Laboratory and demographic predictors of functional assay positive status in suspected heparin-induced thrombocytopenia: A multicenter retrospective cohort study.

Heparin-induced thrombocytopenia (HIT) is an antibody-mediated immune response against platelet factor 4 (PF4) bound to heparin anticoagulants. A priori identification of patients at-risk for HIT remains elusive and a number of risk factors have been identified, but these associations and their effect sizes have limited validation in large cohorts of suspected HIT patients. The aim of this study was to investigate existing anti-PF4/heparin antibody thresholds and model the relationship of demographic variables and anti-PF4/heparin antibody levels with functional assay positivity across multiple institutions in the absence of detailed clinical data. In a large collection of suspected HIT patients (n = 8904), we tested for associations between laboratory and demographic variables and functional assay positive status as well as anti-PF4/heparin antibody levels. We also tested for correlation between IgG-specific and polyspecific (IgG/IgA/IgM) anti-PF4/heparin antibody values and their ability to predict functional assay positive status using area under the receiver operating characteristic (AUROC). Logistic regression identified increasing anti-PF4/heparin antibody OD levels (OR = 51.84 [37.27-74.34], p < 2.0 × 10-16) and female sex (OR = 1.47 [1.19-1.82], p = 3.5 × 10-4) as risk factors for positive functional assay in the largest cohort with consistent effect sizes in two other cohorts. In a subset of 1175 patients, polyspecific and IgG-specific anti-PF4/heparin antibody values were heterogeneous (mean coefficient of variation = 31.9 %), but strongly correlated (rho = 0.878; p < 2 × 10-16) with similar prediction of functional assay positivity (polyspecific AUROC = 0.976 and IgG-specific AUROC = 0.980). Thus, we recapitulate previously identified risk factors of functional assay positivity, providing precise effect sizes in a large observational population of suspected HIT patients. Our data reinforce the necessity of functional assay confirmation and suggest that, despite heterogeneity, polyspecific and IgG-specific anti-PF4/heparin antibody assays predict functional assay positive status similarly, even in the absence of 4Ts scores and detailed clinical data.

Investigation of anti-PF4 versus anti-PF4/heparin reactivity using fluid-phase enzyme immunoassay for 4 anti-PF4 disorders: classic heparin-induced thrombocytopenia (HIT), autoimmune HIT, vaccine-induced immune thrombotic thrombocytopenia, and spontaneous HIT.

BACKGROUND: Four platelet-activating anti-platelet factor 4 (PF4) disorders have been recognized: classic heparin-induced thrombocytopenia (cHIT), autoimmune heparin-induced thrombocytopenia (aHIT), spontaneous heparin-induced thrombocytopenia (SpHIT), and vaccine-induced immune thrombotic thrombocytopenia (VITT). All test immunoglobulin G (IgG) positive using solid-phase enzyme immunoassay (solid-EIA) against PF4/heparin (PF4/H) and/or PF4 alone. Fluid-phase EIA (fluid-EIA) should better discriminate between anti-PF4 and anti-PF4/H antibodies since conformationally altered PF4 bound to solid phase is avoided. OBJECTIVES: To compare anti-PF4 vs anti-PF4/H antibody profiles for anti-PF4 disorders using solid- and fluid-EIA. METHODS: We developed a novel fluid-EIA to measure anti-PF4 vs anti-PF4/H antibodies. RESULTS: Using fluid-EIA, 27 of 27 (100%) cHIT sera tested IgG positive with PF4/H, but only 4 of 27 (14.8%) tested positive against PF4 alone; all 27 exhibited heparin-enhanced binding. In contrast, 17 of 17 (100%) VITT sera tested IgG positive against PF4 alone, with markedly reduced binding against PF4/H; this distinct VITT antibody profile was not evident using solid-EIA. All 15 aHIT sera and all 11 SpHIT sera tested IgG positive against PF4 alone, with variable reactivity in PF4/H-EIA (heparin-enhanced binding in 14 of 15 and 10 of 11 aHIT and SpHIT sera, respectively). Remarkably, 1 SpHIT patient with a VITT-mimicking fluid-EIA profile (PF4 >> PF4/H) also clinically resembled patients with VITT (postviral cerebral vein/sinus thrombosis), with anti-PF4 reactivity correlating inversely with platelet count recovery; moreover, the single aHIT patient with a VITT-mimicking fluid-EIA profile also developed postviral cerebral vein/sinus thrombosis. CONCLUSION: cHIT and VITT sera showed opposite fluid-EIA profiles (cHIT: PF4/H >> PF4, with most testing negative against PF4 alone; VITT: PF4 >> PF4/H, with most testing negative against PF4/H). In contrast, all aHIT and SpHIT sera reacted against PF4 alone but with variable (usually enhanced) reactivity against PF4/H. VITT-mimicking clinical/serologic profiles occurred in only a minority of patients with SpHIT and aHIT.

Temporal presentations of heparin-induced thrombocytopenia following cardiac surgery: A single-center, retrospective cohort study.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is an important adverse drug reaction that can occur postcardiac surgery. Preoperative exposure to unfractionated heparin (UFH) is common, raising the issue of how frequently cardiac surgery-associated HIT occurs after immunizing preoperative exposure to heparin. OBJECTIVE: To determine the frequency and clinical picture of HIT occurring within 4 days of cardiac surgery (early presentation) versus later presentations (typical, delayed). METHODS: We identified patients with laboratory-confirmed HIT following cardiac surgery over 30 years in a single cardiac surgery center. Three different clinical presentations of HIT were identified: typical (HIT-related platelet count fall beginning between postoperative days [PODs] 5-10), delayed (patients with falls after POD10 or who presented following hospital discharge), and early (established before POD5, including during cardiac surgery [acute intraoperative HIT]). RESULTS: Of 129 patients identified with HIT complicating cardiac surgery, 100 had typical and 16 had delayed presentation of HIT; only 13 patients (10.1%) presented with early HIT, all of whom had received exposure to UFH during the 10 days before cardiac surgery. No patient was identified in whom remote preoperative UFH exposure was implicated in explaining early HIT. Notably, five patients appeared to have had acute intraoperative HIT, without immediate adverse consequences. CONCLUSIONS: Approximately 90% of patients with HIT after cardiac surgery appear to develop this complication due to immunization triggered by cardiac surgery; however, in approximately 10% of patients, early presentation during the first four PODs (or intraoperatively) can be explained by recent immunizing exposure to heparin.

Serotonin-release assay-positive but platelet factor 4-dependent enzyme-immunoassay negative: HIT or not HIT?

IgG-specific and polyspecific PF4-dependent enzyme-immunoassays (EIAs) have exceptionally high sensitivity (≥99%) for diagnosis of heparin-induced thrombocytopenia (HIT), a drug reaction caused by platelet-activating antibodies detectable by serotonin-release assay (SRA). The IgG-specific EIAs are recommended for screening, as their high sensitivity is accompanied by relatively high specificity vis-à-vis polyspecific EIAs. We investigated the frequency of SRA-positive/EIA-negative (SRA+/EIA-) HIT, prompted by referral to our reference HIT laboratory of serial blood samples from a patient ("index case") with false-negative IgG-specific EIAs. Despite initial clinical suspicion for HIT, repeat negative IgG-specific EIAs prompted heparin resumption, which triggered recurrent thrombocytopenia and near-fatal cardiac arrest, indicating likely post-heparin HIT-associated anaphylactoid reaction. Further investigations revealed a strong-positive SRA, whether performed with heparin alone, PF4 alone, or PF4/heparin, with inhibition by Fc receptor-blocking monoclonal antibody (indicating IgG-mediated platelet activation); however, five different IgG-specific immunoassays yielded primarily negative (or weak-positive) results. To investigate the frequency of SRA+/EIA- HIT, we reviewed the laboratory and clinical features of patients with this serological profile during a 6-year period in which our reference laboratory investigated for HIT using both SRA and IgG-specific EIA. Although ~0.2% of 8546 patients had an SRA+/EIA- profile, further review of 15 such cases indicated clerical/laboratory misclassification or false-positive SRA in all, with no SRA+/EIA- HIT case identified. We conclude that while SRA+/EIA- HIT is possible-as shown by our index case-this clinical picture is exceptionally uncommon. Moreover, the requirement for a positive EIA is a useful quality control maneuver that reduces risk of reporting a false-positive SRA result.

High-dose IVIG plus cangrelor platelet "anesthesia" during urgent heparin-CPB in a patient with recent SRA-negative HIT-thrombosis with persisting platelet-activating antibodies.

In a high-risk patient with subacute heparin-induced thrombocytopenia (HIT) type A (platelet count recovery following acute HIT but with persisting platelet-activating antibodies), in whom urgent cardiac surgery was required, a key clinical question arose: could intraoperative heparin be given safely with "platelet anesthesia" provided with high-dose intravenous immunoglobulin (IVIG) plus cangrelor (ultra-short-acting antiplatelet agent)? This approach proved successful, without unexpected postoperative thrombocytopenia or thromboembolism. In vitro studies confirmed that both IVIG and cangrelor contributed to perioperative inhibition of HIT antibody-induced platelet activation. Interestingly, despite the patient testing strongly positive in 4 HIT immunoassays (latex immunoturbidimetric assay and 3 enzyme-immunoassays), the serotonin-release assay (SRA) was consistently negative. Nevertheless, platelet-activating HIT antibodies were detectable using modified (platelet factor 4-enhanced) SRA. Our protocol of heparin rechallenge following IVIG/cangrelor provides both intraoperative and early postoperative inhibition of HIT antibody-induced platelet activation and is applicable to patients with circulating functional HIT antibodies requiring urgent heart surgery, including those with "SRA-negative HIT."

Combination of two complementary automated rapid assays for diagnosis of heparin-induced thrombocytopenia (HIT).

BACKGROUND: HIT diagnosis typically uses complementary diagnostic assays (eg, a PF4-dependent enzyme-immunoassay [EIA] and a platelet activation assay such as the serotonin-release assay [SRA]). OBJECTIVES: To determine whether the combination of two automated assays-a latex immunoturbidimetric assay (LIA) that evaluates competitive inhibition of a HIT-like monoclonal antibody and a chemiluminescence immunoassay (CLIA) for detecting anti-PF4/heparin IgG-optimizes diagnostic sensitivity while also yielding good specificity, particularly at high assay reactivities. PATIENTS/METHODS: We determined operating characteristics using combined LIA/CLIA results from a HIT observational trial (n = 430; derivation cohort) and 147 consecutive patients with HIT (n = 147; supplementary derivation cohort). We also evaluated 678 consecutive samples referred for HIT testing (replication cohort). LIA/CLIA reactivities were scored individually as "negative" (<1.00 U/mL, 0 points), "weak" (1.00-4.99 U/mL, 1 point), "moderate" (5.00-15.99 U/mL, 2 points) and "strong" (≥16.00 U/mL, 3 points), thus contributing up to 6 points (maximum) when LIA/CLIA results were combined. We also examined whether higher LIA/CLIA scores predicted presence of platelet-activating antibodies by conventional and modified (PF4- or PF4/heparin-enhanced) SRA. RESULTS: Combined LIA/CLIA testing yielded high diagnostic sensitivity (~99%) similar to EIA. Interpretation of LIA/CLIA results using the 6-point scale indicated progressively greater likelihood for the presence of platelet-activating antibodies with increasing scores (semi-quantitative reactivity). A LIA/CLIA score ≥ 4 points predicted the presence of platelet-activating antibodies by SRA or PF4-enhanced SRA with high probability (~98%). CONCLUSION: Combined LIA/CLIA testing optimizes diagnostic sensitivity, with progressively greater probability of detecting platelet-activating antibodies with higher assay reactivity that reaches 98% when both automated assays yield moderate or strong results.

Fondaparinux cross-reactivity in heparin-induced thrombocytopenia successfully treated with high-dose intravenous immunoglobulin and rivaroxaban.

HIT, a prothrombotic disorder caused by heparin-dependent antibodies, is often treated with fondaparinux, usually with good outcomes. A 70-year-old female developed severe HIT (platelet count, 25 × 109/L) post-glioblastoma resection during heparin thromboprophylaxis, complicated by disseminated intravascular coagulation (DIC) and symptomatic lower-limb deep-vein thrombosis (DVT). Despite therapeutic-dose fondaparinux, thrombocytopenia/hypofibrinogenemia persisted, with new symptomatic catheter-associated upper-extremity DVT. This clinical picture could be explained by autoimmune HIT (aHIT) refractory to fondaparinux or by fondaparinux cross-reactivity, so high-dose intravenous immunoglobulin (IVIG) was given (to treat possible aHIT) and fondaparinux switched to rivaroxaban, with subsequent clinical recovery. In vitro studies revealed strong fondaparinux cross-reactivity, without aHIT antibodies. Moreover, the patient's serotonin-release assay became negative post-IVIG, suggesting in-vivo inhibition of HIT antibody-induced platelet activation. Our case illustrates fondaparinux cross-reactivity in HIT manifesting as persisting thrombocytopenia, new thrombosis, and DIC, with successful rivaroxaban treatment, adding to emerging data that oral factor Xa inhibitors are efficacious for treating HIT.

Serotonin-release assay-negative heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is a prothrombotic drug reaction caused by platelet-activating anti-platelet factor 4 (PF4)/heparin antibodies. Pathogenic HIT antibodies can be detected by the serotonin-release assay (SRA), a platelet activation test. We have regarded the SRA performed in our medical community ("McMaster" SRA) as having high sensitivity and specificity. Recently, the concept of "SRA-negative HIT" has been proposed for enzyme-immunoassay (EIA)-positive/SRA-negative patients with a HIT-compatible clinical picture, who test positive in a PF4-enhanced platelet activation assay. After identifying an index case of SRA-negative HIT, we estimated the frequency of this condition by performing the "PF4-SRA" (modified SRA using high concentrations of added PF4 rather than heparin) in EIA-positive patients from a cohort study evaluating clinical and laboratory diagnosis of HIT. We defined SRA-negative HIT as patients meeting three criteria: clinical picture compatible with HIT (4Ts ≥ 4 points); EIA-positive (≥1.00 units); and PF4-SRA-positive. Among 430 patients, 35 were EIA-positive/SRA-positive and 27 were EIA-positive/SRA-negative. Among these 27 SRA-negative patients, three were found to have subthreshold levels of platelet-activating antibodies by PF4-SRA, of whom one met clinical criteria for SRA-negative HIT. Thus, based on identifying one patient with SRA-negative HIT within a cohort study that found 35 SRA-positive HIT patients, we estimate the sensitivity of the McMaster SRA for diagnosis of HIT to be 35/36 (97.2%; 95% CI, 85.8-99.9%). Although the McMaster SRA is highly sensitive for HIT, occasional SRA-negative but EIA-positive patients strongly suspected of having HIT can have this diagnosis supported by a PF4-enhanced activation assay such as the PF4-SRA.

Timeline of heparin-induced thrombocytopenia seroconversion in serial plasma samples tested using an automated latex immunoturbidimetric assay.

INTRODUCTION: HIT is caused by platelet-activating IgG that recognize multimolecular PF4/heparin complexes. HIT antibodies are generally detectable by PF4-dependent enzyme immunoassay (EIA) and by platelet serotonin-release assay (SRA) at the beginning of the HIT-related platelet count fall. We determined whether an automated immunoassay for HIT, the latex immunoturbidimetric assay (LIA), also detects antibodies early during the course of HIT. The LIA was also used to evaluate a patient with putative SRA-negative HIT. METHODS: We evaluated the timing and magnitude of LIA reactivity in serial plasma samples obtained from 19 SRA-positive patients (17 with abnormal platelet count changes indicating HIT; two with subclinical seroconversion) and one putative SRA-negative HIT patient, all obtained from patients who participated in a clinical trial of heparin thromboprophylaxis. We determined LIA status at the onset of the HIT-related platelet count fall. RESULTS: The LIA was positive in all 19 SRA-positive patients (median value, 7.3 U/mL [range, 1.2-35.5]; cutoff, 1.0 U/mL); for all 13 evaluable patients for whom an informative plasma sample was available at (or shortly before) the onset of the HIT-related platelet count fall, LIA reactivity was positive. Heterogeneity in seroconversion using the LIA was observed; some patients exhibited gradual increases in reactivity, whereas other patients showed rapid increase in reactivity over a few days. The single clinical trial patient who met clinical-pathological criteria for "SRA-negative HIT" tested LIA-positive. CONCLUSION: The LIA detects HIT antibodies at the beginning of the HIT-associated platelet count fall. The LIA was also positive in a patient with SRA-negative HIT.

Neutrophil and Monocyte Counts in Heparin-Induced Thrombocytopenia.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) antibodies activate platelets, monocytes and neutrophils. Despite these findings, it is unknown whether white blood cell (WBC) counts, including neutrophils and monocytes, are altered during HIT. MATERIALS AND METHODS: We evaluated changes in total WBC counts (including WBC subsets), in 50 post-cardiac surgery patients with serologically confirmed HIT (30 patients with HIT-associated thrombosis). Daily leukocyte counts were compared with those measured one day prior to HIT onset; WBC increases were classified as mild (20.0-49.9%), moderate (50.0-99.9%) or major (≥ 100% increase). We also compared changes in WBC counts in HIT patients with and without HIT-associated thrombosis, and non-HIT patients with thrombosis. RESULTS: Most (34/50 [68.0%]) patients with HIT developed WBC count increases (mild, 35.3%; moderate, 44.1%; major, 20.6%). The peak WBC count occurred on day 4 (median) of HIT, which corresponded to day 10 (median) post-surgery. Absolute neutrophil counts increased in most patients (38/50 [76.0%]); whereas absolute monocyte counts rose in some patients, the overall tendency was for the monocyte count to decrease during HIT. Unexpectedly, we found that the increase in total WBC counts, as well as in neutrophils, was seen mainly in patients who developed HIT-associated or non-HIT-associated thrombosis; in contrast, no difference in monocyte levels was seen in patients with or without thrombosis. CONCLUSION: Leukocytosis and neutrophilia are commonly observed in patients with HIT, particularly in patients with HIT-associated thrombosis, as well as non-HIT patients with thrombosis. Thus, leukocytosis/neutrophilia should not infer automatically a diagnosis of infection or inflammation, when evaluating thrombocytopenia in heparin-exposed patients.

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

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is a prothrombotic disorder characterized by heparin-dependent 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 PLT-activating 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 was inhibited 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.

High-dose intravenous immunoglobulin to treat spontaneous heparin-induced thrombocytopenia syndrome.

Essentials Spontaneous HIT syndrome clinically/serologically resembles HIT but without proximate heparin. Rarely, spontaneous HIT syndrome complicates total knee arthroplasty surgery. Mesenteric vein thrombosis is a rare presentation of spontaneous HIT syndrome. IVIg rapidly corrects thrombocytopenia by inhibiting heparin-independent platelet activation. SUMMARY: Spontaneous heparin-induced thrombocytopenia (HIT) syndrome is an autoimmune HIT (aHIT) disorder characterized by thrombocytopenia, thrombosis, and HIT antibodies despite no proximate heparin exposure. For unknown reasons, many cases occur after total knee arthroplasty. A 52-year-old woman presented 12 days posttotal knee replacement (aspirin thromboprophylaxis) with gastrointestinal bleeding (superior mesenteric vein thrombosis); the platelet count was 63 × 109 L-1 . After bowel resection and a brief course of heparin, treatment was changed to argatroban followed by fondaparinux. In addition, high-dose intravenous immunoglobulin (IVIg), 1 g kg-1 on 2 consecutive days, resulted in abrupt platelet count rise from 21 (nadir) pre-IVIg to 137 (post-IVIg), and 2 days later to 200 × 109 L-1 . Heparin-independent serum-induced serotonin-release abruptly decreased from 91% (pre-IVIg) to 14% (post-IVIg); although serotonin-release later rebounded to 49%, the patient's platelet counts remained normal. Our observations support the emerging concept that high-dose IVIg is effective for treating aHIT disorders, including spontaneous HIT syndrome.

Platelet-Activating Antibodies Are Detectable at the Earliest Onset of Heparin-Induced Thrombocytopenia, With Implications for the Operating Characteristics of the Serotonin-Release Assay.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is a prothrombotic drug reaction caused by platelet-activating antibodies that recognize platelet factor 4 (PF4)/heparin complexes. It is unknown whether platelet-activating antibodies are detectable at the onset of the HIT-related platelet count fall. METHODS: Available blood samples from 18 patients obtained at onset of HIT were tested using the serotonin-release assay (SRA), a test for platelet-activating antibodies, and a PF4-dependent enzyme-linked immunosorbent assay (ELISA). Patient samples showing a delay of > 2 days between ELISA and SRA seroconversion were tested for subthreshold levels of platelet-activating antibodies using two modifications of the SRA that amplify detection of HIT antibodies. We also estimated SRA sensitivity and specificity in two postorthopedic surgery clinical trials (633 samples), including assessing whether a positive SRA influenced platelet count recovery in the absence of thrombocytopenia. RESULTS: Platelet-activating HIT antibodies were detected in all 18 patients at the beginning of the HIT-related platelet count fall. Although ELISA seroconversion usually preceded SRA seroconversion by only 1 day (median), subthreshold levels of platelet-activating antibodies were detected in both patients who exhibited a lag between ELISA and SRA seroconversion. SRA sensitivity was 100% (18/18), and its specificity was 97% (597/615). Nonthrombocytopenic SRA-positive patients with ongoing heparin treatment exhibited blunted platelet count recovery vs control subjects, suggesting even higher SRA specificity for detecting abnormal platelet count profiles. CONCLUSIONS: Platelet-activating HIT antibodies are detectable at the onset of the HIT-related platelet count fall. The SRA has high sensitivity and specificity for HIT, and indicates that presence of HIT antibodies can blunt postoperative platelet count recovery.

Platelet count recovery and seroreversion in immune HIT despite continuation of heparin: further observations and literature review.

One of the standard distinctions between type 1 (non-immune) and type 2 (immune-mediated) heparin-induced thrombocytopenia (HIT) is the transience of thrombocytopenia: type 1 HIT is viewed as early-onset and transient thrombocytopenia, with platelet count recovery despite continuing heparin administration. In contrast, type 2 HIT is viewed as later-onset (i. e., 5 days or later) thrombocytopenia in which it is generally believed that platelet count recovery will not occur unless heparin is discontinued. However, older reports of type 2 HIT sometimes did include the unexpected observation that platelet counts could recover despite continued heparin administration, although without information provided regarding changes in HIT antibody levels in association with platelet count recovery. In recent years, some reports of type 2 HIT have confirmed the observation that platelet count recovery can occur despite continuing heparin administration, with serological evidence of waning levels of HIT antibodies ("seroreversion"). We now report two additional patient cases of type 2 HIT with platelet count recovery despite ongoing therapeutic-dose (1 case) or prophylactic-dose (1 case) heparin administration, in which we demonstrate concomitant waning of HIT antibody levels. We further review the literature describing this phenomenon of HIT antibody seroreversion and platelet count recovery despite continuing heparin administration. Our observations add to the concept that HIT represents a remarkably transient immune response, including sometimes even when heparin is continued.

Apixaban for treatment of confirmed heparin-induced thrombocytopenia: a case report and review of literature.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is a life and limb-threatening condition caused by the binding of platelet-activating antibodies (IgG) to multimolecular platelet factor 4 (PF4)/heparin complexes because of heparin exposure. The by-product of this interaction is thrombin formation which substantially increases the risk of venous and/or arterial thromboembolism. Currently, only one anticoagulant, argatroban, is United States Food and Drug Administration-approved for management of HIT; however, this agent is expensive and can only be given by intravenous infusion. Recently, several retrospective case-series, case reports, and one prospective study suggest that direct oral anticoagulants (DOACs) are also efficacious for treating HIT. We further review the literature regarding current diagnosis and clinical management of HIT. CASE PRESENTATION: A 66-year-old male patient developed HIT beginning on day 5 post-cardiovascular surgery; the platelet count nadir on day 10 measured 16 × 109/L. Both the PF4-dependent ELISA and Serotonin-release assay were strongly positive. Despite initial anticoagulation with argatroban (day 6), the patient developed symptomatic Doppler ultrasound-documented bilateral lower extremity deep vein thrombosis on day 14 post-surgery. The patient was transitioned to the DOAC, apixaban, while still thrombocytopenic (platelet count 108) and discharged to home, with platelet count recovery and no further thrombosis at 3-month follow-up. CONCLUSIONS: We report a patient with serologically confirmed HIT who developed symptomatic bilateral lower limb deep vein thrombosis despite anticoagulation with argatroban. The patient was switched to oral apixaban and made a complete recovery. Our patient case adds to the emerging literature suggesting that DOAC therapy is safe and efficacious for management of proven HIT.

Performance characteristics of an automated latex immunoturbidimetric assay [HemosIL® HIT-Ab(PF4-H)] for the diagnosis of immune heparin-induced thrombocytopenia.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is a prothrombotic drug reaction caused by platelet-activating anti-PF4/heparin antibodies. Given time-sensitive treatment considerations, a rapid and accurate laboratory test for HIT antibodies is needed. AIMS: To determine operating characteristics for the HemosIL® HIT-Ab(PF4/H), a rapid, on-demand, fully-automated, latex immunoturbidimetric assay (LIA), for diagnosis of HIT. METHODS: We evaluated LIA sensitivity, specificity, negative (NPV) and positive predictive value (PPV), negative (LR-) and positive likelihood ratio (LR+), using citrated-plasma from 429 patients (prospective cohort study of 4Ts scoring; HIT, n=31), and from consecutive HIT patients (n=125), using reference standard serotonin-release assay (SRA). Comparators included two PF4-dependent enzyme-immunoassays (EIAs). We used stratum-specific likelihood ratios (SSLRs) to determine how differing magnitudes of LIA-positivity influenced post-test probability of HIT. RESULTS: LIA operating characteristics were: sensitivity=97.4% (152/156); specificity=94.0% (374/398); PPV=55.6% (30/54); and NPV=99.7% (374/375). At manufacturers' cutoffs, LIA specificity and PPV were superior to the EIAs. Although a negative LIA pointed strongly against HIT (LR-, 0.034), the post-test probability was ~2% with high 4Ts score. The LIA's LR+ was high (16.0), with SSLRs rising substantially with greater LIA-positivity: 5.7 (1.0-4.9U/mL), 31 (5.0-15.9U/mL), and 128 (≥16U/mL). A LIA-positive result (at 1.0 cutoff) indicated at least 24% HIT probability (low 4Ts score), rising to 90% with high 4Ts score. CONCLUSIONS: Although approximately 1 in 40 SRA-positive patients tested LIA-negative, the LIA's high NPV and PPV indicate that this rapid assay is useful for the diagnostic evaluation of HIT, including in low pre-test situations.