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3.
Crit Care Med ; 49(9): e870-e873, 2021 09 01.
Article in English | MEDLINE | ID: covidwho-1455369

ABSTRACT

OBJECTIVES: To describe the successful recovery from multiple and life-threatening venous thrombosis after ChAdOx1 nCoV-19 vaccination. DESIGN: Case report. SETTING: University Hospital. PATIENT: Few days after the first dose of the ChAdOx1 nCoV-19 vaccine, a 21-year-old woman experienced massive thrombosis in the deep and superficial cerebral veins together with seizures, neurologic focal deficit, and thrombocytopenia. In the neurointensive care unit, her condition worsened despite early decompressive craniectomy. She developed bilateral segmental pulmonary embolism, left hepatic, and left external iliac venous thrombosis. INTERVENTION: Argatroban (0.5-2.2 µg/kg/min) and high-dose IV immunoglobulin (1 g/kg/d for 2 consecutive days) were initiated on day 6 after admission. With these therapies, there was a gradual resolution of multiple sites of venous thrombosis, and platelet count returned to normal. The patient left the ICU with full consciousness, expressive aphasia, and right hemiparesis. CONCLUSIONS: This case of vaccine-induced immune thrombotic thrombocytopenia shows that a good outcome can be obtained even with multiple and life-threatening venous thrombotic lesions. Argatroban and high-dose IV immunoglobulin along with management of severe cerebral venous thrombosis played a major role in this epilogue.


Subject(s)
Antithrombins/therapeutic use , Arginine/analogs & derivatives , COVID-19 Vaccines/adverse effects , Pipecolic Acids/therapeutic use , Sulfonamides/therapeutic use , Thrombocytopenia/drug therapy , Venous Thrombosis/drug therapy , Arginine/therapeutic use , Cerebral Veins/diagnostic imaging , Drug Therapy, Combination , Female , Fondaparinux/therapeutic use , Humans , Immunoglobulins, Intravenous , Thrombocytopenia/etiology , Tomography, X-Ray Computed , Venous Thrombosis/etiology , Young Adult
4.
Tidsskr Nor Laegeforen ; 1412021 04 30.
Article in English, Norwegian | MEDLINE | ID: covidwho-1395073

ABSTRACT

BACKGROUND: New vaccines against COVID-19 are being rolled out globally. AstraZeneca's vaccine ChAdOx1 nCoV-19 was not known to cause vaccine-induced immune thrombotic thrombocytopenia (VITT) at the time of this case. CASE PRESENTATION: The patient was a previously healthy woman in her thirties with headaches that developed one week after vaccination with ChAdOx1 nCoV-19. Three days later, her condition deteriorated rapidly, and she presented to the emergency department with slurred speech, uncoordinated movements and reduced consciousness. Symptoms progressed to left-sided hemiparesis and her level of consciousness deteriorated. Computed tomography (CT) of the head showed a large right-sided haemorrhage and incipient herniation. She was found to have severe thrombocytopenia 37 x 109/l, (ref 145 - 390 x 109/l). In spite of efforts to reduce intracranial pressure, the patient died the following day. Post mortem examination revealed antibodies to PF4, and fresh small thrombi were found in the transverse sinus, frontal lobe and pulmonary artery. INTERPRETATION: Severe thrombocytopenia and antibodies to PF4 make a diagnosis of vaccine-induced immune thrombotic thrombocytopenia (VITT) likely.


Subject(s)
COVID-19 Vaccines , COVID-19 , Cerebral Hemorrhage/chemically induced , Cerebral Hemorrhage/diagnostic imaging , Female , Humans , SARS-CoV-2
5.
J Autoimmun ; 121: 102662, 2021 07.
Article in English | MEDLINE | ID: covidwho-1385817

ABSTRACT

Herein, we consider venous immunothrombotic mechanisms in SARS-CoV-2 infection and anti-SARS-CoV-2 DNA vaccination. Primary SARS-CoV-2 infection with systemic viral RNA release (RNAaemia) contributes to innate immune coagulation cascade activation, with both pulmonary and systemic immunothrombosis - including venous territory strokes. However, anti-SARS-CoV-2 adenoviral-vectored-DNA vaccines -initially shown for the ChAdOx1 vaccine-may rarely exhibit autoimmunity with autoantibodies to Platelet Factor-4 (PF4) that is termed Vaccine-Induced Thrombotic Thrombocytopenia (VITT), an entity pathophysiologically similar to Heparin-Induced Thrombocytopenia (HIT). The PF4 autoantigen is a polyanion molecule capable of independent interactions with negatively charged bacterial cellular wall, heparin and DNA molecules, thus linking intravascular innate immunity to both bacterial cell walls and pathogen-derived DNA. Crucially, negatively charged extracellular DNA is a powerful adjuvant that can break tolerance to positively charged nuclear histone proteins in many experimental autoimmunity settings, including SLE and scleroderma. Analogous to DNA-histone interactons, positively charged PF4-DNA complexes stimulate strong interferon responses via Toll-Like Receptor (TLR) 9 engagement. A chain of events following intramuscular adenoviral-vectored-DNA vaccine inoculation including microvascular damage; microbleeding and platelet activation with PF4 release, adenovirus cargo dispersement with DNA-PF4 engagement may rarely break immune tolerance, leading to rare PF4-directed autoimmunity. The VITT cavernous sinus cerebral and intestinal venous territory immunothrombosis proclivity may pertain to venous drainage of shared microbiotal-rich areas of the nose and in intestines that initiates local endovascular venous immunity by PF4/microbiotal engagement with PF4 autoantibody driven immunothrombosis reminiscent of HIT. According to the proposed model, any adenovirus-vectored-DNA vaccine could drive autoimmune VITT in susceptible individuals and alternative mechanism based on molecular mimicry, vaccine protein contaminants, adenovirus vector proteins, EDTA buffers or immunity against the viral spike protein are secondary factors. Hence, electrochemical DNA-PF4 interactions and PF4-heparin interactions, but at different locations, represent the common denominator in HIT and VITT related autoimmune-mediated thrombosis.


Subject(s)
Autoantibodies/immunology , COVID-19/immunology , Purpura, Thrombocytopenic, Idiopathic/immunology , SARS-CoV-2/immunology , Thrombosis/immunology , Vaccines/adverse effects , COVID-19/pathology , COVID-19/prevention & control , Humans , Platelet Activation/immunology , Platelet Factor 4/immunology , Purpura, Thrombocytopenic, Idiopathic/chemically induced , Purpura, Thrombocytopenic, Idiopathic/pathology , Thrombosis/chemically induced , Thrombosis/pathology , Vaccines/immunology
6.
Eur J Intern Med ; 89: 19-21, 2021 07.
Article in English | MEDLINE | ID: covidwho-1385483

ABSTRACT

The nosological entity of the cerebral venous thrombosis caused by the SARS-CoV-2 vaccination differs from the common cerebral venous thrombosis in that it is due to immune thrombocytopenia triggered by vaccination. Cerebral venous thrombosis is one of several manifestations of this type of immune thrombocytopenia. Albeit many general aspects of management of cerebral venous thrombosis are similar, immune thrombocytopenia requires a specific therapeutic approach, which is not normally adopted for cerebral venous thrombosis due to other causes, therefore its early recognition is essential.


Subject(s)
COVID-19 , Thrombocytopenia , Venous Thrombosis , COVID-19 Vaccines , Humans , SARS-CoV-2 , Thrombocytopenia/chemically induced
7.
N Engl J Med ; 384(23): 2254-2256, 2021 06 10.
Article in English | MEDLINE | ID: covidwho-1387597
9.
Neurologia ; 36(6): 451-461, 2021.
Article in Spanish | MEDLINE | ID: covidwho-1336782

ABSTRACT

INTRODUCTION: Cases of cerebral venous sinus thrombosis have been reported in individuals vaccinated against COVID-19 with non-replicating adenoviral vector vaccines. We issue our recommendations on the diagnosis and management of patients presenting this complication. METHOD: The multidisciplinary working group, led by the Spanish Federation of Medical and Scientific Associations and including representatives of several scientific societies, reviewed the available evidence from the literature and reports of the European Medicines Agency. We establish a definition for suspected cases and issue diagnostic and treatment recommendations regarding vaccine-induced immune thrombotic thrombocytopaenia. RESULTS: We define suspected cases as those cases of cerebral venous sinus thrombosis occurring between 3 and 21 days after the administration of non-replicating adenoviral vector vaccines, in patients with a platelet count below 150,000/µL or presenting a decrease of 50% with respect to the previous value. Findings suggestive of vaccine-induced immune thrombotic thrombocytopaenia include the presence of antibodies to platelet factor 4, D-dimer levels 4 times greater than the upper limit of normal, and unexplained thrombosis. The recommended treatment includes intravenous administration of non-specific human immunoglobulin or alternatively plasmapheresis, avoiding the use of heparin, instead employing argatroban, bivalirudin, fondaparinux, rivaroxaban, or apixaban for anticoagulation, and avoiding platelet transfusion. CONCLUSIONS: Non-replicating adenoviral vector vaccines may be associated with cerebral venous sinus thrombosis with thrombocytopaenia; it is important to treat the dysimmune phenomenon and the cerebral venous sinus thrombosis.

10.
Biochem Biophys Res Commun ; 565: 64-71, 2021 08 06.
Article in English | MEDLINE | ID: covidwho-1251023

ABSTRACT

Neutrophil extracellular traps (NETs) are extracellular webs of DNA, histones and granular contents that are released by neutrophils to control infections. However, NETs that is not properly regulated can propagate inflammation and thrombosis. It was recognized that viruses can induce NETs. As a synthetic analog of viral double-stranded (ds) RNA, polyinosinic-polycytidylic acid [poly(I:C)] is known to induce inflammation and thrombosis. However, whether and how poly(I:C) modulates NETs remains unclear. Here, we have demonstrated that poly(I:C) induced extracellular DNA traps in human neutrophils in a dose-dependent manner. Further, poly(I:C) or dsRNA virus elevated the levels of myeloperoxidase-DNA complexes and citrullinated histone H3, which are specific markers of NETs, in both neutrophil supernatants and mouse plasma. Interestingly, a potent peptidylarginine deiminase 4 (PAD4) inhibitor, BB-CL-Amidine (BB-CLA) or PAD4 knockdown effectively prevented poly(I:C)-induced NETs formation and release. In addition, BB-CLA abrogated poly(I:C)-triggered neutrophil activation and infiltration, and vascular permeability in lungs. BB-CLA also attenuated poly(I:C)-induced thrombocytopenia in circulation, fibrin deposition and thrombus formation in tissues. Taken together, these results suggest that viral mimetic poly(I:C) may induce NETs-dependent inflammation and thrombosis through PAD4, and that inhibiting PAD4 may become a good strategy to protect against viral infection-caused inflammation/thrombosis-related pathological conditions of diseases.


Subject(s)
Extracellular Traps/drug effects , Inflammation/metabolism , Neutrophils/drug effects , Poly I-C/pharmacology , Protein-Arginine Deiminase Type 4/metabolism , Thrombosis/metabolism , Amidines/pharmacology , Animals , Cells, Cultured , Chlorocebus aethiops , Humans , Inflammation/pathology , Male , Mice , Mice, Inbred C57BL , Neutrophil Activation/drug effects , Neutrophils/metabolism , Protein-Arginine Deiminase Type 4/antagonists & inhibitors , Thrombosis/pathology
14.
N Engl J Med ; 384(23): e92, 2021 Jun 10.
Article in English | MEDLINE | ID: covidwho-1279937
15.
BMJ Case Rep ; 14(6)2021 Jun 16.
Article in English | MEDLINE | ID: covidwho-1276915

ABSTRACT

A 27-year-old fit and well man presented with intermittent headaches associated with eye floaters and vomiting. His symptoms started 48 hours after having the first dose of ChADOx1 nCOV-19 vaccine (Vaxzevria, previously AstraZeneca COVID-19 vaccine; AstraZeneca) and bloods showed raised D-dimer, low platelets and fibrinogen. CT venogram demonstrated significant cerebral venous sinus thrombosis. He was immediately started on intravenous immunoglobulins and dabigatran after liasing with haematologist. The next day, he complained of worsening headache and new homonymous hemianopia. Repeat CT of the head showed an acute parenchymal bleed with subdural extension and was given idarucizumab and high-dose steroids. He had an emergency decompressive craniotomy and external ventricular drain as his intracranial pressures were difficult to control. Despite full medical and surgical management, his intracranial pressures continued to rise and his brain injury was felt to be too devastating and was deemed unsurvivable.


Subject(s)
COVID-19 , Sinus Thrombosis, Intracranial , Thrombocytopenia , Adult , COVID-19 Vaccines , Humans , Male , SARS-CoV-2 , Sinus Thrombosis, Intracranial/chemically induced , Sinus Thrombosis, Intracranial/diagnostic imaging , Sinus Thrombosis, Intracranial/drug therapy
16.
Thromb Res ; 204: 40-51, 2021 08.
Article in English | MEDLINE | ID: covidwho-1275736

ABSTRACT

Heparin-induced thrombocytopenia (HIT) is characterized clinically by thrombocytopenia, hypercoagulability, and increased thrombosis risk, and serologically by platelet-activating anti-platelet factor 4 (PF4)/heparin antibodies. Heparin-"induced" acknowledges that HIT is usually triggered by a proximate immunizing exposure to heparin. However, certain non-heparin medications (pentosan polysulfate, hypersulfated chondroitin sulfate, fondaparinux) can trigger "HIT". Further, naturally-occurring polyanions (bacterial lipopolysaccharide, DNA/RNA) can interact with PF4 to recapitulate HIT antigens. Indeed, immunologic presensitization to naturally-occurring polyanions could explain why HIT more closely resembles a secondary, rather than a primary, immune response. In 2008 it was first reported that a HIT-mimicking disorder can occur without any preceding exposure to heparin or polyanionic medications. Termed "spontaneous HIT syndrome", two subtypes are recognized: (a) surgical (post-orthopedic, especially post-total knee arthroplasty, and (b) medical (usually post-infectious). Recently, COVID-19 adenoviral vector vaccination has been associated with a thrombotic thrombocytopenic disorder associated with positive PF4-dependent enzyme-immunoassays and serum-induced platelet activation that is maximal when PF4 is added. Vaccine-induced immune thrombotic thrombocytopenia (VITT) features unusual thromboses (cerebral venous thrombosis, splanchnic vein thrombosis) similar to those seen in spontaneous HIT syndrome. The emerging concept is that classic HIT reflects platelet-activating anti-PF4/heparin antibodies whereas spontaneous HIT syndrome and other atypical "autoimmune HIT" presentations (delayed-onset HIT, persisting HIT, heparin "flush" HIT) reflect heparin-independent platelet-activating anti-PF4 antibodies-although the precise relationships between PF4 epitope targets and the clinical syndromes remain to be determined. Treatment of spontaneous HIT syndrome includes non-heparin anticoagulation (direct oral Xa inhibitors favored over direct thrombin inhibitors) and high-dose immunoglobulin.


Subject(s)
Arthroplasty, Replacement, Knee , COVID-19 , Thrombocytopenia , Thrombosis , Vaccines , Anticoagulants , Arthroplasty, Replacement, Knee/adverse effects , Heparin/adverse effects , Humans , Platelet Factor 4 , SARS-CoV-2 , Syndrome , Thrombocytopenia/chemically induced
17.
Oncol Ther ; 9(2): 255-265, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1275018

ABSTRACT

Coronavirus disease 2019 (COVID-19) has resulted in millions of deaths globally. The pandemic has had a severe impact on oncology care and research. Patients with underlying cancer are more vulnerable to contracting COVID-19, and also have a more severe clinical course following the infection. The rollout of COVID-19 vaccines in many parts of the world has raised hopes of controlling the pandemic. In this editorial, the authors outline key characteristics of the currently approved COVID-19 vaccines, provide a brief overview of key emerging issues such as vaccine-induced immune thrombotic thrombocytopenia and SARS-CoV-2 variants of concern, and review the available data related to the efficacy and side effects of vaccinating patients with cancer.

18.
Blood Adv ; 5(12): 2569-2574, 2021 Jun 22.
Article in English | MEDLINE | ID: covidwho-1273233

ABSTRACT

Recently, reports of severe thromboses, thrombocytopenia, and hemorrhage in persons vaccinated with the chimpanzee adenovirus-vectored vaccine (ChAdOx1 nCoV-19, AZD1222, Vaxzevria; Oxford/AstraZeneca) against severe acute respiratory syndrome coronavirus 2 have emerged. We describe an otherwise healthy 30-year-old woman who developed thrombocytopenia, ecchymosis, portal vein thrombosis, and cerebral venous sinus thrombosis the second week after she received the ChAdOx1 nCoV-19 vaccine. Extensive diagnostic workup for thrombosis predispositions showed heterozygosity for the prothrombin mutation, but no evidence of myeloproliferative neoplasia or infectious or autoimmune diseases. Her only temporary risk factor was long-term use of oral contraceptive pills (OCPs). Although both the prothrombin mutation and use of OCPs predispose to portal and cerebral vein thrombosis, the occurrence of multiple thromboses within a short time and the associated pattern of thrombocytopenia and consumption coagulopathy are highly unusual. A maximum 4T heparin-induced thrombocytopenia (HIT) score and a positive immunoassay for anti-platelet factor 4/heparin antibodies identified autoimmune HIT as a potential pathogenic mechanism. Although causality has not been established, our case emphasizes the importance of clinical awareness. Further studies of this potentially new clinical entity have suggested that it should be regarded as a vaccine-induced immune thrombotic thrombocytopenia.


Subject(s)
COVID-19 , Thrombocytopenia , Thrombosis , Adult , COVID-19 Vaccines , Female , Humans , SARS-CoV-2 , Thrombocytopenia/chemically induced , Thrombosis/etiology , Vaccination
19.
Int J Lab Hematol ; 43(4): 559-570, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1273095

ABSTRACT

COVID-19 (coronavirus disease 2019) represents a pandemic, and several vaccines have been produced to prevent infection and/or severe sequelae associated with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection. There have been several reports of infrequent post vaccine associated thrombotic events, in particular for adenovirus-based vaccines. These have variously been termed VIPIT (vaccine-induced prothrombotic immune thrombocytopenia), VITT (vaccine-induced [immune] thrombotic thrombocytopenia), VATT (vaccine-associated [immune] thrombotic thrombocytopenia), and TTS (thrombosis with thrombocytopenia syndrome). In this report, the laboratory test processes, as utilised to assess suspected VITT, are reviewed. In published reports to date, there are notable similarities and divergences in testing approaches, potentially leading to identification of slightly disparate patient cohorts. The key to appropriate identification/exclusion of VITT, and potential differentiation from heparin-induced thrombocytopenia with thrombosis (HITT), is identification of potentially differential test patterns. In summary, testing typically comprises platelet counts, D-dimer, fibrinogen, and various immunological and functional assays for platelet factor 4 (PF4) antibodies. In suspected VITT, there is a generally highly elevated level of D-dimer, thrombocytopenia, and PF4 antibodies can be identified by ELISA-based assays, but not by other immunological assays typically positive in HITT. In addition, in some functional platelet activation assays, standard doses of heparin have been identified to inhibit activation in suspected VITT, but they tend to augment activation in HITT. Conversely, it is also important to not over-diagnose VITT, given that not all cases of thrombosis post vaccination will have an immune basis and not all PF4-ELISA positive patients will be VITT.


Subject(s)
COVID-19 Vaccines/adverse effects , COVID-19/prevention & control , Purpura, Thrombocytopenic, Idiopathic/diagnosis , Purpura, Thrombocytopenic, Idiopathic/etiology , COVID-19 Vaccines/therapeutic use , Enzyme-Linked Immunosorbent Assay , Humans , Immunologic Tests , SARS-CoV-2/isolation & purification
20.
J Autoimmun ; 122: 102681, 2021 08.
Article in English | MEDLINE | ID: covidwho-1270603

ABSTRACT

Cerebral venous thrombosis (CVT) events have been reported after vaccination with adenoviral COVID-19 vector vaccines. This study aimed to compare the clinical presentations and courses of vaccine-induced thrombotic thrombocytopenia (VITT) between the two adenoviral vector vaccines, Ad26.COV.2.S (Janssen/Johnson & Johnson) and ChAdOx1 nCoV-19 (Astra-Zeneca). We found that CVT after Ad26.COV.2.S vaccination presents later with similar symptoms compared to CVT after administration of ChAdOx1 nCoV-19, albeit with more thrombosis and intracerebral hemorrhage, lower D-dimer and aPTT levels but similar mortality. These findings could help guide clinical assessment and management of CVT after COVID-19 vaccination.


Subject(s)
COVID-19 Vaccines/adverse effects , COVID-19/prevention & control , Venous Thrombosis/etiology , Humans , SARS-CoV-2 , Venous Thrombosis/epidemiology
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