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An update on evidence based diagnostic and confirmatory testing strategies for heparin induced thrombocytopenia using combined immunological and functional assays.
Amiral, J, Seghatchian, J
Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis. 2018;(6):804-811
Abstract
This manuscript aims to provide a concise review on current diagnostic/ confirmatory strategies of Heparin Induced Thrombocytopenia (HIT) with the combined use of immunological / functional assays in addition to the clinical probability. Laboratory diagnosis of HIT is of primordial importance as the related complications could become rapidly severe and life-threatening and can provoke limb amputation in some cases. The first action in the presence of HIT suspicion is to withdraw heparin and to initiate an alternative anticoagulant. Whilst vitamin K antagonists are not appropriate, anticoagulant options include Fondaparinux, Sodium Danaparoid, DOACs, Argatroban, and Bivalirudin. However, if HIT is excluded, patients can benefit again from the high therapeutic and antithrombotic efficacy of this drug, which remains superior to all the substitutive anticoagulant treatments. HIT is suspected in the presence of a platelet count drop > 50% on 2 successive counts, or a platelet count < 100 G/L, and of a significant clinical probability (4 Ts score). Testing patients' plasma is required for establishing the diagnosis. Laboratory investigation involves first the immunological measurement of heparin dependent IgG antibodies (mainly targeted to Heparin-Platelet Factor 4 complexes). When positive, a functional assay for platelet activation, performed at a low and high heparin concentration, allows confirming this disease. In any case, if the immuno-assay is negative, HIT can be excluded with a high probability, and heparin can be continued (if clinical examination favors this decision). Conversely, the higher the IgG antibody concentration is (and affinity), the higher is the probability of developing HIT. The functional assay has now become for confirming the platelet activation capacity of antibodies, and therefore confirming the presence of HIT. Up to now, the gold reference method for testing antibody-dependent platelet activation is the C14-Serotonin Release Assay, available only in very few laboratories working with radio-isotopes. A simple, sensitive, and accurate flow cytometry assay becomes now available to all clinical sites, and it can be easily used for testing the capacity of heparin dependent-antibodies to activate platelets, at low heparin concentration. This technique can be performed in any laboratory equipped with a flow cytometer and can make the HIT confirmation diagnosis rapidly available, which introduces a great improvement for management of patients with HIT. We believe that an evidence-based update on this topic is timely and well warranted.
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Heparin-induced thrombocytopenia-associated thrombosis: from arterial to venous to venous limb gangrene.
Warkentin, TE
Journal of thrombosis and haemostasis : JTH. 2018;(11):2128-2132
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Abstract
Heparin-induced thrombocytopenia (HIT) is an acquired immune-mediated hypercoagulability state that is strongly associated with thrombosis. During the 1970s and 1980s, the prevailing concept was that HIT was associated only with arterial thrombosis, through its unique pathogenesis via heparin-dependent, platelet-activating IgG antibodies. However, in 1990, when I began to encounter HIT in my clinical practice, I found that most such patients developed symptomatic venous thrombosis. This historical sketch summarizes some of the research that challenged the dogma of HIT being a mainly arterial prothrombotic disorder. Two studies - one a substudy of a randomized trial of post-orthopedic surgery thromboprophylaxis, and the second a retrospective five-hospital analysis of consecutive patients with positive test results for HIT antibodies - showed a marked predominance of venous over arterial thrombosis complicating HIT (~ 4 : 1). By the end of the 1990s, an even more dramatic manifestation of HIT-associated venous thrombosis was recognized: venous limb gangrene. Here, ischemic limb necrosis occurs despite palpable arterial pulses, as a result of both macrovascular and microvascular venous thrombosis. The surprising explanation was natural anticoagulant impairment (severe depletion of protein C, a vitamin K-dependent anticoagulant) resulting from treatment of HIT-associated deep vein thrombosis with warfarin (vitamin K antagonist). These insights from HIT research helped to elucidate the pathogenesis of ischemic limb losses in other intense non-HIT hypercoagulability states, including warfarin-associated venous limb gangrene complicating cancer-associated hypercoagulability, and symmetrical peripheral gangrene complicating disseminated intravascular coagulation of critical illness, in which proximate 'shock liver' helps to explain the profound failure of natural anticoagulant systems (protein C; antithrombin) in predisposing to peripheral limb microthrombosis in circulatory shock.
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Management of Perioperative Anticoagulation for Device Implantation.
Stewart, MH, Morin, DP
Cardiac electrophysiology clinics. 2018;(1):99-109
Abstract
Periprocedural management of anticoagulation for cardiac device implantation has evolved over the past 20 years. The traditional paradigm of vitamin K antagonist interruption with heparin bridging has now been shown to be less safe than continuation of vitamin K antagonists at therapeutic levels. Dual antiplatelet therapy during device implantation poses substantial risk but is often necessary. The safest dosing strategy for newer direct oral anticoagulants is still not clear.
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Interactions of methacryloylated gelatin and heparin modulate physico-chemical properties of hydrogels and release of vascular endothelial growth factor.
Claaßen, C, Southan, A, Grübel, J, Tovar, GEM, Borchers, K
Biomedical materials (Bristol, England). 2018;(5):055008
Abstract
Gelatin hydrogels are used as tissue engineering scaffolds and systems for controlled release due to their inherent biodegradability and biocompatibility. In this study gelatin methacryloyl(-acetyl) (GM/A) with various degrees of methacryloylation (DM) and methacryl-modified heparin (HepM) were cross-linked radically via thermal-redox initiation. Investigation of gel yields (79.4%-85.8%) and equilibrium degrees of swelling (EDS; 564.8%-750.3%) by an experimental design approach suggested interaction effects between the applied HepM mass fraction and the DM of gelatin. HepM reduced the cross-linking effectivity (gel yield) only when added to GM with low DM (83% without HepM, 79% with HepM) but not when added to GM with high DM. For EDS combined impacts of the physical and chemical nature of the applied biopolymers are indicated: the elevated hydrophilicity and low cross-linking potential of HepM enhanced EDS in GM gels with low DM (Ø 1.1-fold increase), and lowered the storage moduli of all GM formulations (Ø 1.2-fold decrease). Vascular endothelial growth factor (VEGF) loading before cross-linking of gels resulted in major loss of functional growth factor (Ø 0.5% release), while loading after cross-linking was successful and significant release was detected over 28 days (6.4%-10.4% release). Release kinetics were mainly controlled by the VEGF concentration used for loading, and thus VEGF release and physico-chemical properties of the hydrogels can be tuned independently from each other in a broad range.
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Heparinized saline versus normal saline for maintaining peripheral venous catheter patency in China: An open-label, randomized controlled study.
Xu, L, Hu, Y, Huang, X, Fu, J, Zhang, J
The Journal of international medical research. 2017;(2):471-480
Abstract
Objective To evaluate the effects of heparin saline versus normal saline as locking solution for maintaining patency in peripheral venous catheters in Chinese patients. Methods This open-label, randomized controlled study was conducted in two hepatobiliary surgery wards, where patients received identical treatments, at a tertiary referral hospital. Patients were randomly divided into a normal saline group (NS, 3 ml) or a heparin saline group (HS, 50 IU/ml, 3 ml) for catheter sealing. Results The study enrolled 286 patients and 609 peripheral venous catheters were included in the analysis. The patients in the two groups had no local infections or catheter-related bloodstream infections. There were no significant differences between the two groups in terms of the rate of catheter obstruction, duration time, or the rates of phlebitis, infiltration, and accidental catheter removal. Conclusions No significant differences in the peripheral venous catheter sealing effects were observed between normal saline and heparin saline usage in Chinese patients.
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Molecular dynamics simulations on networks of heparin and collagen.
Kulke, M, Geist, N, Friedrichs, W, Langel, W
Proteins. 2017;(6):1119-1130
Abstract
Synthetic scaffolds containing collagen (Type I) are of increasing interest for bone tissue engineering, especially for highly porous biomaterials in combination with glycosaminoglycans. In experiments the integration of heparin during the fibrillogenesis resulted in different types of collagen fibrils, but models for this aggregation on a molecular scale were only tentative. We conducted molecular dynamic simulations investigating the binding of heparin to collagen and the influence of the telopeptides during collagen aggregation. This aims at explaining experimental findings on a molecular level. Novel structures for N- and C-telopeptides were developed with the TIGER2 replica exchange algorithm and dihedral principle component analysis. We present an extended statistical analysis of the mainly electrostatic interaction between heparin and collagen and identify several binding sites. Finally, we propose a molecular mechanism for the influence of glycosaminoglycans on the morphology of collagen fibrils. Proteins 2017; 85:1119-1130. © 2017 Wiley Periodicals, Inc.
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A noninferiority trial comparing a heparin-grafted membrane plus citrate-containing dialysate versus regional citrate anticoagulation: results of the CiTED study.
Meijers, B, Metalidis, C, Vanhove, T, Poesen, R, Kuypers, D, Evenepoel, P
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2017;(4):707-714
Abstract
BACKGROUND Anticoagulation is a prerequisite for successful haemodialysis. Heparin and low-molecular weight heparins are routinely used despite increased bleeding risk. Regional citrate anticoagulation (RCA) is efficacious, but is laborious and may induce metabolic disturbances. Heparin-grafted membranes are less efficacious. It is not known whether combining citrate-containing dialysate and a heparin-grafted membrane is a valid anticoagulation strategy. METHODS We performed a randomized crossover noninferiority trial, with a prespecified noninferiority threshold of 10% in maintenance dialysis patients ( n = 25). We compared the combination of citrate-containing dialysate plus a heparin-grafted membrane [CiTrate and EvoDial (CiTED) protocol] with RCA. The primary endpoint was completion of dialysis without significant clotting. Secondary endpoints included time to clotting, achieved Kt / V urea , loss of total cell volume, venous air chamber clotting score and systemic-ionized calcium concentration. RESULTS In total, 1284 sessions were performed according to study protocol, 636 in the CiTED arm and 648 in the RCA arm. The primary outcome of preterm interruption due to clotting occurred in 36 (5.7%) of sessions in the CiTED arm, and in 40 (6.2%) sessions in the RCA arm, thereby meeting noninferiority criteria (P < 0.0001). Most of the clotting events occurred in the fourth hour of dialysis. Repetitive clotting occurred in four patients in the CiTED arm and one patient in the RCA arm. Time to preterm interruption due to clotting and achieved Kt / V urea was not significantly different. Systemic-ionized calcium levels during treatment were significantly lower in the RCA arm and clinically relevant hypocalcaemia was noted only in the RCA arm. CONCLUSION The combination of citrate-containing dialysate and a heparin-grafted membrane is a valid alternative to RCA.
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Heparin Binding to an Engineered Virus-like Nanoparticle Antagonist.
Cheong, HY, Groner, M, Hong, K, Lynch, B, Hollingsworth, WR, Polonskaya, Z, Rhee, JK, Baksh, MM, Finn, MG, Gale, AJ, et al
Biomacromolecules. 2017;(12):4113-4120
Abstract
The anticoagulant activity of heparin administered during medical interventions must be reversed to restore normal clotting, typically by titrating with protamine. Given the acute toxicity associated with protamine, we endeavored to generate safer heparin antagonists by engineering bacteriophage Qβ virus-like particles (VLPs) to display motifs that bind heparin. A particle bearing a single amino acid change from wild-type (T18R) was identified as a promising candidate for heparin antagonism. Surface potential maps generated through molecular modeling reveal that the T18R mutation adds synergistically to adjacent positive charges on the particle surface, resulting in a large solvent-accessible cationic region that is replicated 180 times over the capsid. Chromatography using a heparin-sepharose column confirmed a strong interaction between heparin and the T18R particle. Binding studies using fluorescein-labeled heparin (HepFL) resulted in a concentration-dependent change in fluorescence intensity, which could be perturbed by the addition of unlabeled heparin. Analysis of the fluorescence data yielded a dissociation constant of approximately 1 nM and a 1:1 binding stoichiometry for HepFL:VLP. Dynamic light scattering (DLS) experiments suggested that T18R forms discrete complexes with heparin when the VLP:heparin molar ratios are equivalent, and in vitro clotting assays confirmed the 1:1 binding stoichiometry as full antagonism of heparin is achieved. Biolayer interferometry and backscattering interferometry corroborated the strong interaction of T18R with heparin, yielding Kd ∼ 1-10 nM. These biophysical measurements further validated T18R, and VLPs in general, for potential clinical use as effective, nontoxic heparin antagonists.
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Taurolidine-citrate-heparin lock reduces catheter-related bloodstream infections in intestinal failure patients dependent on home parenteral support: a randomized, placebo-controlled trial.
Tribler, S, Brandt, CF, Petersen, AH, Petersen, JH, Fuglsang, KA, Staun, M, Broebech, P, Moser, CE, Jeppesen, PB
The American journal of clinical nutrition. 2017;(3):839-848
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Abstract
Background: In patients with intestinal failure who are receiving home parenteral support (HPS), catheter-related bloodstream infections (CRBSIs) inflict health impairment and high costs.Objective: This study investigates the efficacy and safety of the antimicrobial catheter lock solution, taurolidine-citrate-heparin, compared with heparin 100 IE/mL on CRBSI occurrence.Design: Forty-one high-risk patients receiving HPS followed in a tertiary HPS unit were randomly assigned in a double-blinded, placebo-controlled trial. External, stratified randomization was performed according to age, sex, and prior CRBSI incidence. The prior CRBSI incidence in the study population was 2.4 episodes/1000 central venous catheter (CVC) days [95% Poisson confidence limits (CLs): 2.12, 2.71 episodes/1000 CVC days]. The maximum treatment period was 2 y or until occurrence of a CRBSI or right-censoring because of CVC removal. The exact permutation tests were used to calculate P values for the log-rank tests.Results: Twenty patients received the taurolidine-citrate-heparin lock and 21 received the heparin lock, with 9622 and 6956 treatment days, respectively. In the taurolidine-citrate-heparin arm, no CRBSIs occurred, whereas 7 CRBSIs occurred in the heparin arm, with an incidence of 1.0/1000 CVC days (95% Poisson CLs: 0.4, 2.07/1000 CVC days; P = 0.005). The CVC removal rates were 0.52/1000 CVC days (95% Poisson CLs: 0.17, 1.21/1000 CVC days) and 1.72/1000 CVC days (95% Poisson CLs: 0.89, 3.0/1000 CVC days) in the taurolidine-citrate-heparin and heparin arm, respectively, tending to prolong CVC survival in the taurolidine arm (P = 0.06). Costs per treatment year were lower in the taurolidine arm (€2348) than in the heparin arm (€6744) owing to fewer admission days related to treating CVC-related complications (P = 0.02).Conclusions: In patients with intestinal failure who are life dependent on HPS, the taurolidine-citrate-heparin catheter lock demonstrates a clinically substantial and cost-beneficial reduction of CRBSI occurrence in a high-risk population compared with heparin. This trial was registered at clinicaltrials.gov as NCT01948245.
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Management of the multiple phases of heparin-induced thrombocytopenia.
Cuker, A
Thrombosis and haemostasis. 2016;(5):835-842
Abstract
The clinical course of heparin-induced thrombocytopenia (HIT) may be separated into five sequential phases: 1. suspected HIT, 2. acute HIT, 3. subacute HIT A, 4. subacute HIT B, and 5. remote HIT. Each phase confronts the clinician with a unique set of management questions. In this review, the phases of HIT are defined and key management questions associated with each phase are discussed. Among patients with Suspected HIT, I use the 4Ts score to determine which patients have a sufficiently high probability of HIT to justify discontinuation of heparin and initiation of a non-heparin parenteral anticoagulant. An algorithm for selecting an appropriate non-heparin anticoagulant based on the patient's clinical stability, renal and hepatic function, drug availability, and physician comfort is provided. In patients with Acute HIT, I generally avoid prophylactic platelet transfusion and inferior vena cava filter insertion because of a potential increased risk of thrombosis. I perform 4-limb screening compression ultrasonography. In patients with symptomatic thromboembolism or asymptomatic proximal deep-vein thrombosis, I treat with anticoagulation for three months. In patients without thrombosis, I discontinue anticoagulation upon platelet count recovery. I do not transition patients to an oral anticoagulant until platelet count recovery (i. e. Subacute HIT A). I increasingly choose direct oral anticoagulants over vitamin K antagonists in this setting because of their greater convenience and safety. In Subacute HIT B and Remote HIT, I use heparin for cardiovascular surgery, whereas I use bivalirudin in patients with Acute HIT and Subacute HIT A in whom surgery cannot be delayed.