Vaccines from Oxford/AstraZeneca and Johnson & Johnson Cause Blood Clots?

choi

Papers just come out.

(1) yesterday (Friday)

Scully M et al, Pathologic Antibodies to Platelet Factor 4 after ChAdOx1 nCoV-19 Vaccination. New England Journal of Medicine _: _ (online publication Apr 16, 2021).
https://www.nejm.org/doi/full/10.1056/NEJMoa2105385

Quote from abstract:

"METHODS[:] We report findings in 23 patients who presented with thrombosis and thrombocytopenia 6 to 24 days after receiving the first dose of the ChAdOx1 nCoV-19 vaccine (AstraZeneca). On the basis of their clinical and laboratory features, we identify a novel underlying mechanism and address the therapeutic implications.

"RESULTS [:] In the absence of previous prothrombotic medical conditions, 22 patients presented with acute thrombocytopenia [thrombocyte = platelets] and thrombosis, primarily cerebral venous thrombosis, and 1 patient presented with isolated thrombocytopenia and a hemorrhagic phenotype. All the patients had low or normal fibrinogen levels and elevated d-dimer levels at presentation. No evidence of * * * causative precipitants was identified. Testing for antibodies to platelet factor 4 (PF4) was positive in 22 patients (with 1 equivocal result) and negative in 1 patient.

Note:
(a) Marie Scully is the principal investigator. At the end of this report is: "Address reprint requests to Prof Scully at the Department of Haematology, University College London Hospitals NHS Foundation Trust, 250 Euston Rd., London NW1 2PG, United Kingdom."
(i) Professor Marie Scully. University College London Hospitals NHS Foundation Trust, undated
https://www.uclh.nhs.uk/our-serv ... fessor-marie-scully  
(right table: Location: University College Hospital)
(A) Her degree is MD. I fail to find her education.
(B) John Sculley was Apple Inc's CEO 1983-1993
(C) The Irish name Scully is "from [Gaelic] scolaidhe scholar." Dictionary of American Family Names, by Oxford Univ Press.
(ii) University College London Hospital
https://en.wikipedia.org/wiki/University_College_Hospital
("The hospital was founded as the North London Hospital in 1834, eight years after UCL (then known as the London University), in order to provide clinical training for the 'medical classes' of the university * * * [new hospital] opened in 2005")
(A) This photo shows the tall building is of the same color is part of the new hospital.

University College Hospital, UCLH Arts. undated
https://artuk.org/visit/venues/u ... ital-uclh-arts-5947
(B) from the Web: "UCLH Arts is the hospital arts programme which serves UCLH NHS Foundation Trust and its surrounding community. It organises exhibitions, music performances and other cultural events for the benefit of patients, staff and members of the general public."

(b) The research on the cause and correlation of blood clot is developing. So you need not pay too much attention to it, until the theory is confirmed, including what causes blood clot. Note the quotation above: "No evidence of * * * causative precipitants was identified."


(2) A picture is worth a thousand words.

Cai Z et al, Structural Features and PF4 Functions that Occur in Heparin-Induced Thrombocytopenia (HIT) Complicated by COVID-19. Antibodies 9: 52 (published Oct 10, 2020; "This article belongs to the Special Issue Antibodies, B Cell Responses and Immune Responses to SARS-CoV-2 Infections")
https://www.mdpi.com/2073-4468/9/4/52/htm

Quote:

"1. Introduction[:] Platelet factor 4 (PF4, CXCL4) is a small chemokine protein released by activated platelets [1]. The mature size of PF4 is 70-amino-acid protein, or 7.8 kDa [Da = dalton, a unit of mass; 1 dalton is ABOUT the mass (weight) of a proton or neutron]. Its major physiological function is to promote blood coagulation. This function is related to PF4's affinity for heparin and other glycosaminoglycans (GAGs), which are long linear polysaccharides consisting of repeating disaccharide units. By neutralizing the negatively charged heparan sulfate side chains of GAGs on the surface of platelets and endothelial cells, PF4 facilitates platelet aggregation to form a thrombus." (citations omitted).

"2. Platelets and Viral Infection of the Lung[:] * * * The Fcγ receptor, FcγRIIA, is expressed on the surface of activated platelets and is responsible for the endocytosis of immunoglobulin G (IgG) coated pathogens. * * *

"4. Structural Basis for PF4 Function: Binding Activity of PF4 to Polysaccharides[:] Heparin is a naturally occurring GAG * * * GAGs are long linear polysaccharides consisting of repeating disaccharide units.

"6. Structural Basis for Heparin-Induced Thrombocytopenia (HIT)[:] PF4 is a cationic monomeric protein with a propensity to form tetramers that assemble into oligomers in the presence of polyanions [such as heparin]. * * * Not all PF4 antibodies are pathogenic and lead to HIT. Pathogenic HIT antibodies are known to bind PF4 in the presence of heparin. However, current clinical tests are not effective to determine whether the PF4 antibodies are pathogenic or non-pathogenic. Arepally and colleagues identified that the murine monoclonal antibody KKO forms PF4/heparin complexes and causes heparin-induced thrombosis and thrombocytopenia in a murine model, thus classifying KKO as a pathogenic antibody. * * * To understand how PF4 structurally interacts with heparin and pathogenic HIT antibodies, our laboratory successfully crystallized PF4 in complex with fondaparinux [64]. More importantly, we also obtained the crystal structure of PF4 tetramer with the pathogenic antibody KKO [64]." (citations omitted except reference No 64; brackets containing 64 are original).

Note:
(a)
(i) The last author is the principal investigator: 张洪涛.

Hongtao Zhang. Research Associate Professor, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, undated
https://www.med.upenn.edu/apps/faculty/index.php/g275/p19412
("Education: BS (Biochemistry) Beijing University, China, 1991. MS (Molecular Biology) Beijing University, China, 1994. PhD (Pharmacology) University Of Pennsylvania, 1998")

It is unusual to get a biological PhD in US in four years.
(ii) This article is a review, not an original repot of research. None of the references (at the bottom of the article) is from Zhang himself.

(b) One could read
Plate Factor 4 in en.wikipedia.org
, which is short and says little (but maybe good enough for a layperson). But it is important for me to point out -- and the Wikipedia does not (much explain) -- that the scheme of the 3-dimentional structure is a tetramer, not monomer, of platelet factor 4.

(c) Follow me with Zhang's article. Read only quotations above, and view figures exclusively.
(i) KKO is the name of the monoclonal antibody from mouse. No need to know why it gets the name, as we must name the antibody somehow.
(ii)
(A) Figure 1 in the right upper corner demonstrates one disaccharide unit that would repeat linearly multiple times. Critically, the right one (of the two) contains an N (nitrogen, part of an amino group (-NH2) ).
(B) "The discovery of heparin was announced in 1916."  en.wikipedia.org for Heparin.
(C) Here is the story of the discovery:
Gregory B Lim, Discovery and Purification of Heparin. Nature Reviews Cardiology _: _ (2017).
https://www.nature.com/articles/nrcardio.2017.171.pdf
https://www.nature.com/articles/nrcardio.2017.171
(D) "Heparin is made by the liver, lungs, and other tissues in the [human] body." National Cancer Institute."
(iii) Figure 2 shows the gross structure of heparin (colored in red) + KKO (only an Fab is present; colored in blue AND gray) + three of four PF4s (colored in various shades of green; the fourth can not be seen in this view, because it is in the back).
(iv) Figure 3(A) has two (linked) Fabs with a tetrameric PF4 (4 monomers, respectively colored in magenta, cyan, green and yellow).

(d) I will now explain:
(i) Fab stands for  
Fragment antigen-binding
https://en.wikipedia.org/wiki/Fragment_antigen-binding
("[section ]1 Preparation[:] * * * The enzyme papain [an enzyme from papaya] can be used to cleave an immunoglobulin monomer into two Fab fragments and an Fc fragment [as shown in middle panel of the figure in this section]."
(A) Compared with the left panel, one may see that a Fab consists of one light chain and part of one heavy chain -- the other part of a heavy chain forms half of Fc (Fragment crystallizable region).
https://en.wikipedia.org/wiki/Fragment_crystallizable_region
(B) Note (c)(iv) above displays Figure 3(A) has two Fab linked by a chain. Return to section 1 Preparation of the preceding Wiki page. This -- two Fab linked by a chain -- is created by pepsin (an enzyme from stomach). See right panel.  
(C) In Figures both 2 and 3 of Zhang's article, blue and gray represents one light chain plus part of one heavy chain. The article does not specify which color represents light or heavy chain.
(ii) C-X-C motif chemokine
https://proteopedia.org/wiki/index.php/C-X-C_motif_chemokine
("C-X-C motif chemokine [ligand] (CXCL) are small chemokines which contain the sequence Cys-X-Cys at their C-terminal")
(A) a chemokine is a kind of cytokines.
(B) cytokine (n; from rom cyto- + Ancient Greek kínēsis movement)
https://en.wiktionary.org/wiki/cytokine
(C) Cys means amino acid cysteine. X means any other amino acids. The figure shows sulfate ions, with oxygen atoms in red and one sulfur atom in yellow.
(iii) In humans, extraneous heparin forms a complex with PF4, which specific antibodies bind. The Fc portions of the complex attach it (complex) to platelets, which next releases C-X-C motif ligand CXCL4.