Spontaneous Heparin-induced Thrombocytopenia Syndrome Research Articles

COVID-19 Vaccination-Associated Spontaneous Heparin-Induced Thrombocytopenia Syndrome

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) has emerged as the deadliest outbreak in recent American history, surpassing the estimated U.S. fatalities from the 1918 influenza pandemic. Since its identification in December 2019 in Wuhan, China, COVID-19 has contributed to the death of nearly six million people worldwide. The United States (U.S.) Food and Drug Administration (FDA) initially issued emergency use authorization for three vaccines for prevention of COVID-19, and currently two have received full FDA approval. Herein, we report a case of severe thrombocytopenia in a man following heterologous booster vaccination with the Pfizer-BioNTech COVID-19 vaccine with concomitant presence of a heparin-P4 antibody but without proximate heparin exposure. The degree of thrombocytopenia was severe, but the patient had a natural recovery of platelet count over the next 2 weeks without need for any immunomodulatory therapies. This is the first case report of COVID vaccine-associated heparin-induced thrombocytopenia (HIT)-like platelet disorder without proximate heparin exposure, also called spontaneous HIT syndrome. Keywords: Thrombocytopenia, Cor

Spontaneous HIT syndrome post-knee replacement surgery with delayed recovery of thrombocytopenia: a case report and literature review

Recently published reports have established a heparin-induced thrombocytopenia (HIT)-mimicking thromboembolic disorder without proximate heparin exposure, called spontaneous HIT syndrome. Although the pathophysiology remains unclear, anti-platelet factor 4 (PF4)/heparin antibodies possibly triggered by exposure to knee cartilage glycosaminoglycans or other non-heparin polyanions found on bacterial surfaces and nucleic acids have been postulated. We present a 53-year-old female receiving antithrombotic prophylaxis with aspirin following right total knee replacement surgery (without perioperative or any previous lifetime heparin exposure) who acutely presented with high-risk pulmonary embolism (PE) and right great saphenous vein thrombophlebitis on postoperative day (POD) 14; her platelet count at presentation was 13 × 109/L. Prior to diagnostic consideration of spontaneous HIT syndrome, the patient briefly received unfractionated heparin (UFH) and one dose of enoxaparin. The patient’s serum tested strongly positive for anti-PF4/heparin antibodies by two different PF4-dependent enzyme-linked immunosorbent assays (ELISAs) and by serotonin release assay (SRA). Failure of fondaparinux anticoagulation (persisting HIT-associated disseminated intravascular coagulation) prompted switching to argatroban. Severe thrombocytopenia persisted (platelet count nadir, 12 × 109/L, on POD21), and 9 days after starting argatroban symptomatic right leg deep-vein thrombosis (DVT) occurred, prompting switch to rivaroxaban. Thereafter, her course was uneventful, although platelet count recovery was prolonged, reaching 99 × 109/L by POD45 and 199 × 109/L by POD79. The patient’s serum elicited strong serotonin release in the absence of heparin (seen even with 1/32 serum dilution) that was enhanced by pharmacological concentrations of UFH (0.1 and 0.3 IU/mL) and fondaparinux (0.1–1.2 μg/mL, i.e., in vitro fondaparinux “cross-reactivity”). Ultimately, platelet count recovery was associated with seroreversion to a negative SRA (documented at POD151). Our literature review identified joint replacement surgery, specifically knee replacement, to be a relatively common trigger of spontaneous HIT syndrome. Further, including our patient case, 5 of 7 patients with spontaneous HIT syndrome post-orthopedic surgery who received treatment with argatroban developed new and/or progressive lower-limb DVT or recurrent PE despite anticoagulation with this parenteral direct thrombin inhibitor, suggesting that this patient population is at high risk of breakthrough thrombotic events despite treatment with this HIT treatment-approved anticoagulant. Our case also illustrates successful outcome with rivaroxaban for treatment of spontaneous HIT syndrome, consistent with emerging literature supporting safety and efficacy of direct oral anticoagulant therapy for treatment of acute HIT.

Management of heparin-induced thrombocytopenia.

The purpose of this review is to summarize recent findings on heparin-induced thrombocytopenia (HIT), a prothrombotic disorder caused by platelet-activating IgG targeting platelet factor 4 (PF4)/polyanion complexes. HIT can explain unusual clinical events, including adrenal hemorrhages, arterial/intracardiac thrombosis, skin necrosis, anaphylactoid reactions, and disseminated intravascular coagulation. Sometimes, HIT begins/worsens after stopping heparin ('delayed-onset' HIT). Various HIT-mimicking disorders are recognized (e.g., acute disseminated intravascular coagulation/'shock liver' with limb ischemia). HIT has features of both B-cell and T-cell immune responses; uptake of PF4/heparin complexes into macrophages ('macropinocytosis') facilitates the anti-PF4/heparin immune response. Antibody-induced activation of monocytes and platelets via their FcγIIA receptors triggers an intense procoagulant response. Sometimes, HIT antibodies recognize PF4 bound to (platelet-associated) chondroitin sulfate, explaining how HIT might occur without concurrent or recent heparin (delayed-onset HIT, 'spontaneous HIT syndrome'). The molecular structure of HIT antigen(s) has been characterized, providing a rationale for future drug design to avoid HIT and improve its treatment. The poor correlation between partial thromboplastin time and plasma argatroban levels (risking subtherapeutic anticoagulation) and need for intravenous administration of argatroban have led to increasing 'off-label' treatment with fondaparinux or one of the direct oral anticoagulants. Understanding the molecular mechanisms and unusual clinical features of HIT will improve its management.

Spontaneous heparin-induced thrombocytopenia (HIT) syndrome: HIT without any heparin exposure.

Heparin-induced thrombocytopenia (HIT) is a pro-thrombotic side effect of heparin therapy caused by HIT antibodies with platelet-activating properties. Recent advances in understanding of spontaneous HIT syndrome, which can occur even without any heparin exposure despite its clinical and serological characteristics being similar to those of HIT, reveal the following HIT clinical features atypical for an immune-mediated disease. Heparin-naïve patients can develop IgG antibodies as early as day 4, as in a secondary immune response. Evidence for an anamnestic response upon heparin re-exposure is lacking. In addition, HIT antibodies are relatively short-lived, unlike those in a secondary immune response. Antigen immunoassays are commonly used worldwide for serological diagnosis of HIT. However, such assays do not indicate whether HIT antibodies have platelet-activating properties, leading to low diagnostic specificity for HIT. The detection of platelet-activating antibodies using a washed platelet activation assay is crucial for making a HIT diagnosis. These atypical clinical and serological features should be carefully considered while appropriately diagnosing HIT, which leads to appropriate therapy such as immediate administration of an alternative anticoagulant for preventing thromboembolic events and re-administration of heparin during surgery involving cardiopulmonary bypass when HIT antibodies are no longer detectable.

Spontaneous heparin-induced thrombocytopenia syndrome: 2 new cases and a proposal for defining this disorder

AbstractThe existence of spontaneous heparin-induced thrombocytopenia (HIT) syndrome (or autoimmune HIT), defined as a transient prothrombotic thrombocytopenic disorder without proximate heparin exposure serologically indistinguishable from HIT, is controversial. We describe 2 new cases presenting with thrombotic stroke/thrombocytopenia: one following shoulder hemi-arthroplasty (performed without heparin) and the other presenting to the emergency room without prior hospitalization, heparin exposure, or preceding infection. Both patients tested strongly positive for anti-platelet factor 4 (PF4)/heparin immunoglobulin (Ig)G in 2 different immunoassays and in the platelet serotonin-release assay. Crucially, both patients’ sera also caused strong (>80%) serotonin release in the absence of heparin, a serologic feature characteristic of delayed-onset HIT (ie, where heparin use precedes HIT but is not required for subsequent development or worsening of thrombocytopenia). We propose that a rigorous definition of spontaneous HIT syndrome should include otherwise unexplained thrombocytopenia/thrombosis without proximate heparin exposure and with anti-PF4/heparin IgG antibodies that cause strong in vitro platelet activation even in the absence of heparin.

Spontaneous Heparin-Induced Thrombocytopenia Syndrome: Two New Cases and a Proposal For Defining This Disorder

IntroductionHeparin-induced thrombocytopenia (HIT) is a transient, autoimmune-like, prothrombotic disorder caused by heparin-dependent, platelet-activating IgG reactive against platelet factor 4/heparin (PF4/H). There is an emerging literature (Am J Med 2008;121:632-6. J Thromb Haemost 2008;6:1598-1600; Thromb Haemost 2013;109:669-75) pointing to rare instances of “spontaneous” HIT in patients without preceding heparin. We report 2 new cases and propose a definition for this controversial disorder. CASE #1. A 62-y.o. man presented with left middle cerebral artery stroke and thrombocytopenia (platelet count, 65×109/L). There was no previous history of thrombocytopenia, surgery, hospitalization, or heparin exposure. Clot extraction performed with heparin was complicated by further platelet count decline to 27 (nadir) and progressive thrombosis of the carotid artery. Aspirin was started, and the platelets recovered to >150 by day 13. CASE #2. A 54-y.o. female developed right leg swelling, left-upper extremity weakness/paresthesias, and thrombocytopenia (61×109/L) 15 days post-shoulder hemiarthroplasty; no intra-/postoperative heparin had been given. Brain MRI demonstrated acute infarct in the left posterior inferior cerebellar artery territory; angiography showed non-visualization of the left vertebral artery. Ultrasound revealed right lower-limb deep-vein thrombosis. Heparin treatment resulted in further platelet count fall to 37 (nadir). Treatment with argatroban, followed by fondaparinux, was associated with platelet count recovery to >150 by day 39. MethodsTesting for HIT antibodies was performed by commercial EIA-IgG/A/M (Immucor GTI Diagnostics), in-house EIA-IgG (McMaster), and serotonin-release assay (SRA). ResultsBoth patients' sera (obtained before any heparin administration) tested strongly positive for HIT antibodies (Table), including strong platelet activation at 0.1 and 0.3 IU/mL heparin, as well as at 0 U/mL heparin, with no platelet activation at 100 IU/mL heparin: these serological features are characteristic of “delayed-onset HIT” (Ann Intern Med 2001;135:502-6). Antibody reactivity declined markedly by 2 to 4 weeks (including loss of platelet-activating properties at 0 IU/mL heparin), in keeping with the usual transience of HIT antibodies (N Engl J Med 2001;344:1286-92), and paralleling both patients' platelet count recovery. DiscussionThese cases further support spontaneous HIT as an unusual explanation for acute arterial stroke and thrombocytopenia. One patient had preceding orthopedic surgery, an event previously reported with spontaneous HIT (Thromb Haemost 2013;109:669-75). The strong serum-dependent platelet activation at 0 IU/mL heparin helps to explain how thrombocytopenia and thrombosis can occur in a patient not receiving heparin. RECOMMENDATION. Based on the serological findings of these and previous cases, we propose that a definitive diagnosis of spontaneous HIT syndrome should be based upon all of the following criteria: thrombocytopenia, thrombosis, lack of proximate heparin exposure, strong-positive PF4-dependent immunoassay(s), and a strong-positive platelet activation assay featuring both heparin-dependent (e.g., high heparin neutralization) and heparin-independent platelet activation (at 0 IU/mL heparin). Disclosures:Warkentin:Pfizer Canada: Honoraria; Paringenix: Consultancy; Immucor GTI Diagnostics: Research Funding; WL Gore: Consultancy; GSK: Research Funding.