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MFI was measured by flow cytometry. Nonparametric tests were used to analyze the relationship between platelet count and time after infection. Prism software v. We observed a strong inverse correlation between platelet count and viral load in swabs of the throat Figure 1C and nose Figure 1D , as we initially observed in humans. Immunohistopathology and platelet electron microscopy of ferrets infected with different influenza viruses.

G-I Virus titer in homogenized organs heart, liver, and spleen at days 0. Dotted line represents the lower limit of detection. Adapted from Van den Brand et al 39 with permission. Red arrows: viruses. The bars represent nm. The bars bar represent nm. We hypothesized that the subtype-dependent degree of thrombocytopenia observed in the ferrets was the result of a different interaction between virus and platelet.

Therefore, we explored virus binding to isolated human platelets by using biolayer interferometry BLI in detail Figure 3A. Interestingly, although all binding affinities turned out to be similar, each virus approached a different saturation level Figure 3D. The saturation level is represented herein by the maximum wavelength shift, which corresponds to the maximum capacity of the virus to bind to platelets Figure 3C ; dotted horizonal line.

Influenza virus subtypes that bind to platelet sialoglycans. Red arrow: single platelet. B Determination of mean virus particle count by NTA. The K D value for PR8 9. D Enlargement of the dotted box in panel C. Estimated plateau values b are 3. Obtained threshold glycan densities are given above each curve. Both forms are abundantly present at the glycocalyx of human cells. They require a minimal glycan density of 1. Notably, this 2.

Interestingly, although this virus bound irreversibly at high glycan density We went on to investigate virus uptake by platelets, which we observed in our ferret model and which had been shown recently by others in more detail in humans.

Internalization of virus particles commenced within 1 minute at an estimated initial rate of 1 virus particle every 2 seconds. Uptake was completely abolished by the removal of the SA glycan receptors from the platelet surface, using exogenous NA Figure 4D. Previous studies had implicated the C-type lectin receptor DC-SIGN dendritic cell—specific intercellular adhesion molecule-3—grabbing nonintegrin in dengue virus binding to platelets, by showing the inhibition of primary platelet binding of dengue virus type 2 using an anti-DC-SIGN monoclonal antibody.

Virus phagocytosis by platelets is dependent on the presence of SAs. A Virus uptake over time by human platelets. Red arrows: internalized viruses. Error bars, standard error of the mean. C Temperature-dependent virus uptake. D Platelet desialylation with exogenous NA abolishes virus uptake. A key characteristic of platelet ageing is the gradual loss of SAs from the glycans abundantly present on their cell surface, which can also be accelerated by the intravenous injection of NA in mice.

Therefore, we considered that the influenza virus NA removed SAs from cell surface glycans and proposed the possibility that the interaction between platelets and viruses stimulates accelerated clearance of circulating platelets during influenza and thereby causes thrombocytopenia. Again, we observed that the degree of SA removal was dependent on virus subtype. Virus binding also resulted in the activation of these platelets by the increased expression of P-selectin CD62P on the platelet surface Figure 5B.

Platelet activation was dependent on virus concentration Figure 5C and was accompanied by platelet aggregation Figure 5D. The degree of platelet aggregation seemed to differ among virus strains and blood donors. This observation shows that virus-triggered platelet activation depends on the activity of the virus NA.

Platelet activation and aggregation upon binding of an influenza virus. B Virus activation of platelets in human plasma. Final virus concentration 50 pM. D Aggregation of platelets by influenza virus subtypes in 3 donors.

Thrombocytopenia is a well-known complication of viral and bacterial infection. We provided evidence to explain the mechanism of influenza virus-induced thrombocytopenia, 24,25,62 and showed how the influenza virus is associated with thrombocytopenia by direct interaction with platelets.

We explained this by showing the requirement of a 2. We showed virus particles in platelets isolated from the blood of infected ferrets Figure 2J-L and detected viral RNA in the heart, liver, and spleen of the animals as early as 12 hours after infection Figure 2G-I.

We propose that they are subsequently recognized and cleared from the blood in the liver, spleen, or intestinal tract. These observations together highlight their role in the early innate immune response to respiratory virus infection. Platelets fulfill key functions in pulmonary immune responses and inflammatory lung diseases. Because platelet activation is accompanied by the release of granules, this process may contribute to the cytokine storm associated with acute respiratory distress syndrome ARDS.

We previously showed in patients with influenza treated with OSC that platelet counts increase significantly during OSC therapy. We proposed an alternative mode of action by showing that NAI therapy inhibited platelet activation during influenza Figure 5B.

Platelet activation is not currently thought to play a major role during influenza. However, we believe a disturbed platelet function during influenza may have a strong impact on clinical outcome, especially in patients with an underlying cardiovascular medical condition. We propose that influenza viruses bind the GP-X-IV complex and, as a side effect, trigger downstream activation signaling, including the thromboxane A2 pathway.

We did not find such an inhibitory effect Figure 5E , indicating that DC-SIGN plays a minor role in the interaction between influenza viruses and platelets. In summary, the evidence supports an early platelet innate immune response in the respiratory tract, further clarifying the process of thrombocytopenia during influenza and other respiratory virus infections that are associated with acute cardiovascular and thrombotic events. This work was supported by grants from the European Hematology Association A.

Contribution: E. The current affiliation for J. The current affiliation for E. Sign In or Create an Account. Sign In. Skip Nav Destination Content Menu. Close Key Points. Article Navigation. Influenza-induced thrombocytopenia is dependent on the subtype and sialoglycan receptor and increases with virus pathogenicity A.

Gerard Jansen , A. This Site. Google Scholar. Judith van den Brand , Judith van den Brand. Malte Tieke , Malte Tieke. Arjan Barendrecht , Arjan Barendrecht. Kerstin Rohn , Kerstin Rohn. Geert van Amerongen , Geert van Amerongen. Koert Stittelaar , Koert Stittelaar. Albert Osterhaus , Albert Osterhaus. Thijs Kuiken , Thijs Kuiken. Jurriaan Huskens , Jurriaan Huskens. Marianne Boes , Marianne Boes. Coen Maas , Coen Maas. Erhard van der Vries Erhard van der Vries.

Blood Adv 4 13 : — Article history Submitted:. Cite Icon Cite. Visual Abstract View large Download slide. View large Download slide. Figure 1. View large Download PPT. Figure 2. Figure 3. Figure 4. Figure 5. Original data are available in response to an e-mail request to the corresponding author. Conflict-of-interest disclosure: The authors declare no competing financial interests. Search ADS. The lung is a site of platelet biogenesis and a reservoir for haematopoietic progenitors.

Comparison of different platelet count thresholds to guide administration of prophylactic platelet transfusion for preventing bleeding in people with haematological disorders after myelosuppressive chemotherapy or stem cell transplantation. Dual-track clearance of circulating bacteria balances rapid restoration of blood sterility with induction of adaptive immunity.

Amicus or adversary revisited: platelets in acute lung injury and acute respiratory distress syndrome. In vivo platelet activation in critically ill patients with primary influenza A H1N1. Thrombocytopenia as a mortality risk factor in acute respiratory failure in H1N1 influenza. Risk of myocardial infarction and stroke after acute infection or vaccination. This means that during the 14 day period if you change your mind or decide for any other reason that you do not want the goods, you can notify us of your decision to cancel the contract and receive a refund.

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