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Background: COVID-19 vaccinations in the United States are effective in preventing illness and hospitalization yet concern over post-vaccination venous thromboembolism (VTE) risk has led to vaccine hesitancy., Methods: The aim of this study was to compare VTE rates before and after COVID-19 vaccination. COVID-19 vaccinated patients ≥18 years between November 1, 2020 through November 1, 2021 were analyzed using electronic medical records across the Mayo Clinic enterprise. The primary outcome was imaging confirmed acute VTE (upper or lower deep vein thrombosis or pulmonary embolism) occurring 90 days before and after the date of first vaccine dose., Results: A total of 792 010 patients with at least one COVID-19 vaccination were identified (Pfizer, n = 452 950, Moderna, n = 290 607, and Janssen [Johnson & Johnson], n = 48 453). A total of 1565 VTE events occurred in the 90 days before (n = 772) and after (n = 793) COVID-19 vaccination. VTE post-vaccination occurred in 326 patients receiving Moderna (0.11%, incidence rate [IR] 4.58 per 1000p-years), 425 patients receiving Pfizer (0.09%, IR 3.84 per 1000p-years), and 42 receiving Janssen (0.09%, IR 3.56 per 1000p-years). Compared to the pre-vaccination timeframe, the adjusted hazard ratio (aHR) for VTE after the Janssen vaccination was 0.97 (95% confidence interval [CI] 0.63-1.50), aHR 1.02 (95% CI 0.87-1.19) for Moderna, and aHR 1.00 (95% CI 0.87-1.15) for Pfizer., Conclusion: In this large cohort of COVID-19 vaccinated patients, no increased risk for acute VTE post-vaccination was identified for the authorized vaccines in the United States., (© 2022 International Society on Thrombosis and Haemostasis.)

Heparan sulfate (HS) and chondroitin sulfate (CS) are two structurally distinct natural polysaccharides. Here, we report the synthesis of a library of seven structurally homogeneous HS and CS chimeric dodecasaccharides (12-mers). The synthesis was accomplished using six HS biosynthetic enzymes and four CS biosynthetic enzymes. The chimeras contain a CS domain on the reducing end and a HS domain on the nonreducing end. The synthesized chimeras display anticoagulant activity as measured by both in vitro and ex vivo experiments. Furthermore, the anticoagulant activity of H/C 12-mer 5 is reversible by protamine, a U.S. Food and Drug Administration-approved polypeptide to neutralize anticoagulant drug heparin. Our findings demonstrate the synthesis of unnatural HS-CS chimeric oligosaccharides using natural biosynthetic enzymes, offering a new class of glycan molecules for biological research.

Rare cases of COVID-19 vaccinated individuals develop anti-platelet factor 4 (PF4) antibodies that cause thrombocytopenia and thrombotic complications, a syndrome referred to as vaccine-induced immune thrombotic thrombocytopenia (VITT). Currently, information on the characteristics and persistence of anti-PF4 antibodies that cause VITT after Ad26.COV2.S vaccination is limited, and available diagnostic assays fail to differentiate Ad26.COV2.S and ChAdOx1 nCoV-19-associated VITT from similar clinical disorders, namely heparin-induced thrombocytopenia (HIT) and spontaneous HIT. Here we demonstrate that while Ad26.COV2.S-associated VITT patients are uniformly strongly positive in PF4-polyanion enzyme-linked immunosorbent assays (ELISAs); they are frequently negative in the serotonin release assay (SRA). The PF4-dependent p-selectin expression assay (PEA) that uses platelets treated with PF4 rather than heparin consistently diagnosed Ad26.COV2.S-associated VITT. Most Ad26.COV2.S-associated VITT antibodies persisted for >5 months in PF4-polyanion ELISAs, while the PEA became negative earlier. Two patients had otherwise unexplained mild persistent thrombocytopenia (140-150 x 10 3 /µL) 6 months after acute presentation. From an epidemiological perspective, differentiating VITT from spontaneous HIT, another entity that develops in the absence of proximate heparin exposure, and HIT is important, but currently available PF4-polyanion ELISAs and functional assay are non-specific and detect all three conditions. Here, we report that a novel un-complexed PF4 ELISA specifically differentiates VITT, secondary to both Ad26.COV2.S and ChAdOx1 nCoV-19, from both spontaneous HIT, HIT and commonly-encountered HIT-suspected patients who are PF4/polyanion ELISA-positive but negative in functional assays. In summary, Ad26.COV2.S-associated VITT antibodies are persistent, and the un-complexed PF4 ELISA appears to be both sensitive and specific for VITT diagnosis., (© 2022 Wiley Periodicals LLC.)

Heparin-induced thrombocytopenia (HIT) is an immune complication of heparin therapy caused by antibodies to complexes of platelet factor 4 (PF4) and heparin. Pathogenic antibodies to PF4/heparin bind and activate platelets to propagate a hypercoagulable state culminating in life-threatening thrombosis. The serotonin-release assay (SRA) is considered the gold-standard test to diagnose HIT. However, the sensitivity of the SRA was questioned with reported cases of clinical diagnosis of HIT and negative SRA. Herein, we present the utility of platelet factor 4-dependent P-selectin expression assay (PEA) in diagnosing HIT in a patient with thrombocytopenia and recurrent thrombosis who repeatedly tested negative with SRA., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Heparin-induced thrombocytopenia (HIT) is a life-threatening, prothrombotic, antibody-mediated disorder. To maximize the likelihood of recovery, early and accurate diagnosis is critical. Widely available HIT assays, such as the platelet factor 4 (PF4) heparin enzyme-linked immunosorbent assay (ELISA) lack specificity, and the gold-standard carbon 14-labeled serotonin release assay (SRA) is of limited value for early patient management because it is available only through reference laboratories. Recent studies have demonstrated that pathogenic HIT antibodies selectively activate PF4-treated platelets and that a technically simpler assay, the PF4-dependent P-selectin expression assay (PEA), may provide an option for rapid and conclusive results. Based upon predefined criteria that combined 4Ts scores and HIT ELISA results, 409 consecutive adults suspected of having HIT were classified as disease positive, negative, or indeterminate. Patients deemed HIT indeterminate were considered disease negative in the primary analysis and disease positive in a sensitivity analysis. The ability of PEA and SRA to identify patients judged to have HIT was compared using receiver operating characteristic curve statistics. Using these predefined criteria, the diagnostic accuracy of PEA was high (area under the curve [AUC], 0.94; 95% confidence interval [CI], 0.87-1.0) and similar to that of SRA (AUC, 0.91; 95% CI, 0.82-1.0). In sensitivity analysis, the AUCs of PEA and SRA were also similar at 0.88 (95% CI, 0.78-0.98) and 0.86 (95% CI, 0.77-0.96), respectively. The PEA, a technically simple nonradioactive assay that uses ∼20-fold fewer platelets compared with the SRA, had high accuracy for diagnosing HIT. Widespread use of the PEA may facilitate timely and more effective management of patients with suspected HIT., (© 2021 by The American Society of Hematology.)

Background: Heparin-induced thrombocytopenia can be a life-threatening and limb-threatening complication of heparin therapy. Incidence and complication rates of this condition have been extrapolated from studies with modest sample sizes, and despite the availability of therapeutic interventions the outcomes of heparin-induced thrombocytopenia are not well understood. We aimed to estimate disease burden, complication rates, and costs of heparin-induced thrombocytopenia in the USA., Methods: In this population-based study we analysed data from 2009 to 2013 from the Nationwide (National) Inpatient Sample (NIS), a large, all-payer inpatient health-care database in the USA. To validate the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code for heparin-induced thrombocytopenia (289.84), we defined the sensitivity and specificity of this code using patient data from 2013 from a local hospital (Froedtert Memorial Lutheran Hospital, Milwaukee, WI, USA). The primary outcomes assessed were the incidence of hospital discharges with codes for heparin-induced thrombocytopenia and of discharges for heparin-induced thrombocytopenia associated with cardiopulmonary bypass, haemodialysis, hip or knee arthroplasty, trauma or injury (or both), and gingival or periodontal disease (or both). We also assessed the incidence of thrombosis, bleeding, limb or digit amputation, mortality, length of hospital stay, and associated hospital charges., Findings: Between 2009 and 2013, 97 566 discharges from the NIS assigned the ICD-9-CM code for heparin-induced thrombocytopenia, and 149 911 247 discharges coded for non-heparin-induced thrombocytopenia, were analysed. Overall, heparin-induced thrombocytopenia was identified in 97 566 (0·065%; SE 0·0012) of 150 008 813 discharges, corresponding to approximately one in 1500 hospital admissions. Patients undergoing cardiopulmonary bypass had the highest rates of heparin-induced thrombocytopenia (7702 [0·63%; SE 0·03] of 1 230 362), followed by those undergoing haemodialysis (23 012 [0·47%; 0·01] of 4 908 100), those with gingival or periodontal disease, or both (106 [0·12%; 0·03] of 88 621), and those with trauma or injury, or both (541 [0·09%; 0·01] of 602 944); patients with hip (845 [0·04%; 0·004] of 1 943 353) and knee (676 [0·02%; 0·002] of 3 022 602) arthroplasty had the lowest rates of heparin-induced thrombocytopenia. Thrombosis (29 079 [29·8%; SE 0·4] of 97 566) and bleeding (6044 [6·2%; 0·2] of 97 566) were common complications in heparin-induced thrombocytopenia, and 1446 (23·9%; 1·2) of 6044 patients with heparin-induced thrombocytopenia who had haemorrhage died. 742 (0·76%; SE 0·06) of 97 566 patients with heparin-induced thrombocytopenia discharges underwent amputations compared with 173 043 (0·12%; 0·001) of 149 911 247 with non-heparin-induced thrombocytopenia discharges (adjusted odds ratio 5·095 [95% CI 4·309-6·023]; p<0·0001). Overall, in-hospital mortality was 9842 (10·1%; SE 0·2) of 97 508 in discharge summaries coded for heparin-induced thrombocytopenia compared with 3 206 700 (2·1%; 0·01) of 149 811 891 in discharges for non-heparin-induced thrombocytopenia (adjusted odds ratio 4·075 [95% CI 3·846-4·317]; p<0·0001). The median length of stay among live discharges was 8·9 days (IQR 4·6-17·1) and total hospital charges were US$83 072 (IQR 37 240-188 419) for heparin-induced thrombocytopenia discharges compared with 2·6 days (1·4-4·8) and $21 360 (11 426-41 917) for non-heparin-induced thrombocytopenia discharges (p<0·0001 for both). 333 discharges from a local hospital were analysed to assess the diagnostic sensitivity and specificity of the heparin-induced thrombocytopenia ICD-9-CM code; sensitivity was 90·9% (95% CI 57·1-99·5) and specificity was 94·4% (91·1-96·6)., Interpretation: Complication rates for heparin-induced thrombocytopenia remain high and more effective preventive and treatment interventions are needed., Funding: None., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Cellular collection is an important and increasingly used apheresis procedure. These collections are performed by leukocytapheresis, a procedure involving the removal of a patient's or donor's white blood cells, and are used to collect hematopoietic progenitor cells, specific cell populations (such as T-lymphocytes), and granulocytes. Hematopoietic progenitor cell apheresis and T-lymphocyte collection are performed by procedures that enrich for mononuclear cells. Hematopoietic progenitor cells are used for autologous and allogeneic hematopoietic stem cell transplantation, whereas T-cell collection is being used increasingly in novel cellular therapy approaches and for donor lymphocyte infusions to induce graft-versus-leukemia effect. Granulocytes are collected from healthy donors to treat severe sepsis in patients who are refractory to antimicrobial therapies. Less frequently, cellular depletion of leukocytes may be indicated in leukemic patients who have severe hyperleukocytosis resulting in leukoaggregation and decreased tissue perfusion. In these procedures, establishing and maintaining adequate vascular access are critical prerequisites to ensuring a successful procedure. For most types of leukocytapheresis procedures, efforts should be made to ensure that they are performed using peripheral veins, and the use of an intravascular access device should be considered only after it is determined that peripheral access is not feasible or desirable. However, in some settings (such as in patients undergoing autologous hematopoietic stem cell transplantation), intravascular access devices are often used to facilitate both the leukocytapheresis procedure and the subsequent transplant. Here, different types of vascular access approaches used in cellular collections are discussed, and this information is supplemented by the author's experience and practice in areas where published information is limited., (© 2018 AABB.)

Background: Heparin-induced thrombocytopenia (HIT) complicated by severe thrombocytopenia and thrombosis can pose significant treatment challenges. Use of alternative anticoagulants in this setting may increase bleeding risks, especially in patients who have a protracted disease course. Additional therapies are lacking in this severely affected patient population., Methods: We describe three patients with HIT who had severe thromboembolism and prolonged thrombocytopenia refractory to standard treatment but who achieved an immediate and sustained response to IVIg therapy. The mechanism of action of IVIg was evaluated in these patients and in five additional patients with severe HIT. The impact of a common polymorphism (H/R 131) in the platelet IgG receptor FcγRIIa on IVIg-mediated inhibition of platelet activation was also examined., Results: At levels attained in vivo, IVIg inhibits HIT antibody-mediated platelet activation. The constant domain of IgG (Fc) but not the antigen-binding portion (Fab) is required for this effect. Consistent with this finding, IVIg had no effect on HIT antibody binding in a solid-phase HIT immunoassay (platelet factor 4 enzyme-linked immunoassay). The H/R131 polymorphism in FcγRIIa influences the susceptibility of platelets to IVIg treatment, with the HH131 genotype being most susceptible to IVIg-mediated inhibition of antibody-induced activation. However, at high doses of IVIg, activation of platelets of all FcγRIIa genotypes was significantly inhibited. All three patients did well on long-term anticoagulation therapy with direct oral anticoagulants., Conclusions: These studies suggest that IVIg treatment should be considered in patients with HIT who have severe disease that is refractory to standard therapies., (Copyright © 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Almost without exception, patients with heparin-induced thrombocytopenia/thrombosis (HIT) have antibodies that recognize platelet factor 4 (PF4) in a complex with heparin; however, many heparin-treated patients without HIT are also antibody-positive. A platelet activation test, the serotonin release assay (SRA), is useful for identifying a subset of antibodies that are platelet-activating and most likely to cause HIT. However, this "gold standard" assay for HIT diagnosis is technically demanding and is routinely available only through referral laboratories, limiting its availability for timely diagnosis and management., Methods: We compared the diagnostic performance of the SRA with that of a technically simple platelet activation assay, the PF4-dependent P-selectin expression assay (PEA), which uses platelets pretreated with PF4 as targets for antibody detection. Archived serum samples from 91 patients for whom clinical information (HIT 4Ts [thrombocytopenia, timing of platelet count fall, thrombosis, and other causes of thrombocytopenia] score) was available were used. Patients with an intermediate 4Ts score and a PF4 ELISA (enzyme-linked immunosorbent assay) optical density ≥ 2.0, or a high 4Ts score and a PF4 ELISA optical density ≥ 1.0, were considered HIT positive; others were designated HIT negative., Results: The PEA had higher diagnostic accuracy (area under the curve, 0.92 vs 0.82; P = .02) than the SRA, using this definition of HIT. Eleven of 16 serum samples that were PEA positive and SRA negative were HIT positive. Studies done with identical target platelets and serially diluted samples from patients with HIT showed that the PEA is inherently more sensitive than the SRA for the detection of platelet-activating antibodies., Conclusions: The PEA is technically less demanding than the SRA and may be more accurate for the diagnosis of HIT., (Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Red cell exchange (RCE) is a common procedure in adults with sickle cell disease (SCD). Implantable dual lumen Vortex (DLV) ports can be used for RCE in patients with poor peripheral venous access. We performed a retrospective cohort study of RCE procedures performed in adults with SCD. The main objective of the study was to compare the inlet speed, duration of procedures and rate of complications performed through DLV ports to those performed through temporary central venous and peripheral catheters. Twenty-nine adults with SCD underwent a total of 318 RCE procedures. Twenty adults had DLV ports placed and 218 procedures were performed using DLV ports. Mean length of follow-up after DLV port placement was 397 ± 263 days. Six DLV ports were removed due to infection and 1 for malfunction after a mean of 171 ± 120 days. Compared to temporary central venous and peripheral catheters, DLV port procedures had a greater rate of procedural complications, a longer duration, and a lower inlet speed (all P < 0.01). When accounting for the maximum allowable inlet speed to avoid citrate toxicity, 40% of DLV port procedures were greater than 10% below maximum speed, compared to 7 and 14% of procedures performed through temporary central venous and peripheral catheters (P < 0.0001). In conclusion, DLV ports can be used for RCE in adults with SCD, albeit with more procedural complications and longer duration. The smaller internal diameter and longer catheter of DLV ports compared to temporary central venous catheters likely accounts for the differences noted., (© 2015 Wiley Periodicals, Inc.)

Background: Granulocyte transfusion from healthy donors is used in the treatment of patients with granulocyte function defects, or transient neutropenia and severe bacterial or fungal infections resistant to maximal antimicrobial treatment., Study Design and Methods: This study evaluated the performance and safety of the newly developed granulocyte collection protocol of the Spectra Optia in a prospective, multicenter, open-label, randomized, paired crossover trial compared with the COBE Spectra apheresis system in a population of 32 evaluable healthy subjects. All subjects received granulocyte-colony-stimulating factor and dexamethasone before collection., Results: Granulocyte procedures from Spectra Optia apheresis procedures had an approximately 23% higher polymorphonuclear (PMN) collection efficiency (CE) than the COBE Spectra collections (mean, 53.7% vs. 43.2%; p < 0.01), while the platelet CE (10.9% vs. 10.8%, respectively) and hematocrit (7.4% vs. 7.4%) were comparable between collections on both devices. Spectra Optia collections generated a higher total PMN yield per liter of blood processed than those produced by the COBE Spectra (with means of 8.6 × 10(10) vs. 6.8 × 10(10) , respectively). Granulocyte viability was more than 99% with both devices, and chemotaxic and bacterial killing activities of circulating versus collected granulocytes were similarly preserved. Fewer operator adjustments were required with Spectra Optia and there was no significant difference in the number or intensity of adverse events between instruments., Conclusion: CE of the granulocyte collection procedure with the Spectra Optia was approximately 10 percentage points higher than with the COBE Spectra, required less operator involvement, and is safe for clinical implementation., (© 2014 AABB.)