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Introduction: Scientists have found the cause of blood clots caused by AstraZeneca's new crown vaccine! The researchers found that the vaccine caused some people to develop antibodies to the platelet factor 4 protein, which promotes platelet function and activates the coagulation cascade to cause blood to clot.
The new crown vaccine is the most important countermeasure against new crown pneumonia.
From December 2020 to March 2021, the European Medicines Agency approved 4 vaccines, namely: the mRNA vaccine (BNT162b2) of BioNTech and Pfizer, the mRNA vaccine of Moderna (mRNA-1273), British AstraZeneca vaccine (ChAdOx1 nCov-19) and Ad26.
COV2.
S vaccine (Johnson & Johnson/Janssen).
As of April 7, 2021, the EU has received more than 82 million doses of vaccine; in Germany, about a quarter of vaccinators have received the AstraZeneca vaccine.
Beginning in late February 2021, several abnormal thrombotic events have been observed in patients after vaccination with AstraZeneca, accompanied by thrombocytopenia.
The first case In mid-February 2021 (day 0), a previously healthy 49-year-old medical staff received her first dose of AstraZeneca vaccine.
In the next few days, she developed fatigue, myalgias and headaches.
From the 5th day, she developed chills, fever, nausea and upper abdominal discomfort; on the 10th day she was admitted to the local hospital.
The laboratory test results are shown in Table 1.
The platelet count is 18,000 per cubic millimeter, and the D-dimer level is 35 mg per liter (reference value, <0.
5).
Computed tomography (CT) shows portal vein thrombosis and peripheral pulmonary embolism.
This patient died on the 11th day.
In addition to the medical results of the diagnosis, the autopsy also found cerebral venous thrombosis.
Table 1: Laboratory characteristics of the first case doi: 10.
1056/NEJMoa2104840 series of cases By March 15, 2021, another 10 patients were found to have one or more types of thrombosis 5 to 16 days after vaccination with AstraZeneca complication.
Thrombotic events included cerebral venous thrombosis (9 cases), splenic vein thrombosis (3 cases), pulmonary embolism (3 cases) and other types of thrombosis (4 cases); 5 out of 10 patients had more than one type of thrombosis Thrombotic events.
In this analysis, one patient (patient 11) had a fatal cerebral hemorrhage.
Clinical and laboratory characteristics of 11 patients Among these patients, the median age was 36 years (range 22 to 49 years); 9 of the 11 patients were women.
All patients were accompanied by thrombocytopenia.
None of these patients had received heparin treatment before the onset of symptoms or the diagnosis of thrombosis.
In view of the significant clinical similarity between this disease and autoimmune heparin-induced thrombocytopenia (a prothrombotic thrombocytopenia caused by heparin and certain other anions, which is characterized by heparin independent of platelet activation properties).
, The researchers obtained serum from 9 patients to study platelet activation antibodies against platelet factor 4 (PF4)-heparin.
The relevant research results will be published online in the NEJM journal on April 9, 2021.
Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccinationdoi: 10.
1056/NEJMoa2104840 In order to measure direct antibody binding, the researchers used two immunoassays: one is PF4-heparin enzyme-linked immunosorbent assay (ELISA) and the other is PF4 ELISA, which measures antibody binding by secondary anti-human IgG.
According to the optical density unit, the reactivity in ELISA is defined as strong (≥2.
00), medium (1.
00～1.
99) or weak (0.
50～0.
99). In the PF4 enhanced platelet activation test, the reactivity is graded according to the time elapsed before platelet aggregation.
The shorter the reaction time, the stronger the platelet activation (strong activation, 1 to 5 minutes; moderate activation,> 5 to 15 minutes; Weak activation, >15 to 30 minutes).
The author purified platelets from whole blood (obtained from healthy volunteers).
The platelets were pre-incubated with AstraZeneca vaccine (1:2000 dilution) in buffer and washed before use.
The washed platelets (75 microliters) were incubated with buffer, low molecular weight heparin (LMWHs) or PF4 (Chromatec) in the presence or absence of FcγIIa receptor blocking antibody IV.
3.
In some experiments, unfractionated heparin (UFH) (100 IU per milliliter) was added to inhibit PF4-dependent reactions, or AstraZeneca vaccine (1:50 dilution) was added to each well.
The serum was incubated with PF4 and platelets in the presence of immunoglobulin (Privigen IVIG) at a concentration of 10 mg per milliliter.
After establishing the test conditions using the sera of the initial four patients (i.
e.
, patients 1 to 4), the authors studied another 24 serum samples that were positive on immunoassays in order to verify their findings.
They called this modified platelet activation test the PF4 enhanced platelet activation test.
The results of the study found that the sera of patients 1-4 showed strong reactivity in the PF4-heparin ELISA test, with an optical density exceeding 3.
00 units (reference value, <0.
50) (as shown in the figure below).
In addition, the author noted with interest In the clinical course of patient 2, the patient developed pulmonary embolism and mild thrombocytopenia (platelet count, 107,000 per cubic millimeter), and there was no diffuse intravascular coagulation.
The patient received a therapeutic dose of low-molecular-weight heparin (LMWHs) for 3 days, clinically improved, and the platelet count increased to 132000; at this time, the PF4-heparin ELISA result was positive, and he switched to oral apixaban (apixaban), clinical and experimental The room continued to recover.
Panel A shows the serological characteristics of the 4 initial patients, which were evaluated by the platelet activation test.
Three of the four serum samples showed weak to moderate reactivity under the buffer control, and this reactivity can be inhibited by low molecular weight heparin.
By adding heparin (UFH) (100IU per milliliter), all reactive reactions are suppressed to below 0.
50 units.
Figure A: The reactivity of the patient's serum to the platelet activation test and the immune test.
The 4 colors represent the serum samples of 4 patients.
In these three samples, PF4 (10 micrograms per milliliter) greatly enhanced the reactivity; Subsequently, when retested with platelets from other volunteers, patient 2's serum showed strong platelet activation in the presence of PF4.
All reactions were blocked by monoclonal antibody IV.
3 and immunoglobulin (dose 10 mg per milliliter), indicating that platelet activation has occurred through platelet Fcγ receptors (Figure A).
There was no platelet activation in the control group (data not shown).
Precipitate platelets from platelet-rich plasma, then resuspend the precipitated platelets in washing buffer, pre-incubate with AstraZeneca vaccine (1:2000), or co-incubate with AstraZeneca vaccine (1:50), Can enhance platelet activation.
Figure 1B shows the platelet activation results of serum samples from 24 patients with clinically suspected vaccine-induced immune thrombotic thrombocytopenia.
These patients were positive in the PF4-heparin ELISA screening.
Figure B: The reactivity of the patient's serum to the platelet activation test and the immune test, but about half of the serum samples (13 out of 24 people) showed platelet activation in the buffer control, and most of the samples (19 out of 24 people) Inhibited by low molecular weight heparins (LMWHs); almost all samples (22 out of 24) showed platelet activation after adding PF4.
Except for one serum sample, the remaining samples were inhibited by high-dose heparin (UFH).
Figure 1C shows that the serum samples obtained from all 28 patients (including patients 1, 2, 3, 4, 5, 8, 9, 10, and 11) have strong results in the PF4-heparin and PF4 ELISA experiments.
The reactivity, and this reactivity can be inhibited by high-dose heparin.
Figure C: The reactivity of patient serum to platelet activation test and immune test.
The affinity purified antibodies using immobilized PF4 or immobilized PF4-heparin showed the same reaction pattern as the original serum, in other words, they were at 10μg per milliliter The presence of PF4 strongly activates platelets, and this effect is completely inhibited by high concentrations of heparin.
In summary, in this study, vaccination with ChAdOx1 nCov-19 vaccine can lead to rare immune thrombotic thrombocytopenia mediated by platelet activating antibody against PF4, which is clinically similar to immune thrombotic thrombocytopenia For autoimmune heparin-induced thrombocytopenia.
At the same time, in another European country: Norway, elderly people living in public institutions and medical professionals who have close contact with Covid-19 patients have been given priority to receive Pfizer vaccines.
In addition, the AstraZeneca vaccine has been vaccinated to medical staff under 65 who have no close contact with Covid-19 patients.
As of the suspension of vaccination on March 20, 2021, a total of 132,686 people in Norway had received the first dose of AstraZeneca, and no one had received the second dose.
Within 10 days after the first dose of ChAdOx1 nCoV-19 vaccine, 5 patients' medical staff experienced severe thrombocytopenia and thrombosis at abnormal sites.
Four of the patients had severe cerebral hemorrhage.
These 5 patients were treated at Oslo University Hospital.
Thrombosis and Thrombocytopenia after ChAdOx1 nCoV-19 Vaccination.
doi:10.
1056/NEJMoa2104882.
Based on this, Norwegian researchers reported in another study that these 5 patients had veins 7 to 10 days after the first dose of ChAdOx1 nCov-19 vaccine Thrombosis and thrombocytopenia.
These 5 patients were medical staff between 32 and 54 years old and all had high levels of PF4-polyanion complex antibodies.
However, they have not been exposed to heparin before.
Given that these 5 patients occurred among more than 130,000 vaccinated persons in Norway, these researchers pointed out that these patients represent a rare variant of vaccine-related spontaneous heparin-induced thrombocytopenia, which they call vaccine-induced Immune thrombocytopenia.
The relevant research results will be published online in the NEJM journal on April 9, 2021.
Science has been advancing.
Scientists have found the cause of blood clots caused by AstraZeneca's new crown vaccine.
This study found that this will help the vaccine to promote and develop effective treatment of this side effect globally.
Written | towersimper/Jessica editor | Jessica authorized to reprint, submit and break the news, please contact Metz Medical Administrator MedSci (WeChat ID: medsci_m) Attention! Dear Metz Medicine readers want to participate in more discussions? If you know it, you must know why! Why do clinicians do scientific research? Come to the Metz live broadcast room on the 14th and follow Dr.
Fabao Zhang to find the key to open the door of scientific research~ Scan the QR code below to get the seat first!
The new crown vaccine is the most important countermeasure against new crown pneumonia.
From December 2020 to March 2021, the European Medicines Agency approved 4 vaccines, namely: the mRNA vaccine (BNT162b2) of BioNTech and Pfizer, the mRNA vaccine of Moderna (mRNA-1273), British AstraZeneca vaccine (ChAdOx1 nCov-19) and Ad26.
COV2.
S vaccine (Johnson & Johnson/Janssen).
As of April 7, 2021, the EU has received more than 82 million doses of vaccine; in Germany, about a quarter of vaccinators have received the AstraZeneca vaccine.
Beginning in late February 2021, several abnormal thrombotic events have been observed in patients after vaccination with AstraZeneca, accompanied by thrombocytopenia.
The first case In mid-February 2021 (day 0), a previously healthy 49-year-old medical staff received her first dose of AstraZeneca vaccine.
In the next few days, she developed fatigue, myalgias and headaches.
From the 5th day, she developed chills, fever, nausea and upper abdominal discomfort; on the 10th day she was admitted to the local hospital.
The laboratory test results are shown in Table 1.
The platelet count is 18,000 per cubic millimeter, and the D-dimer level is 35 mg per liter (reference value, <0.
5).
Computed tomography (CT) shows portal vein thrombosis and peripheral pulmonary embolism.
This patient died on the 11th day.
In addition to the medical results of the diagnosis, the autopsy also found cerebral venous thrombosis.
Table 1: Laboratory characteristics of the first case doi: 10.
1056/NEJMoa2104840 series of cases By March 15, 2021, another 10 patients were found to have one or more types of thrombosis 5 to 16 days after vaccination with AstraZeneca complication.
Thrombotic events included cerebral venous thrombosis (9 cases), splenic vein thrombosis (3 cases), pulmonary embolism (3 cases) and other types of thrombosis (4 cases); 5 out of 10 patients had more than one type of thrombosis Thrombotic events.
In this analysis, one patient (patient 11) had a fatal cerebral hemorrhage.
Clinical and laboratory characteristics of 11 patients Among these patients, the median age was 36 years (range 22 to 49 years); 9 of the 11 patients were women.
All patients were accompanied by thrombocytopenia.
None of these patients had received heparin treatment before the onset of symptoms or the diagnosis of thrombosis.
In view of the significant clinical similarity between this disease and autoimmune heparin-induced thrombocytopenia (a prothrombotic thrombocytopenia caused by heparin and certain other anions, which is characterized by heparin independent of platelet activation properties).
, The researchers obtained serum from 9 patients to study platelet activation antibodies against platelet factor 4 (PF4)-heparin.
The relevant research results will be published online in the NEJM journal on April 9, 2021.
Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccinationdoi: 10.
1056/NEJMoa2104840 In order to measure direct antibody binding, the researchers used two immunoassays: one is PF4-heparin enzyme-linked immunosorbent assay (ELISA) and the other is PF4 ELISA, which measures antibody binding by secondary anti-human IgG.
According to the optical density unit, the reactivity in ELISA is defined as strong (≥2.
00), medium (1.
00～1.
99) or weak (0.
50～0.
99). In the PF4 enhanced platelet activation test, the reactivity is graded according to the time elapsed before platelet aggregation.
The shorter the reaction time, the stronger the platelet activation (strong activation, 1 to 5 minutes; moderate activation,> 5 to 15 minutes; Weak activation, >15 to 30 minutes).
The author purified platelets from whole blood (obtained from healthy volunteers).
The platelets were pre-incubated with AstraZeneca vaccine (1:2000 dilution) in buffer and washed before use.
The washed platelets (75 microliters) were incubated with buffer, low molecular weight heparin (LMWHs) or PF4 (Chromatec) in the presence or absence of FcγIIa receptor blocking antibody IV.
3.
In some experiments, unfractionated heparin (UFH) (100 IU per milliliter) was added to inhibit PF4-dependent reactions, or AstraZeneca vaccine (1:50 dilution) was added to each well.
The serum was incubated with PF4 and platelets in the presence of immunoglobulin (Privigen IVIG) at a concentration of 10 mg per milliliter.
After establishing the test conditions using the sera of the initial four patients (i.
e.
, patients 1 to 4), the authors studied another 24 serum samples that were positive on immunoassays in order to verify their findings.
They called this modified platelet activation test the PF4 enhanced platelet activation test.
The results of the study found that the sera of patients 1-4 showed strong reactivity in the PF4-heparin ELISA test, with an optical density exceeding 3.
00 units (reference value, <0.
50) (as shown in the figure below).
In addition, the author noted with interest In the clinical course of patient 2, the patient developed pulmonary embolism and mild thrombocytopenia (platelet count, 107,000 per cubic millimeter), and there was no diffuse intravascular coagulation.
The patient received a therapeutic dose of low-molecular-weight heparin (LMWHs) for 3 days, clinically improved, and the platelet count increased to 132000; at this time, the PF4-heparin ELISA result was positive, and he switched to oral apixaban (apixaban), clinical and experimental The room continued to recover.
Panel A shows the serological characteristics of the 4 initial patients, which were evaluated by the platelet activation test.
Three of the four serum samples showed weak to moderate reactivity under the buffer control, and this reactivity can be inhibited by low molecular weight heparin.
By adding heparin (UFH) (100IU per milliliter), all reactive reactions are suppressed to below 0.
50 units.
Figure A: The reactivity of the patient's serum to the platelet activation test and the immune test.
The 4 colors represent the serum samples of 4 patients.
In these three samples, PF4 (10 micrograms per milliliter) greatly enhanced the reactivity; Subsequently, when retested with platelets from other volunteers, patient 2's serum showed strong platelet activation in the presence of PF4.
All reactions were blocked by monoclonal antibody IV.
3 and immunoglobulin (dose 10 mg per milliliter), indicating that platelet activation has occurred through platelet Fcγ receptors (Figure A).
There was no platelet activation in the control group (data not shown).
Precipitate platelets from platelet-rich plasma, then resuspend the precipitated platelets in washing buffer, pre-incubate with AstraZeneca vaccine (1:2000), or co-incubate with AstraZeneca vaccine (1:50), Can enhance platelet activation.
Figure 1B shows the platelet activation results of serum samples from 24 patients with clinically suspected vaccine-induced immune thrombotic thrombocytopenia.
These patients were positive in the PF4-heparin ELISA screening.
Figure B: The reactivity of the patient's serum to the platelet activation test and the immune test, but about half of the serum samples (13 out of 24 people) showed platelet activation in the buffer control, and most of the samples (19 out of 24 people) Inhibited by low molecular weight heparins (LMWHs); almost all samples (22 out of 24) showed platelet activation after adding PF4.
Except for one serum sample, the remaining samples were inhibited by high-dose heparin (UFH).
Figure 1C shows that the serum samples obtained from all 28 patients (including patients 1, 2, 3, 4, 5, 8, 9, 10, and 11) have strong results in the PF4-heparin and PF4 ELISA experiments.
The reactivity, and this reactivity can be inhibited by high-dose heparin.
Figure C: The reactivity of patient serum to platelet activation test and immune test.
The affinity purified antibodies using immobilized PF4 or immobilized PF4-heparin showed the same reaction pattern as the original serum, in other words, they were at 10μg per milliliter The presence of PF4 strongly activates platelets, and this effect is completely inhibited by high concentrations of heparin.
In summary, in this study, vaccination with ChAdOx1 nCov-19 vaccine can lead to rare immune thrombotic thrombocytopenia mediated by platelet activating antibody against PF4, which is clinically similar to immune thrombotic thrombocytopenia For autoimmune heparin-induced thrombocytopenia.
At the same time, in another European country: Norway, elderly people living in public institutions and medical professionals who have close contact with Covid-19 patients have been given priority to receive Pfizer vaccines.
In addition, the AstraZeneca vaccine has been vaccinated to medical staff under 65 who have no close contact with Covid-19 patients.
As of the suspension of vaccination on March 20, 2021, a total of 132,686 people in Norway had received the first dose of AstraZeneca, and no one had received the second dose.
Within 10 days after the first dose of ChAdOx1 nCoV-19 vaccine, 5 patients' medical staff experienced severe thrombocytopenia and thrombosis at abnormal sites.
Four of the patients had severe cerebral hemorrhage.
These 5 patients were treated at Oslo University Hospital.
Thrombosis and Thrombocytopenia after ChAdOx1 nCoV-19 Vaccination.
doi:10.
1056/NEJMoa2104882.
Based on this, Norwegian researchers reported in another study that these 5 patients had veins 7 to 10 days after the first dose of ChAdOx1 nCov-19 vaccine Thrombosis and thrombocytopenia.
These 5 patients were medical staff between 32 and 54 years old and all had high levels of PF4-polyanion complex antibodies.
However, they have not been exposed to heparin before.
Given that these 5 patients occurred among more than 130,000 vaccinated persons in Norway, these researchers pointed out that these patients represent a rare variant of vaccine-related spontaneous heparin-induced thrombocytopenia, which they call vaccine-induced Immune thrombocytopenia.
The relevant research results will be published online in the NEJM journal on April 9, 2021.
Science has been advancing.
Scientists have found the cause of blood clots caused by AstraZeneca's new crown vaccine.
This study found that this will help the vaccine to promote and develop effective treatment of this side effect globally.
Written | towersimper/Jessica editor | Jessica authorized to reprint, submit and break the news, please contact Metz Medical Administrator MedSci (WeChat ID: medsci_m) Attention! Dear Metz Medicine readers want to participate in more discussions? If you know it, you must know why! Why do clinicians do scientific research? Come to the Metz live broadcast room on the 14th and follow Dr.
Fabao Zhang to find the key to open the door of scientific research~ Scan the QR code below to get the seat first!
