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      Severe Autoimmune LMWH-Induced Thrombocytopenia Presenting with Aortic Thromboses, Adrenal Hemorrhage and Pulmonary Embolism: Response to High-Dose Intravenous Immunoglobulin

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      Canadian Journal of General Internal Medicine
      Dougmar Publishing Group, Inc.

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          Abstract

          The occurrence of heparin-induced thrombocytopenia (HIT) in the setting of low-molecular-weight heparin (LMWH) exposure is uncommon, with incidence reported at around 0.2%. Delayed-onset (autoimmune) HIT in the setting of LMWH use is rarer, with only two other case reports in the literature. An 83-year old man was admitted to hospital for an acute exacerbation of chronic obstructive pulmonary disease, receiving low-molecular-weight heparin (LMWH, tinzaparin) while in hospital for prophylaxis against deep venous thrombosis (DVT). One day after discharge, he presented to the emergency department with acute chest pain and dyspnea. Computed tomography revealed bilateral pulmonary embolism, multiple abdominal aortic thromboses, and unilateral adrenal hemorrhage, and he was given a bolus of intravenous unfractionated heparin (UFH) in the emergency department. His platelet count (prior to UFH bolus) was found to be markedly reduced (39 × 109/L) from normal values two days prior. We suspected heparin-induced thrombocytopenia (HIT) to have caused the thrombocytopenia and thromboses (arterial and venous), and thus anticoagulation therapy was changed from heparin to argatroban. His HIT assay was strongly positive, including features of autoimmune reactivity (serum-induced platelet activation in the absence of heparin). HIT developing after exposure to tinzaparin is relatively rare, and use of a scoring system helped to facilitate an early diagnosis. Additionally, this case demonstrates heparin-independent platelet activation, a marker for autoimmune HIT (aHIT).  The patient's serum tested strongly positive for IgG-specific anti-PF4/heparin EIA and serotonin release assay. The presence of these antibodies would also explain the further decline in his platelet count to 10 x 109/L after he received a bolus dose of heparin at the beginning of his second hospitalization. This case highlights the third reported case of delayed-onset HIT in the setting of LMWH, and the rapid response to high-dose intravenous immunoglobulin.

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          Autoimmune heparin-induced thrombocytopenia.

          Autoimmune heparin-induced thrombocytopenia (aHIT) indicates the presence in patients of anti-platelet factor 4 (PF4)-polyanion antibodies that are able to activate platelets strongly even in the absence of heparin (heparin-independent platelet activation). Nevertheless, as seen with serum obtained from patients with otherwise typical heparin-induced thrombocytopenia (HIT), serum-induced platelet activation is inhibited at high heparin concentrations (10-100 IU mL-1heparin). Furthermore, upon serial dilution, aHIT serum will usually show heparin-dependent platelet activation. Clinical syndromes associated with aHIT include: delayed-onset HIT, persisting HIT, spontaneous HIT syndrome, fondaparinux-associated HIT, heparin 'flush'-induced HIT, and severe HIT (platelet count of < 20 × 109 L-1) with associated disseminated intravascular coagulation (DIC). Recent studies have implicated anti-PF4 antibodies that are able to bridge two PF4 tetramers even in the absence of heparin, probably facilitated by non-heparin platelet-associated polyanions (chondroitin sulfate and polyphosphates); nascent PF4-aHIT-IgG complexes recruit additional heparin-dependent HIT antibodies, leading to the formation of large multimolecular immune complexes and marked platelet activation. aHIT can persist for several weeks, and serial fibrin, D-dimer, and fibrinogen levels, rather than the platelet count, may be helpful for monitoring treatment response. Although standard anticoagulant therapy for HIT ought to be effective, published experience indicates frequent failure of activated partial thromboplastin time (APTT)-adjusted anticoagulants (argatroban, bivalirudin), probably because of underdosing in the setting of HIT-associated DIC, known as 'APTT confounding'. Thus, non-APTT-adjusted therapies with drugs such as danaparoid and fondaparinux, or even direct oral anticoagulants, such as rivaroxaban or apixaban, are suggested therapies, especially for long-term management of persisting HIT. In addition, emerging data indicate that high-dose intravenous immunoglobulin can interrupt HIT antibody-induced platelet activation, leading to rapid platelet count recovery.
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            Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis.

            Heparin-induced thrombocytopenia (HIT) is an uncommon but potentially devastating complication of anticoagulation with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). Our objective was to determine and compare the incidences of HIT in surgical and medical patients receiving thromboprophylaxis with either UFH or LMWH. All relevant studies identified in the MEDLINE database (1984-2004), not limited by language, and from reference lists of key articles were evaluated. Randomized and nonrandomized controlled trials comparing prophylaxis with UFH and LMWH and measuring HIT or thrombocytopenia as outcomes were included. Two reviewers independently extracted data on thromboprophylaxis (type, dose, frequency, and duration), definition of thrombocytopenia, HIT assay, and rates of the following outcomes: HIT, thrombocytopenia, and thromboembolic events. HIT was defined as a decrease in platelets to less than 50% or to less than 100 x 10(9)/L and positive laboratory HIT assay. Fifteen studies (7287 patients) were eligible: 2 randomized controlled trials (RCTs) measuring HIT (1014 patients), 3 prospective studies (1464 patients) with nonrandomized comparison groups in which HIT was appropriately measured in both groups, and 10 RCTs (4809 patients) measuring thrombocytopenia but not HIT. Three analyses were performed using a random effects model and favored the use of LMWH: (1) RCTs measuring HIT showed an odds ratio (OR) of 0.10 (95% confidence interval [CI], 0.01-0.2; P = .03); (2) prospective studies measuring HIT showed an OR of 0.10 (95% CI, 0.03-0.33; P < .001); (3) all 15 studies measured thrombocytopenia. The OR was 0.47 (95% CI, 0.22-1.02; P = .06). The inverse variance-weighted average that determined the absolute risk for HIT with LMWH was 0.2%, and with UFH the risk was 2.6%. Most studies were of patients after orthopedic surgery.
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              Treatment and prevention of heparin-induced thrombocytopenia: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).

              This chapter about the recognition, treatment, and prevention of heparin-induced thrombocytopenia (HIT) is part of the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs. Grade 2 suggests that individual patient values may lead to different choices. Among the key recommendations in this chapter are the following: For patients receiving heparin in whom the clinician considers the risk of HIT to be > 1.0%, we recommend platelet count monitoring over no platelet count monitoring (Grade 1C). For patients who are receiving heparin or have received heparin within the previous 2 weeks, we recommend investigating for a diagnosis of HIT if the platelet count falls by >/= 50%, and/or a thrombotic event occurs, between days 5 and 14 (inclusive) following initiation of heparin, even if the patient is no longer receiving heparin therapy when thrombosis or thrombocytopenia has occurred (Grade 1C). For patients with strongly suspected (or confirmed) HIT, whether or not complicated by thrombosis, we recommend use of an alternative, nonheparin anticoagulant (danaparoid [Grade 1B], lepirudin [Grade 1C], argatroban [Grade 1C], fondaparinux [Grade 2C], or bivalirudin [Grade 2C]) over the further use of unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) therapy or initiation/continuation of vitamin K antagonists (VKAs) [Grade 1B]. The guidelines include specific recommendations for nonheparin anticoagulant dosing that differ from the package inserts. For patients with strongly suspected or confirmed HIT, we recommend against the use of vitamin K antagonist (VKA) [coumarin] therapy until after the platelet count has substantially recovered (usually, to at least 150 x 10(9)/L) over starting VKA therapy at a lower platelet count (Grade 1B); that VKA therapy be started only with low maintenance doses (maximum, 5 mg of warfarin or 6 mg of phenprocoumon) over higher initial doses (Grade 1B); and that the nonheparin anticoagulant (eg, lepirudin, argatroban, danaparoid) be continued until the platelet count has reached a stable plateau, the international normalized ratio (INR) has reached the intended target range, and after a minimum overlap of at least 5 days between nonheparin anticoagulation and VKA therapy rather than a shorter overlap (Grade 1B). For patients receiving VKAs at the time of diagnosis of HIT, we recommend use of vitamin K (10 mg po or 5 to 10 mg IV) [Grade 1C].
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                Author and article information

                Journal
                Canadian Journal of General Internal Medicine
                Can Journ Gen Int Med
                Dougmar Publishing Group, Inc.
                2369-1778
                1911-1606
                August 27 2018
                August 27 2018
                : 13
                : 3
                : 29-34
                Article
                10.22374/cjgim.v13i3.254
                035a5432-977d-412b-a578-ce53cd22c12d
                © 2018

                Copyright of articles published in all DPG titles is retained by the author. The author grants DPG the rights to publish the article and identify itself as the original publisher. The author grants DPG exclusive commercial rights to the article. The author grants any non-commercial third party the rights to use the article freely provided original author(s) and citation details are cited. To view a copy of this license, visit https://creativecommons.org/licenses/by-nc/4.0/


                General medicine,Geriatric medicine,Neurology,Internal medicine
                General medicine, Geriatric medicine, Neurology, Internal medicine

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