Heparin Induced Thrombocytopenia in Patients with COVID-19

Abstract Background Acute respiratory and renal failure as well as systemic coagulopathy are critical aspects of the morbidity and mortality in patients with COVID-19. Heparin Induced Thrombocytopenia (HIT) occurs when IgG antibodies form against platelet factor 4-Heparin complex, resulting in platelet activation and removal, leading to a prothrombotic state. Studies have shown that only 6% who are investigated serologically for HIT actually have the diagnosis. Methods A retrospective analysis was performed on all COVID-19 positive patients hospitalized between March and June 2020. Patients with suspicion for HIT were tested for HIT antibodies with IgG-specific platelet factor 4(PF4)-dependent enzyme immunoassay (EIA). Confirmatory testing with serotonin release assay (SRA) and heparin-induced platelet aggregation were used in cases with intermediate or low optical density (OD) with EIA positivity (EIA+). Due to rarity of disease, a through literature review on HIT in COVID-19 patients was also analyzed. Results Incidence of EIA + in COVID-19 patients was 0.6%, significantly higher than in the general population 0.2% (p < 0.0001). The incidence of thromboembolic events in EIA + patients was 87.5%, significantly higher than the rate of 10.90% in all COVID-19 patients (p < 0.0001). The mortality rate in EIA + patients was 50%, significantly greater than the mortality rate of 12% in all hospitalized COVID-19 patients (p = 0.0011). Serological confirmation of HIT diagnosis was 37.5% which is significantly higher than confirmation of HIT in nonCOVID-19 patients 6% (p < 0.0001). Of 39 HIT antibody positive patients in the literature, 23.07% had positive confirmatory testing (6 SRA, 3 HIPAA) which is significantly higher than 5.6% in the general population (p = 0.00001). The incidence of thrombosis in EIA + COVID-19 patients in the literature was 56.4% which is significantly higher than reported rates of thrombotic events in in all COVID-19 patients in the literature at 4.8%1 (p = 0.00001). Conclusion Our study indicates incidence of HIT is higher in the COVID-19 population. This can be attributed to the cytokine storm and severe sepsis seen in critically ill COVID-19 patients. Our study also suggests that development of HIT can contribute to increased risk for thromboembolic events as well as mortality of COVID-19 patients, however, our study is limited due to small sample size.

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Heparin Induced Thrombocytopenia in Patients with COVID-19

Blood ◽

10.1182/blood-2020-134702 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 17-18

Author(s):

Surbhi Warrior ◽

Elizabeth Behrens ◽

Sefer Gezer ◽

Parameswaran Venugopal ◽

Shivi Jain

Keyword(s):

Risk Factors ◽

Mechanical Ventilation ◽

Platelet Factor 4 ◽

Thromboembolic Events ◽

Platelet Factor ◽

Heparin Induced Thrombocytopenia ◽

Increased Risk ◽

The Impact ◽

4T Score ◽

Immune Assay

Background The Coronavirus disease-2019 (COVID-19) is a global pandemic caused by novel coronavirus SARS-CoV-2. Acute respiratory and renal failure as well as systemic coagulopathy are critical aspects of the morbidity and mortality in patients with COVID-19. Heparin Induced Thrombocytopenia (HIT) occurs when IgG antibodies form against platelet factor 4-Heparin complex, resulting in platelet activation and removal, leading to a prothrombotic state. HIT is suspected when there is a platelet count decrease of more than 50% after exposure to heparin, along with hypercoagulability. Clinical Scoring systems like 4T Score (Thrombocytopenia, Timing, Thrombosis, no other cause of Thrombocytopenia) have been developed to assess the pretest probability of HIT. The use of unfractionated heparin, post-orthopedic and post-cardiac surgery state, female gender, and old age are recognized as risk factors for HIT. There is a nine-fold increased risk of developing HIT in patients requiring hemodialysis. ICU patients and patients with VTE without thrombocytopenia are considered to have low pre-test probability for HIT. Studies have shown that only 6% who are investigated serologically for HIT actually have the diagnosis. We conducted this study to assess the incidence and risk factors for HIT in COVID-19 positive patients and its impact on mortality. Methods A retrospective analysis was performed on all patients who were COVID-19 positive and hospitalized between March 1, 2020 and June 26, 2020 at our institution. Patients with intermediate or high suspicion for HIT, based on 4T score of 4 or higher, underwent IgG-specific platelet factor 4(PF4)-dependent enzyme immune assay (EIA). Washed platelet assays such as serotonin release assay (SRA) and heparin-induced platelet aggregation (HIPA) were used as confirmatory tests in cases with intermediate or low optical density (OD) with EIA. The incidence of HIT, its impact on mortality, and positivity of IgG-specific PF4-EIA in COVID-19 patients were studied, and statistical analysis was done with X2 testing. Subgroup analysis was performed based on demographic factors and risk factors for HIT, including exposure to heparin or low molecular weight heparin (LMWH), history of or cancer, recent orthopedic or cardiac surgery, exposure to renal replacement therapy (RRT), and severity of disease (D-dimer >6 ULN, Acute Kidney Injury, ICU admission, and mechanical ventilation requirement). These factors were analyzed by Fisher's exact test to determine their impact on mortality. The hospital course for HIT antibody-positive patients was further analyzed to study the impact of COVID-19 related therapy, such as Remdesivir, Tocilizumab, Hydroxychloroquine, Steroids, and anticoagulation after diagnosis of HIT. Results WEight out of 1265 hospitalized COVID-19 positive patients tested positive for IgG-specific platelet factor 4(PF4)-dependent enzyme immune assay (EIA+). Incidence of EIA+ in COVID-19 patients was 0.6%, which is significantly higher than in the general population 0.2% (p<.0001, 95% CI 0.25-1.20%). The incidence of thromboembolic events in EIA+ patients was 87.5%, significantly higher than the rate of 10.90% in all COVID-19 patients (p<.0001, CI 41.96- 86.98%). The mortality rate in EIA+ patients was 50%, significantly greater than the mortality rate of 12% in all hospitalized COVID-19 patients (p=.0011, CI 9.46-66.53). Serological confirmation of HIT diagnosis was 37.5% (2 had OD>1, 1 was SRA positive) which is significantly higher than confirmation of HIT in nonCOVID-19 patients 6% (p<.0001, 95% CI 29.57-85.32%). All 3 confirmed HIT patients (100%) had severe disease (3/3 required ICU admission, 2/3 required mechanical ventilation, the one not requiring mechanical ventilation required RRT). Conclusion Our study indicates incidence of HIT is higher in the COVID-19 population. The incidence of positive EIA for patients with intermediate to high 4T scores is also higher in COVID-19 positive patients. This can be attributed to the cytokine storm and severe sepsis seen in critically ill COVID-19 patients. Our study also suggests that development of HIT can contribute to increased risk for thromboembolic events as well as mortality of COVID-19 patients, however, our study is limited due to small sample size. Therefore, prospective studies are needed to analyze the impact of HIT on morbidity, mortality and long-term outcomes in COVID-19 patients. Table Disclosures No relevant conflicts of interest to declare.

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Heparin Re-Exposure in Patients with Heparin-Induced Thrombocytopenia (HIT)

Blood ◽

10.1182/blood.v124.21.4265.4265 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4265-4265 ◽

Cited By ~ 2

Author(s):

Prajwal Dhakal ◽

Vijaya R. Bhatt

Keyword(s):

Conflicts Of Interest ◽

Small Sample Size ◽

Small Sample ◽

Platelet Factor 4 ◽

Systemic Review ◽

Enzyme Linked Immunosorbent Assay ◽

Platelet Factor ◽

Platelet Recovery ◽

Risk Of Recurrence ◽

History Of

Abstract Introduction Patients with a history of HIT, who require cardiopulmonary bypass (CPB), have limited anticoagulation options. Unfractionated heparin (UFH) is preferred by surgeons during CPB because of their extensive experience, short half-life of the drug, and the availability of protamine sulfate to reverse its effect. However, heparin re-challenge may be associated with a risk of recurrence of HIT. A number of instances of successful heparin re-exposure during CPB have been reported in HIT patients. However, small sample size of these reports and a lack of systemic review have prevented better understanding of the potential complications. The objective of this study was to determine the safety of heparin re-exposure in HIT patients and various strategies utilized to reduce the recurrence of HIT. Methods Using several search terms, all cases of heparin re-exposure in HIT patients published and indexed in English language in Pubmed by June 2014 were reviewed. The bibliography of each relevant article was searched for additional related reports. The diagnosis of HIT was based on the clinical probability or 4T scoring system and laboratory tests. The exposure to either UFH or low molecular weight heparin (LMWH) in patients with a history of HIT was considered a re-exposure. In two cases, heparin was used multiple times for repeated cardiovascular surgeries after an initial diagnosis of HIT. Each re-exposure was determined as a different instance of re-exposure during analysis. Results A total of 136 patients with a history of HIT had 141 instances of heparin re-exposure. Median age was 56 years (6 weeks -87 yrs) and 67% were males. Regarding the original HIT diagnosis, UFH (98%) and nadroparin (2%) were the causative agents. Thrombotic complications occurred in 23%. The pretest probability score was high in 79% and moderate in 21%. Platelet aggregation studies (66%), enzyme linked immunosorbent assay (ELISA)/enzyme immunoassay (EIA) (20%), serotonin release assay (SRA) (2%), and both SRA and EIA (12%) were performed for diagnosis. Cardiac (76%) and vascular surgeries (11%) were the most common indications for heparin re-exposure. Although 67% were re-exposed to heparin after 3 months of HIT diagnosis, 11%, 8% and 15% were re-exposed within 1 week, between 1 week to 1 month, and 1 month to 3 months of HIT diagnosis respectively. Anti-platelet factor 4/heparin antibodies were positive in 63% before re-exposure. UFH (93%) or LMWH (7%) were the utilized agents during re-exposure. Sixteen patients (11%) underwent plasmapheresis to lower the level of anti-platelet factor 4/heparin antibodies before the re-exposure. Non-heparin anticoagulants such as bivalirudin, fondaparinux, danaparoid, r-hirudin, argatroban, lepirudin, and warfarin were used singly or in combination after the exposure in 63% of patients. With heparin re-exposure, 4.2% had complications, which included recurrence of HIT (2.1%), and bleeding (2.1%). Among the patients with HIT recurrence (n=3), one patient was re-exposed to UFH within a week of HIT diagnosis and shortly after platelet recovery with LMWH (Intensive Care Med. 1991;17(3):185-6.). The other two patients were initially diagnosed with HIT more than 5 years back and tested negative for anti-platelet factor 4/heparin antibody prior to heparin re-exposure. Conclusion A review of the published reports indicates that intra-operative heparin re-exposure in patients with HIT has a small risk of developing thrombocytopenia or recurrence of HIT. The use of pre-exposure plasmapheresis in patients with positive anti-platelet factor 4/heparin antibody and post-exposure non-heparin anticoagulants may have reduced the risk of recurrence of HIT. Given several limitations of such retrospective review, prospective studies are needed to validate these results. Disclosures No relevant conflicts of interest to declare.

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Platelet Trends Are Not Predictive of Heparin Induced Thrombocytopenia in Patients on Extra Corporeal Membrane Oxygenation

Blood ◽

10.1182/blood-2018-99-115396 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3767-3767

Author(s):

Daniel Stapor ◽

Anil Rengan ◽

Mark Weiner ◽

Huaqing Zhao ◽

Nadia Ali

Keyword(s):

Platelet Count ◽

Conflicts Of Interest ◽

Small Sample ◽

Clinical Suspicion ◽

Platelet Factor ◽

Heparin Induced Thrombocytopenia ◽

Membrane Oxygenation ◽

Increased Risk ◽

Test Result ◽

Over Time

Abstract Introduction: Extracorporeal membrane oxygenation (ECMO) is a form of a cardiopulmonary bypass circuit that is utilized for patients in dire need of cardiac or pulmonary support. The circuit exposes blood to artificial surfaces which leads to platelet activation, clotting and thrombocytopenia. The addition of heparin is required in order to prevent clots from forming along the circuit. Heparin-induced thrombocytopenia (HIT) and heparin induced thrombocytopenia and thrombosis (HITT) are serious adverse effects of heparin treatment characterized by formation of antibodies to heparin platelet factor 4 (PF4) complexed with heparin which leads to thrombocytopenia and a greatly increased risk of arterial and venous thrombosis. The well-established incidence of HIT ranges from 0.5-5% in patients exposed to heparin for more than four days. The reported incidence of HIT in ECMO patients ranges from less than 1% to 8.3%. However this data comes from only a few studies with small sample sizes. Our institution has a large lung center and as a result ECMO is utilized frequently. When patients are suspected to have HIT, they are taken off heparin and switched to a different anticoagulant. For patients without HIT, the switch to a different anticoagulant is unnecessary and exposes the patient to additional risks such as a higher risk of bleeding. Our aim was to calculate the incidence of HIT and HITT at our institution. Furthermore we wanted to examine the platelet trends of all patients on ECMO specifically comparing and contrasting the patients who are deemed true HIT positive vs. all other patients on ECMO. Methods: We conducted a retrospective analysis of all patients on ECMO at Temple University Hospital from July 1, 2012 to December 31, 2017. The data for this study was drawn from the T'PAU (Temple Population Access Utility) research data warehouse that has successfully merged data from the Epic EMR and the McKesson administrative system that houses important summary data on inpatient admissions going back through July 2012. Our inclusion criteria consisted of all patients on ECMO who had a clinical suspicion of HIT and thus had a screening test sent for HIT, the ELISA polyclonal IgG testing against PF4. The diagnosis of HIT or HITT was confirmed by PF4 antibody positivity with an optical density (OD) >1.0, serotonin release assay (SRA) positivity or a positive PF4 antibody test >0.4 and the presence of thrombosis. Linear mixed-effects model was used to estimate and compare platelet count change over time between true HIT patients and patients who tested negative for the HIT ELISA. Results: There were 164 patients on ECMO between July 1st, 2012 and December 31, 2017. A total of 77 patients had the HIT ELISA sent while on ECMO. Of those, 15 patients had a positive test result (OD > 0.4) and 62 had a negative test result. Of the patients with positive results, 5 patients had an OD > 1.0. Three of the 10 patients with an OD < 1.0 were found to have thrombosis. Therefore 8 patients had true HIT out of a total of 164 patients on ECMO, for an incidence of 4.88%. There was no difference of the change of platelet count over time between the HIT (n=8) and non-HIT (n=62) groups (P=0.98). Conclusion: The incidence of HIT in our ECMO patient population is similar to the incidence of HIT in all patients who have been exposed to heparin for four or more days. Patients requiring ECMO are very ill and with the accompanying thrombocytopenia that develops with the initiation of ECMO, the clinical suspicion for HIT is high. Unlike the majority of hospitalized patients, patients on ECMO are a unique population and platelet count trends are not necessarily a clinically reliable indicator for HIT. Our research supports that the full clinical picture should be taken in account when suspecting HIT in patients on ECMO, especially when considering a change in anticoagulation. Disclosures No relevant conflicts of interest to declare.

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Comparison between Platelet Factor 4/Heparin Complexes ELISA and Platelet Aggregation Test in Heparin-induced Thrombocytopenia

Thrombosis and Haemostasis ◽

10.1055/s-0038-1649823 ◽

1995 ◽

Vol 74 (02) ◽

pp. 804-805 ◽

Cited By ~ 8

Author(s):

Philippe Nguyên ◽

Chantal Droullé ◽

Gérard Potron

Keyword(s):

Platelet Aggregation ◽

Platelet Factor 4 ◽

Platelet Factor ◽

Heparin Induced Thrombocytopenia ◽

Heparin Complexes

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Faculty Opinions recommendation of Platelet factor 4 binds to bacteria, [corrected] inducing antibodies cross-reacting with the major antigen in heparin-induced thrombocytopenia.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.9384959.10016058 ◽

2011 ◽

Author(s):

A Koneti Rao

Keyword(s):

Platelet Factor 4 ◽

Platelet Factor ◽

Heparin Induced Thrombocytopenia ◽

Major Antigen

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The incidence and prevalence of cardiovascular diseases in gout: a systematic review and meta-analysis

Rheumatology International ◽

10.1007/s00296-021-04876-6 ◽

2021 ◽

Author(s):

Peter Cox ◽

Sonal Gupta ◽

Sizheng Steven Zhao ◽

David M. Hughes

Keyword(s):

Systematic Review ◽

Cardiovascular Disease ◽

Cardiovascular Risk ◽

Cardiovascular Diseases ◽

Small Sample Size ◽

Meta Analysis ◽

Random Effect ◽

Small Sample ◽

Future Research ◽

Increased Risk

AbstractThe aims of this systematic review and meta-analysis were to describe prevalence of cardiovascular disease in gout, compare these results with non-gout controls and consider whether there were differences according to geography. PubMed, Scopus and Web of Science were systematically searched for studies reporting prevalence of any cardiovascular disease in a gout population. Studies with non-representative sampling, where a cohort had been used in another study, small sample size (< 100) and where gout could not be distinguished from other rheumatic conditions were excluded, as were reviews, editorials and comments. Where possible meta-analysis was performed using random-effect models. Twenty-six studies comprising 949,773 gout patients were included in the review. Pooled prevalence estimates were calculated for five cardiovascular diseases: myocardial infarction (2.8%; 95% confidence interval (CI)s 1.6, 5.0), heart failure (8.7%; 95% CI 2.9, 23.8), venous thromboembolism (2.1%; 95% CI 1.2, 3.4), cerebrovascular accident (4.3%; 95% CI 1.8, 9.7) and hypertension (63.9%; 95% CI 24.5, 90.6). Sixteen studies reported comparisons with non-gout controls, illustrating an increased risk in the gout group across all cardiovascular diseases. There were no identifiable reliable patterns when analysing the results by country. Cardiovascular diseases are more prevalent in patients with gout and should prompt vigilance from clinicians to the need to assess and stratify cardiovascular risk. Future research is needed to investigate the link between gout, hyperuricaemia and increased cardiovascular risk and also to establish a more thorough picture of prevalence for less common cardiovascular diseases.

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Mediterranean Diet and Lifestyle Habits during Pregnancy: Is There an Association with Small for Gestational Age Infants? An Italian Single Centre Experience

Nutrients ◽

10.3390/nu13061941 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1941

Author(s):

Rachele De Giuseppe ◽

Manuela Bocchi ◽

Silvia Maffoni ◽

Elsa Del Bo ◽

Federica Manzoni ◽

...

Keyword(s):

Gestational Diabetes ◽

Mediterranean Diet ◽

Gestational Age ◽

Small For Gestational Age ◽

Small Sample Size ◽

Demographic Data ◽

Small Sample ◽

Activity Level ◽

Lifestyle Habits ◽

Increased Risk

Background. The small-for-gestational-age (SGA) in infants is related to an increased risk of developing Non-Communicable Diseases later in life. The Mediterranean diet (MD) is related to lower odds of being SGA. The study explored retrospectively the association between SGA, maternal MD adherence, lifestyle habits and other SGA risk factors during pregnancy. Methods. One hundred women (16–44 years) with a pregnancy at term were enrolled. Demographic data, parity, pre-gestational BMI, gestational weight gain, pregnancy-related diseases, and type of delivery were collected. The MD adherence (MEDI-LITE score ≥ 9), physical activity level, and smoking/alcohol consumption were registered. SGA neonates were diagnosed according to the neonatal growth curves. Results. Women were divided into “SGA group” vs. “non-SGA group”. The MD was adopted by 71% of women and its adherence was higher in the “non-SGA group” (p = 0.02). The prevalence of pregnancy-related diseases (gestational diabetes/pregnancy-induced hypertension) was higher in the “SGA group” (p = 0.01). The logistic regression showed that pregnancy-related diseases were the only independent risk factor for SGA. Conclusions. MD may indirectly reduce the risk of SGA since it prevents and exerts a positive effect on pregnancy-related diseases (e.g., gestational diabetes and hypertension). The small sample size of women in the SGA group of the study imposes a major limitation to the results and conclusions of this research, suggesting however that it is worthy of further investigation.

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Combination of AST to ALT and neutrophils to lymphocytes ratios as predictors of locally advanced disease in patients with bladder cancer subjected to radical cystectomy: Results from a single-institutional series

Urologia Journal ◽

10.1177/03915603211035191 ◽

2021 ◽

pp. 039156032110351

Author(s):

Alessandro Uleri ◽

Rodolfo Hurle ◽

Roberto Contieri ◽

Pietro Diana ◽

Nicolòmaria Buffi ◽

...

Keyword(s):

Bladder Cancer ◽

Radical Cystectomy ◽

Advanced Disease ◽

Independent Predictor ◽

Small Sample Size ◽

Statistical Significance ◽

Locally Advanced ◽

Small Sample ◽

Locally Advanced Disease ◽

Increased Risk

Background: Bladder cancer (BC) staging is challenging. There is an important need for available and affordable predictors to assess, in combination with imaging, the presence of locally-advanced disease. Objective: To determine the role of the De Ritis ratio (DRR) and neutrophils to lymphocytes ratio (NLR) in the prediction of locally-advanced disease defined as the presence of extravescical extension (pT ⩾ 3) and/or lymph node metastases (LNM) in patients with BC treated with radical cystectomy (RC). Methods: We retrospectively analyzed clinical and pathological data of 139 consecutive patients who underwent RC at our institution. Logistic regression models (LRMs) were fitted to test the above-mentioned outcomes. Results: A total of 139 consecutive patients underwent RC at our institution. Eighty-six (61.9%) patients had a locally-advanced disease. NLR (2.53 and 3.07; p = 0.005) and DRR (1 and 1.17; p = 0.01) were significantly higher in patients with locally-advanced disease as compared to organ-confined disease. In multivariable LRMs, an increasing DRR was an independent predictor of locally-advanced disease (OR = 3.91; 95% CI: 1.282–11.916; p = 0.017). Similarly, an increasing NLR was independently related to presence of locally-advanced disease (OR = 1.28; 95% CI: 1.027–1.591; p = 0.028). In univariate LRMs, patients with DRR > 1.21 had a higher risk of locally advanced disease (OR = 2.83; 95% CI: 1.312–6.128; p = 0.008). Similarly, in patients with NLR > 3.47 there was an increased risk of locally advanced disease (OR = 3.02; 95% CI: 1.374–6.651; p = 0.006). In multivariable LRMs, a DRR > 1.21 was an independent predictor of locally advanced disease (OR = 2.66; 95% CI: 1.12–6.35; p = 0.027). Similarly, an NLR > 3.47 was independently related to presence of locally advanced disease (OR = 2.24; 95% CI: 0.95–5.25; p = 0.065). No other covariates such as gender, BMI, neoadjuvant chemotherapy or diabetes reached statistical significance. The AUC of the multivariate LRM to assess the risk of locally advanced disease was 0.707 (95% CI: 0.623–0.795). Limitations include the retrospective nature of the study and the relatively small sample size.

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