IVIg for Treatment of Severe Refractory Heparin-Induced Thrombocytopenia

Padmanabhan, Anand; Jones, Curtis G.; Pechauer, Shannon M.; Curtis, Brian R.; Bougie, Daniel W.; Irani, Mehraboon S.; Bryant, Barbara; Alperin, Jack B.; DeLoughery, Thomas G.; Mulvey, Kevin P.; Dhakal, Binod; Wen, Renren; Wang, Demin; Aster, Richard H.

doi:10.1016/j.chest.2017.03.050

Cited by 114 publications

(129 citation statements)

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“…Laboratory testing revealed that IVIG therapy significantly inhibited platelet activation by the patient's HIT antibody in the PEA when low concentrations of PF4 were used (PEA, low PF4) but had little effect on SRA and HIT ELISA test results, consistent with the presence of strong, platelet‐activating HIT antibodies, as noted previously (Fig. ).…”

Section: Case Presentation/resultsmentioning

confidence: 99%

“…Patients with histidine at aa131 in FcγRIIa, on the other hand, are competent to be bound by both normal IgG 2 and IgG 1 , leading to greater protection from HIT antibody‐mediated platelet activation. The patient was heterozygous for histidine and arginine, a genotype associated with limited ability (relative to HH131) of the patient's own plasma immunoglobulins to inhibit HIT antibody‐mediated platelet activation …”

Section: Case Presentation/resultsmentioning

confidence: 99%

“…The patient consented to research testing under an approved Institutional Review Board protocol (Medical College of Wisconsin, Protocol PRO00023318). The PF4‐dependent P‐selectin expression assay (PEA) for detection of platelet‐activating HIT antibodies was performed as previously described . Briefly, pooled washed O blood group normal platelets (1 × 10) were treated with PF4 (37.5 μg/mL PEA or 3.75 μg/mL PEA, low PF4 PEA) for 20 minutes followed by patient serum for 1 hour.…”

Section: Methodsmentioning

confidence: 99%

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Use of intravenous immunoglobulin G to treat spontaneous heparin‐induced thrombocytopenia

et al. 2018

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BACKGROUND Spontaneous heparin‐induced thrombocytopenia (HIT) is a rare but serious prothrombotic syndrome characterized by thrombosis, thrombocytopenia, and strong platelet‐activating HIT antibodies in the absence of heparin exposure, and is frequently characterized by a suboptimal response to standard therapies. Here, we present the first report of intravenous immunoglobulin G (IVIG) use in a patient with spontaneous HIT. STUDY DESIGN AND METHODS Patient information, including demographic, clinical, and laboratory results, were obtained from the electronic medical record. Laboratory testing was performed in the serotonin release assay, platelet factor 4 (PF4)‐dependent P‐selectin expression assay, and PF4/polyvinylsulfonate enzyme‐linked immunosorbent assay to study the impact of IVIG on HIT antibody‐mediated platelet activation. The patient was also genotyped for a polymorphism in the IgG receptor on platelets, FcγRIIa, at amino acid position 131. RESULTS A 30‐year‐old man had a thrombotic stroke and thrombocytopenia and strong HIT serologies in the absence of proximate heparin use. Direct thrombin inhibitor therapy was not associated with a prompt response. Due to severity and extent of thrombosis and persistent thrombocytopenia, he was treated with high‐dose IVIG. This treatment was associated with rapid and sustained normalization of platelet counts and a gradual improvement in thrombotic complications. Platelet activation induced by HIT antibodies in the PF4‐dependent P‐selectin expression assay (low PF4) was significantly lower after IVIG treatment, correlating well with platelet rise. Consistent with the severity of thrombosis, the patient was found to possess the 131HR polymorphism in FcγRIIa. CONCLUSION These results suggest that IVIG may be a useful adjunctive therapy in spontaneous HIT.

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Section: Case Presentation/resultsmentioning

confidence: 99%

Section: Case Presentation/resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Use of intravenous immunoglobulin G to treat spontaneous heparin‐induced thrombocytopenia

et al. 2018

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“…Interestingly, there is an inverse relationship between the severity of thrombocytopenia and the degree of heparin‐independent platelet activation induced by patient serum . High‐dose intravenous gamma globulin (IVIG) interrupts HIT antibody‐induced platelet activation, resulting in rapid platelet count recovery …”

Section: Autoimmune Hit (Ahit)mentioning

confidence: 99%

“…39 High-dose intravenous gamma globulin (IVIG) interrupts HIT antibody-induced platelet activation, resulting in rapid platelet count recovery. 31,40…”

Section: Persisting Hitmentioning

confidence: 99%

Laboratory diagnosis of heparin‐induced thrombocytopenia

Warkentin

2019

Int J Lab Hematology

111

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Heparin‐induced thrombocytopenia (HIT) is a clinical‐pathological disorder; thus, laboratory testing for the pathogenic platelet‐activating antiplatelet factor 4 (PF4)/heparin antibodies is central for diagnosis. The “iceberg” model summarizes the inter‐relationship between platelet activation assays and PF4‐dependent immunoassays, with platelet‐activating antibodies comprising a subset of anti‐PF4/heparin antibodies. The platelet serotonin‐release assay (SRA), performed by reference laboratories, has high sensitivity and specificity for HIT (~95% each), and is especially suited for detecting highly pathogenic HIT sera containing both heparin‐dependent and heparin‐independent platelet‐activating antibodies; this latter subgroup of antibodies explains “autoimmune HIT” disorders (delayed‐onset, persisting, spontaneous, heparin “flush,” fondaparinux‐associated). Recently, SRA‐negative HIT has become recognized, in which serum from some HIT patients contains subthreshold levels of platelet‐activating antibodies (by SRA) that become detectable using a PF4‐enhanced platelet activation assay. Unusual immunologic features of HIT include early antibody detectability (at onset of platelet count fall) and antibody transience (seroreversion). Widely available PF4‐dependent enzyme immunoassays (EIAs) have high sensitivity but poor specificity for HIT, although specificity is enhanced with IgG‐specific EIAs and strong positive results; unfortunately, EIA results are usually not available in real time. Automated rapid immunoassays, such as the chemiluminescence immunoassay (CLIA) and latex immunoturbidimetric assay (LIA), facilitate real‐time laboratory diagnosis. Recently available likelihood ratio (LR) data for positive (LR+) and negative (LR−) test results allow clinicians to adjust their pretest probabilities for HIT, using Bayesian analysis, into real‐time posttest probabilities that are dramatically increased (test positive) or decreased (test negative). Moreover, (semi‐)quantitative CLIA‐ and LIA‐positive results (weak, moderate, strong positive) can further refine the posttest probability of HIT.

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Clinical Characteristics and Pharmacological Management of COVID-19 Vaccine–Induced Immune Thrombotic Thrombocytopenia With Cerebral Venous Sinus Thrombosis

et al. 2021

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IMPORTANCEThe COVID-19 pandemic saw one of the fastest developments of vaccines in an effort to combat an out-of-control pandemic. The 2 most common COVID-19 vaccine platforms currently in use, messenger RNA (mRNA) and adenovirus vector, were developed on the basis of previous research in use of this technology. Postauthorization surveillance of COVID-19 vaccines has identified safety signals, including unusual cases of thrombocytopenia with thrombosis reported in recipients of adenoviral vector vaccines. One of the devastating manifestations of this syndrome, termed vaccine-induced immune thrombotic thrombocytopenia (VITT), is cerebral venous sinus thrombosis (CVST). This review summarizes the current evidence and indications regarding biology, clinical characteristics, and pharmacological management of VITT with CVST.OBSERVATIONS VITT appears to be similar to heparin-induced thrombocytopenia (HIT), with both disorders associated with thrombocytopenia, thrombosis, and presence of autoantibodies to platelet factor 4 (PF4). Unlike VITT, HIT is triggered by recent exposure to heparin. Owing to similarities between these 2 conditions and lack of high-quality evidence, interim recommendations suggest avoiding heparin and heparin analogues in patients with VITT. Based on initial reports, female sex and age younger than 60 years were identified as possible risk factors for VITT. Treatment consists of therapeutic anticoagulation with nonheparin anticoagulants and prevention of formation of autoantibody-PF4 complexes, the latter being achieved by administration of high-dose intravenous immunoglobin (IVIG). Steroids, which can theoretically inhibit the production of new antibodies, have been used in combination with IVIG. In severe cases, plasma exchange should be used for clearing autoantibodies. Monoclonal antibodies, such as rituximab and eculizumab, can be considered when other therapies fail. Routine platelet transfusions, aspirin, and warfarin should be avoided because of the possibility of worsening thrombosis and magnifying bleeding risk.CONCLUSIONS AND RELEVANCE Adverse events like VITT, while uncommon, have been described despite vaccination remaining the most essential component in the fight against the COVID-19 pandemic. While it seems logical to consider the use of types of vaccines (eg, mRNA-based administration) in individuals at high risk, treatment should consist of therapeutic anticoagulation mostly with nonheparin products and IVIG.

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IVIg for Treatment of Severe Refractory Heparin-Induced Thrombocytopenia

Abstract: These studies suggest that IVIg treatment should be considered in patients with HIT who have severe disease that is refractory to standard therapies.

Cited by 114 publications

References 41 publications

Use of intravenous immunoglobulin G to treat spontaneous heparin‐induced thrombocytopenia

Use of intravenous immunoglobulin G to treat spontaneous heparin‐induced thrombocytopenia

Laboratory diagnosis of heparin‐induced thrombocytopenia

Clinical Characteristics and Pharmacological Management of COVID-19 Vaccine–Induced Immune Thrombotic Thrombocytopenia With Cerebral Venous Sinus Thrombosis

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