The effect of covid-19 vaccine in patients with immune thrombocytopenia

Background: Immune thrombocytopenia (ITP) is an acquired autoimmune disorder against platelets characterized by a low platelet count and increased bleeding risk. ITP is likely to rise from defective immune tolerance in addition to a triggering event, such as vaccination. COVID-19 vaccination is associated with a small increased risk of development of de novo ITP. In patients historically diagnosed with ITP, relapse of thrombocytopenia after COVID-19 vaccination has been described. However, the precise platelet dynamics in previously diagnosed ITP patients after COVID-19 vaccination is unknown Aims: To investigate the effect of the COVID-19 vaccine on platelet count, the occurrence of severe bleeding complications and necessity of rescue medication in patients historically diagnosed with ITP. Methods: Platelet counts of ITP patients and healthy controls were collected immediately before, 1 and 4 weeks after the first and second vaccination. Linear mixed effects modelling was applied to analyse platelet count dynamics over time. Results: We included 218 ITP patients (50.9% women) with a mean (SD) age of 58 (17) years and 200 healthy controls (60.0% women) with a mean (SD) age of 58 (13) years. Healthy controls and ITP patients had similar baseline characteristics (Table 1). 201/218 (92.2%)ITP patients received the mRNA-1273 vaccine, 16/218 (7.3%) the BNT162b vaccine and 1/218 (0.46%) the Vaxzevria vaccine. All healthy controls received the mRNA-1273 vaccine. Fifteen (6.8%) patients needed rescue medication (Table 1). Significantly more ITP patients who needed rescue medication were on ITP treatment prior COVID-19 vaccination compared to patients without exacerbation (56.2% (7/16) vs 27.4% (55/202), p=0.016). We found a significant effect of vaccination on platelet count over time in both ITP patients and healthy controls (Figure 1A). Platelet counts of ITP patients decreased 7.9% between baseline and 4 weeks after second vaccination (p=0.045). Rescue medication and prior treatment significantly increased platelet count over time (p=0.042 and p=0.044). Healthy controls decreased 4.5% in platelet count (p<0.001) between baseline and 4 weeks after second vaccination. There was no significant difference in platelet count between ITP patients and healthy controls (p=0.78) (Figure 2). IPT patients with a baseline platelet count of >150x10 9/L had a significant decrease of platelet count 4 weeks after second vaccination compared to baseline (median platelet count (IQR) 205 (94) vs 203 x10 9/L (109) p=0.001). No significant decrease was seen in ITP patients with a baseline platelet count <150 x10 9/L. Median (IQR) platelet counts were similar between patients with and without exacerbation, except for 4 weeks after second vaccination (112 (105) vs 45 x 10 9/L (70), p=0.025) (Figure 1B). No significant effect was observed over time in ITP patients with rescue medication (p=0.478) (Figure 1C). In ITP patients without rescue medication, COVID-19 vaccination had a significant effect over time (p=0.001), especially 1 week after second vaccination (Figure1B). Of the 15 patients who needed rescue medication, 8/15 patients (53.3%) received rescue medication within 4 weeks after first vaccination and 4/15 (26.67%) needed rescue medication after the first as well as after the second vaccination. 3/15 (20.0%) patients needed rescue medication after the second vaccination. In the total ITP population, 5/218 (2.2%) experienced a WHO grade 2-4 bleeding complication and 3/218 (1.4%) needed platelet transfusion. 4/5 (80%) bleedings occurred before the second vaccination. One of these patients had fatal varices bleeding, although platelet count was normal. Conclusion: COVID-19 vaccination has a significant effect on platelet count in ITP patients and healthy controls. In 6.8% of ITP patients rescue medication was needed and in 2.2% of ITP patients a WHO grade 2-4 bleeding occurred. The majority of rescue medication was given and the majority bleeding complications occurred in the 4 weeks after the first vaccination. Our results demonstrate th t close monitoring of platelet count after COVID-19 vaccination is important in patients historically diagnosed with ITP.

Does Fibrin Structure Contribute to the Increased Risk of Thrombosis in COVID-19 ICU Patients?

Introduction: SARS-CoV-2 is responsible for a global pandemic, with almost 200 million confirmed cases. SARS-CoV-2 infection can lead to various disease states, from only mild symptoms in the majority of cases to severe disease, which is associated with an increased incidence of venous thromboembolism (VTE). We hypothesized that an altered fibrin network structure contributes to VTE in COVID-19 patients by affecting thrombus stability and fibrinolysis sensitivity. By studying the fibrin network of COVID-19 patients, we aimed to unravel the mechanisms that contribute to the increased risk of VTE in COVID-19 patients. Methods: Between April 2020 and December 2020, we collected plasma samples from patients with COVID-19 admitted to the intensive care unit (ICU) of the Erasmus Medical Center. We included patients with confirmed VTE diagnosed on CT-angiography, and COVID-19 patients without confirmed VTE during ICU admission. Samples were collected on admission to the ICU and after confirmed VTE or at similar time points in ICU patients without confirmed VTE. In addition, we collected plasma from COVID-19 patients at admission to general wards without confirmed VTE and from healthy controls. Clots were formed by mixing citrated plasma with thrombin (final concentration 1 U/ml) and calcium (17 mM). We imaged the clots using stimulated emission depletion (STED) microscopy, a super-resolution technique in which a depletion laser is used to selectively switch off fluorophores surrounding the focal point, thereby increasing the resolution. In these images, fibrin fiber diameters were measured using the Local Thickness plugin of ImageJ. Fiber density was quantified as percentage of area in Z-stacks of confocal microscopy images. Finally, a clot lysis assay based on turbidity was used to determine sensitivity to fibrinolysis (clot lysis time) and clot density (difference between maximum and baseline absorbance). Differences in fibrin network properties between groups were tested using One-Way ANOVA with Bonferroni post-hoc tests and linear regression with and without adjustment for fibrinogen levels. Results: We included 21 COVID-19 ICU patients with confirmed VTE, 20 COVID-19 ICU patients without confirmed VTE, 10 COVID-19 ward patients and 7 healthy controls. Mean age was comparable between the groups, while BMI was higher in COVID-19 patients than in healthy controls (Table 1). Levels of fibrinogen, D-dimer and anti-Xa were significantly higher in COVID-19 ICU patients than in COVID-19 ward patients and healthy controls. FVIII levels were significantly higher in COVID-19 ICU patients than in healthy controls, while FXIII levels were significantly lower. On admission to the ICU, clot density was significantly higher in COVID-19 ICU patients with and without confirmed VTE than in healthy controls (Figure 1 and Table 2). However, after adjustment for fibrinogen levels, this difference disappears. Clot lysis time was significantly longer in clots from COVID-19 ICU patients than in clots from healthy controls, regardless of fibrinogen levels (Table 2). COVID-19 ICU patients with confirmed VTE also showed a significant longer clot lysis time than COVID-19 ward patients. Interestingly, in the clot lysis assay, fibrinolysis did not occur in 25% of COVID-19 ICU patients with VTE versus 9.5% of COVID-19 ICU patients without VTE (Figure 2). This fibrinolysis shutdown was never observed in clots from healthy controls and COVID-19 ward patients. Fibrin fiber diameters were comparable between the groups. In the clots from plasma samples collected at admission to the ICU, there were no differences between COVID-19 ICU patients with and without VTE (Figure 2). However, when comparing clots prepared from plasma collected at the second time point (after VTE or at a similar time point for patients without VTE), we observed significant longer clot lysis times in patients with confirmed VTE (97.4 [88.5-158.8] min) than in patients without confirmed VTE (80.0 [76.0-97.8] min) (p=0.03). Finally, there were no significant changes between clots fro plasma before and after VTE or between the two time points in patients without VTE, except for a decreased clot lysis time over time for COVID-19 ICU patients without confirmed VTE. Conclusion: Our results suggest that SARS-CoV-2 infection increases clot density and decreases clot susceptibility to fibrinolysis, and that these changes relate to the severity of the disease. [Formula presented] Disclosures: Kruip: Daiichi Sankyo: Research Funding;Bayer: Honoraria, Research Funding.

COVID-19 vaccination and anticoagulation: Potential effects on anticoagulation control in patients using vitamin kantagonists

Background : In January 2021, the Dutch vaccination programme against SARS-CoV-2 was started. Clinical studies have shown that systemic reactions including fever and chills occur in up to 50% of vaccine recipients. It is unclear whether these systematic reactions have an effect on anticoagulation control, potentially leading to an increased risk of thrombotic events and bleeding complications. Aims : To investigate whether COVID-19 vaccination with the Pfizer vaccine is associated with suboptimal anticoagulation control in patients using Vitamin K antagonists (VKAs). Methods : A case-crossover study was performed in a cohort of outpatients from three Dutch anticoagulation clinics who received a COVID-19 vaccination. All patients had their international normalized ratio (INR) measured 0-6 weeks before and 1-2 weeks after vaccination. INR results and VKA dosages before the first COVID-19 vaccination, the reference period, were compared with those after the first vaccination. Data extraction after the second vaccination will be performed in the near future, after which these analyses will be repeated and included in the final presentation at the congress. Results : A total of 2197 outpatient VKA-users were included, with a mean age of 86 years, of whom 38.5% were male and 71.7% used acenocoumarol (Table 1). There was no difference in mean INR level before and after vaccination (2.51 vs 2.54, mean difference 0.033 (95% CI, -0.071 to 0.0051). The mean dosage of phenprocoumon did not differ before and after vaccination (0.47 tablets/day (0.25)). Similarly, the mean dosage of acenocoumarol was comparable before and after vaccination (1.72 tablets/day (0.81) versus 1.71 tablets/ day (0.82). Most vaccine recipients remained in therapeutic range and INR > 5 was as likely to be reported after vaccination (1.0% and 2.6%) as it was before vaccination (1.0% and 1.6%) (Table 2). Conclusions : COVID-19 vaccination did not influence anticoagulation control in patients using VKAs.

Excess mortality in a population of vitamin k antagonist users during the first wave of the COVID-19 pandemic in thenetherlands compared with excess mortality in the general dutch population

Background : Excess mortality has been observed in the general population during the COVID-19 pandemic, but it is unknown whether preexisting anticoagulant treatment affects survival, given that COVID-19 associated hypercoagulability adversely impacts prognosis. Aims : To investigate whether preexisting vitamin K antagonist (VKA) treatment is associated with lower excess mortality during the first wave of the COVID-19 pandemic in the Netherlands when compared with excess mortality in the general population. Methods : All atrial fibrillation (AF) patients (≥60 years) receiving long-term VKA therapy before week 11, 2020 were included from three Dutch anticoagulation clinics. The corresponding patient population managed by the same clinics in 2019 (i.e., all AF patients (≥60 years) receiving long-term VKA therapy before week 11, 2019) was enrolled as a control cohort. Difference in survival within 9 weeks (i.e., week 11 to 19) between the two cohorts was evaluated by Cox regression analysis. This was compared with the difference in survival during the same time frame of the general elderly (≥60 years) Dutch populations in 2020 versus 2019. Results : The study included 22,730 VKA users for the cohort in 2019 and 19,476 for the cohort in 2020, of which baseline characteristics were comparable. The cumulative incidences for all-cause mortality of the VKA users and the general population are presented in Table 1. Conclusions : Elderly patients with AF receiving long-term VKA therapy in the Netherlands appeared to have a lower excess mortality during the first wave of the COVID-19 pandemic when compared to the general elderly population.

Incidence of thrombotic complications and overall survival in hospitalized patients with COVID-19 in the second and first wave.

INTRODUCTION: In the first wave, thrombotic complications were common in COVID-19 patients. It is unknown whether state-of-the-art treatment has resulted in less thrombotic complications in the second wave. METHODS: We assessed the incidence of thrombotic complications and overall mortality in COVID-19 patients admitted to eight Dutch hospitals between September 1st and November 30th 2020. Follow-up ended at discharge, transfer to another hospital, when they died, or on November 30th 2020, whichever came first. Cumulative incidences were estimated, adjusted for competing risk of death. These were compared to those observed in 579 patients admitted in the first wave, between February 24th and April 26th 2020, by means of Cox regression techniques adjusted for age, sex and weight. RESULTS: In total 947 patients with COVID-19 were included in this analysis, of whom 358 patients were admitted to the ICU; 144 patients died (15%). The adjusted cumulative incidence of all thrombotic complications after 10, 20 and 30 days was 12% (95% confidence interval (CI) 9.8-15%), 16% (13-19%) and 21% (17-25%), respectively. Patient characteristics between the first and second wave were comparable. The adjusted hazard ratio (HR) for overall mortality in the second wave versus the first wave was 0.53 (95%CI 0.41-0.70). The adjusted HR for any thrombotic complication in the second versus the first wave was 0.89 (95%CI 0.65-1.2). CONCLUSIONS: Mortality was reduced by 47% in the second wave, but the thrombotic complication rate remained high, and comparable to the first wave. Careful attention to provision of adequate thromboprophylaxis is invariably warranted.

Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis.

INTRODUCTION: We recently reported a high cumulative incidence of thrombotic complications in critically ill patients with COVID-19 admitted to the intensive care units (ICUs) of three Dutch hospitals. In answering questions raised regarding our study, we updated our database and repeated all analyses. METHODS: We re-evaluated the incidence of the composite outcome of symptomatic acute pulmonary embolism (PE), deep-vein thrombosis, ischemic stroke, myocardial infarction and/or systemic arterial embolism in all COVID-19 patients admitted to the ICUs of 2 Dutch university hospitals and 1 Dutch teaching hospital from ICU admission to death, ICU discharge or April 22nd 2020, whichever came first. RESULTS: We studied the same 184 ICU patients as reported on previously, of whom a total of 41 died (22%) and 78 were discharged alive (43%). The median follow-up duration increased from 7 to 14 days. All patients received pharmacological thromboprophylaxis. The cumulative incidence of the composite outcome, adjusted for competing risk of death, was 49% (95% confidence interval [CI] 41-57%). The majority of thrombotic events were PE (65/75; 87%). In the competing risk model, chronic anticoagulation therapy at admission was associated with a lower risk of the composite outcome (Hazard Ratio [HR] 0.29, 95%CI 0.091-0.92). Patients diagnosed with thrombotic complications were at higher risk of all-cause death (HR 5.4; 95%CI 2.4-12). Use of therapeutic anticoagulation was not associated with all-cause death (HR 0.79, 95%CI 0.35-1.8). CONCLUSION: In this updated analysis, we confirm the very high cumulative incidence of thrombotic complications in critically ill patients with COVID-19 pneumonia.

Incidence of thrombotic complications in critically ill ICU patients with COVID-19.

INTRODUCTION: COVID-19 may predispose to both venous and arterial thromboembolism due to excessive inflammation, hypoxia, immobilisation and diffuse intravascular coagulation. Reports on the incidence of thrombotic complications are however not available. METHODS: We evaluated the incidence of the composite outcome of symptomatic acute pulmonary embolism (PE), deep-vein thrombosis, ischemic stroke, myocardial infarction or systemic arterial embolism in all COVID-19 patients admitted to the ICU of 2 Dutch university hospitals and 1 Dutch teaching hospital. RESULTS: We studied 184 ICU patients with proven COVID-19 pneumonia of whom 23 died (13%), 22 were discharged alive (12%) and 139 (76%) were still on the ICU on April 5th 2020. All patients received at least standard doses thromboprophylaxis. The cumulative incidence of the composite outcome was 31% (95%CI 20-41), of which CTPA and/or ultrasonography confirmed VTE in 27% (95%CI 17-37%) and arterial thrombotic events in 3.7% (95%CI 0-8.2%). PE was the most frequent thrombotic complication (n = 25, 81%). Age (adjusted hazard ratio (aHR) 1.05/per year, 95%CI 1.004-1.01) and coagulopathy, defined as spontaneous prolongation of the prothrombin time > 3 s or activated partial thromboplastin time > 5 s (aHR 4.1, 95%CI 1.9-9.1), were independent predictors of thrombotic complications. CONCLUSION: The 31% incidence of thrombotic complications in ICU patients with COVID-19 infections is remarkably high. Our findings reinforce the recommendation to strictly apply pharmacological thrombosis prophylaxis in all COVID-19 patients admitted to the ICU, and are strongly suggestive of increasing the prophylaxis towards high-prophylactic doses, even in the absence of randomized evidence.