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Rationale for the Role of Heparin and Related GAG Antithrombotics in COVID-19 Infection.
Magnani, HN
Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis. 2021;:1076029620977702
Abstract
The SARS-CoV-2 pandemic has focused attention on prevention, restriction and treatment methods that are acceptable worldwide. This means that they should be simple and inexpensive. This review examines the possible role of glycosaminoglycan (GAG) antithrombotics in the treatment of COVID-19. The pathophysiology of this disease reveals a complex interplay between the hemostatic and immune systems that can be readily disrupted by SARS-CoV-2. Some of the GAG antithrombotics also possess immune-modulatory actions and since they are relatively inexpensive they could play an important role in the management of COVID-19 and its complications.
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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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Pharmacotherapy of heparin-induced thrombocytopenia: therapeutic options and challenges in the clinical practices.
Al-Eidan, FA
Journal of vascular nursing : official publication of the Society for Peripheral Vascular Nursing. 2015;(1):10-20
Abstract
Heparin-induced thrombocytopenia (HIT) is an immune response to heparin associated with significant morbidity and mortality in hospitalized patients if unidentified as soon as possible, owing to thromboembolic complications involving both arterial and venous systems. Early diagnoses based on a comprehensive interpretation of clinical and laboratory information improves clinical outcomes. Management principles of strongly suspected HIT should not be delayed for laboratory result confirmation. Treatment strategies have been introduced including new, safe, and effective agents. This review summarizes the clinical therapeutic options for HIT addressing the use of parenteral direct thrombin inhibitors and indirect factor Xa inhibitors as well as the potential non-vitamin K antagonist oral anticoagulants.
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The complex clinical picture of side effects to anticoagulation.
Trautmann, A, Seitz, CS
The Medical clinics of North America. 2010;(4):821-34, xii-iii
Abstract
Inflammatory plaques at injection sites are frequent side effects of heparin treatment and a clinical symptom of delayed-type hypersensitivity (DTH) to heparin. In most cases, changing the subcutaneous therapy from unfractionated to low-molecular-weight heparin or treatment with heparinoids does not provide improvement because of extensive cross-reactivity. Because of their completely different chemical structure, hirudins are a safe alternative for anticoagulation. Despite DTH to subcutaneously injected heparins, patients tolerate heparin intravenously. Therefore, in case of therapeutic necessity and DTH to heparins, the simple shift from subcutaneous to intravenous heparin administration is justified. Skin necrosis is a rare complication of anticoagulation. Heparin-induced skin necrosis is 1 of the symptoms of immune-mediated heparin-induced thrombocytopenia and should result in the immediate cessation of heparin therapy to prevent potentially fatal thrombotic events. This is in contrast to coumarin-induced skin necrosis, where therapy may be continued or restarted at a lower dose.
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Agents for the treatment of heparin-induced thrombocytopenia.
Warkentin, TE
Hematology/oncology clinics of North America. 2010;(4):755-75, ix
Abstract
Heparin-induced thrombocytopenia (HIT) is an immune-mediated adverse drug effect characterized by platelet activation, hypercoagulability, and increased risk of thrombosis, both venous and arterial. A diagnosis of HIT usually signifies that heparin products, including unfractionated and low-molecular-weight heparin, are contraindicated. Although it is uncertain whether heparin continuation really worsens clinical outcomes, it is clear that vitamin K antagonists such as warfarin do worsen outcomes, as they promote microvascular thrombosis, with the potential for limb amputation (venous limb gangrene). Thus, alternative nonheparin anticoagulants are at the forefront of HIT therapy. This review proposes that alternative anticoagulants (danaparoid, fondaparinux) that share certain properties of heparin-namely its irreversible antithrombin-mediated inhibition of factor Xa-and that have relatively long half-lives, have several advantages in the therapy for HIT over short-acting agents that inhibit thrombin directly (recombinant hirudin, argatroban, and bivalirudin).
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HIT: lessons learned.
Warkentin, TE
Pathophysiology of haemostasis and thrombosis. 2006;(1-2):50-7
Abstract
The peculiar pathogenesis of heparin-induced thrombocytopenia (HIT), involving a "self" antigen-platelet factor 4 (PF4) bound to heparin-and resulting antibody-mediated platelet activation, is a model for thrombosis triggered by drug-induced autoimmunity. The high probability of forming an immune response to heparin, and the highly-variable clinical significance of a positive laboratory test-depending on the type of assay and the magnitude of a given positive test result-provides lessons regarding appropriate interpretation of diagnostic laboratory testing in the context of pretest probability. The relatively high risk of inducing microvascular thrombosis due to coumarin-induced vitamin K antagonism attests to the dangers of a compromised protein C natural anticoagulant system in the setting of a hypercoagulability state such as HIT. Unusual immunologic features of HIT, such as the dissociation between immunogenicity (induction of immune response) and cross-reactivity (capacity to form the antigens recognized by HIT antibodies)of the implicated polysaccharide anticoagulants, and the generally rapid formation and disappearance of anti-PF4/heparin antibodies, suggest that further lessons regarding HIT immunopathogenesis remain to be learned.
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Effects of two differently heparin-coated extracorporeal circuits on markers for brain and myocardial dysfunction.
Flom-Halvorsen, HI, Ovrum, E, Brosstad, F, Tangen, G, Ringdal, M, Oystese, R
Perfusion. 2002;(5):339-45
Abstract
OBJECTIVE The two most commonly used heparin-coated systems for cardiopulmonary bypass (CPB) are the Carmeda Bio-Active Surface (CBAS) (Medtronic, Minneapolis, MN, USA) and the Duraflo II coating (Baxter Healthcare, Irvine, CA, USA). The two surfaces are technically unequal and previous experimental studies have demonstrated disparities in effects on the immune system and blood cells. However, little is known concerning the influence of the two surfaces on markers for brain and myocardial dysfunction. METHODS Forty patients undergoing elective, primary coronary bypass grafting with CPB were prospectively randomized to either the CBAS system or the Duraflo II circuit. During and after CPB, biological markers for brain dysfunction and myocardial injury were analysed. RESULTS Both markers for brain dysfunction S-100B and neuron-specific enolase (NSE) increased significantly during CPB (p = 0.01). The elevation during bypass correlated significantly with the duration of CPB (r = 0.39 and r = 0.38, respectively, both p < 0.02). NSE was somewhat more elevated in the Duraflo II group at the end of CPB (p = 0.01) and 5 h after CPB (p = 0.02); for S-100B, there were no intergroup differences. Also, the markers related to myocardial injury, myoglobin and creatine kinase (CK-MB) mass increased during CPB (p = 0.01), while elevation of troponin-I occurred 5 h after CPB (p = 0.01). There were no statistically significant intergroup differences. No significant correlation was seen between the release of cardiac markers and the duration of CPB. The clinical course was similar in both groups. CONCLUSIONS Except for a slightly higher elevation of NSE at the end of CPB and 5 h after CPB in the Duraflo II group, there were no significant differences between the CBAS group and the Duraflo II group concerning markers for brain and myocardial dysfunction.