Autoimmune heparin‐induced thrombocytopenia and venous limb gangrene after aortic dissection repair: in vitro and in vivo effects of intravenous immunoglobulin

Abstract

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is a prothrombotic disorder characterized by heparindependent antibodies that activate platelets (PLTs) via PLT FcγIIa receptors. "Autoimmune" HIT (aHIT) indicates a HIT subset where thrombocytopenia progresses or persists despite stopping heparin; aHIT sera activate PLTs strongly even in the absence of heparin (heparin-independent PLTactivating properties). Affected patients are at risk of severe complications, including dual macro-and microvascular thrombosis leading to venous limb gangrene. High-dose intravenous immunoglobulin (IVIG) offers an approach to interrupt heparin-independent PLT-activating effects of aHIT antibodies. CASE REPORT:A 78-year-old male who underwent cardiopulmonary bypass for aortic dissection developed aHIT, disseminated intravascular coagulation, and deep vein thrombosis; progression to venous limb gangrene occurred during partial thromboplastin time (PTT)-adjusted bivalirudin infusion (underdosing from "PTT confounding"). Thrombocytopenia recovered with high-dose IVIG, although the PLT count increase began only after the third dose of a 5-day IVIG regimen (0.4 g/kg/day × 5 days). We reviewed case reports and case series of IVIG for treating HIT, focusing on various IVIG dosing regimens used. RESULTS: Patient serum-induced PLT activation wasinhibited in vitro by IVIG in a dose-dependent fashion; inhibition of PLT activation by IVIG was much more marked in the absence of heparin versus the presence of heparin (0.2 U/mL). Our literature review indicated 1 g/kg × 2 IVIG dosing as most common for treating HIT, usually associated with rapid PLT count recovery. CONCLUSION:Our clinical and laboratory observations support dose-dependent efficacy of IVIG for decreasing PLT activation and thus correcting thrombocytopenia in aHIT. Our case experience and literature review suggests dosing of 1 g/kg IVIG × 2 for patients with severe aHIT. ABBREVIATIONS: aHIT = autoimmune heparin-induced thrombocytopenia; DIC = disseminated intravascular coagulation; DVT = deep vein thrombosis; HIT = heparin-induced thrombocytopenia; ITP = idiopathic thrombocytopenic purpura; PE = pulmonary embolism; PF4 = platelet factor 4; POD = postoperative day; PTT(s) = partial thromboplastin time(s); SRA = serotonin release assay; UFH = unfractionated heparin. From the

High-dose intravenous immunoglobulin for the treatment and prevention of heparin-induced thrombocytopenia: a review

“…These nine patients had severe thrombocytopenia (median platelet count nadir, 14 × 10 9 /L), with 6 of 9 having HITassociated thrombosis, and another patient with GI bleeding. As reviewed elsewhere [57,61], these 9 patients showed favorable responses to IVIG, with platelet counts rising in all patients, to a median value of >100 × 10 9 /L by five days after starting IVIG. No apparent new or progressive thrombotic events were reported, and bleeding stopped in the patient who had GI bleeding.…”

“…By performing the SRA both in the presence and absence of heparin, they showed that heparinindependent platelet-activating properties of aHIT sera are readily inhibited by addition of IVIG in vitro. Similarly, the McMaster Platelet Immunology group has also shown that it is easier to inhibit aHIT serum-induced serotonin-release by IVIG in the absence of heparin vis-à-vis its presence ( Figure 3) [59,61].…”

“…Notably, one patient who received the total recommended IVIG dose (2 g/kg) over 5, rather than 2, days were found to have no platelet count rise until after the third (of 5) doses given [61]; considering the known dose-dependent effect of IVIG, this clinical course argues for giving a total dose of IVIG of 2g/kg (i.e. 1 g/kg administered on 2 consecutive days) so as to increase the chance that a sufficient plasma IgG level is attained that inhibits HIT antibody-induced platelet activation.…”

“…Although interest in IVIG to treat HIT appears to be a recent topic, its first use and scientific rationale were described several decades ago. However, this treatment received only minimal attention until the past five years, coinciding with the emergence of increasing recognition of aHIT, as well as reports supporting the use of IVIG for treating aHIT from HIT research groups in Canada [59,61], Germany [49], and the United States [52, 57,58]. Figure 1 shows the number of reported cases per year of publication, and also gives a historical timeline of events relating to use of IVIG to treat HIT [11,27,37,41,48,52,56,58,[66][67][68][69].…”

Anticoagulation in Patients With Heparin-Induced Thrombocytopenia Antibodies: New Armamentarium for an Individually Tailored Approach in Cardiac Surgery

“…4 The use of IVIG for treatment of HIT was first evaluated in the late 1980s and 90s. 5 It recently has been rediscovered and proven to provide potent and long-lasting inhibition of HIT-associated platelet activation and thrombosis. 5,6 The administration of IVIG thus potentially could compensate for the potential shortcomings of a heparin/cangrelor/protamine strategy in cardiac surgery with CPB.…”