sciences

Coagulopathy and Fibrinolytic Pathophysiology in COVID-19 and SARS-CoV-2 Vaccination

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