HAL Id: dumas-02990525
https://dumas.ccsd.cnrs.fr/dumas-02990525
Submitted on 5 Nov 2020
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Validation clinique de la technique HemoIL AcuStar
HIT dans le diagnostic de la thrombopénie induite par
l’héparine : étude rétrospective de 1300 dossiers
Zeina Marashi
To cite this version:
Zeina Marashi. Validation clinique de la technique HemoIL AcuStar HIT dans le diagnostic de la
thrombopénie induite par l’héparine : étude rétrospective de 1300 dossiers. Sciences du Vivant [q-bio].
2020. �dumas-02990525�
Validation clinique de la technique HemoIL AcuStar HIT
dans le diagnostic de la thrombopénie induite par l'héparine :
étude rétrospective de 1300 dossiers.
Présentée et publiquement soutenue devant
LA FACULTÉ DES SCIENCES MEDICALES ET PARAMEDICALES
DE MARSEILLE
Le 13 Octobre 2020
Par Madame Zeina MARASHI épouse
SABOUNI
Née le 10 janvier 1986 à Alep (SYRIE)
Pour obtenir le grade de Docteur en Médecine
D.E.S. de BIOLOGIE MÉDICALE
Membres du Jury de la Thèse :
Président
Directeur
Assesseur
Assesseur
Monsieur le Professeur GUIEU Régis
Madame le Professeur CAMOIN Laurence
Madame le Docteur (MCU-PH) GUIDON Catherine
Monsieur le Docteur (MCU-PH) SUCHON Pierre
Monsieur le Docteur GENIN Adrien
Assesseur
Validation clinique de la technique HemoIL AcuStar HIT
dans le diagnostic de la thrombopénie induite par l'héparine :
étude rétrospective de 1300 dossiers.
Présentée et publiquement soutenue devant
LA FACULTÉ DES SCIENCES MEDICALES ET PARAMEDICALES
DE MARSEILLE
Le 13 Octobre 2020
Par Madame Zeina MARASHI épouse
SABOUNI
Née le 10 janvier 1986 à Alep (SYRIE)
Pour obtenir le grade de Docteur en Médecine
D.E.S. de BIOLOGIE MÉDICALE
Membres du Jury de la Thèse :
Président
Directeur
Assesseur
Assesseur
Monsieur le Professeur GUIEU Régis
Madame le Professeur CAMOIN Laurence
Madame le Docteur (MCU-PH) GUIDON Catherine
Monsieur le Docteur (MCU-PH) SUCHON Pierre
Monsieur le Docteur GENIN Adrien
Assesseur
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REMERCIEMENTS
A Monsieur le Professeur Régis GUIEU
Vous avez accepté sans hésiter de présider le jury de cette thèse. Veuillez recevoir, Monsieur
le Professeur, l’expression de ma sincère reconnaissance et l’assurance de mon profond
respect.
Mon directeur de thèse, Madame la Professeur Laurence CAMOIN-JAU
Vous m’avez fait l’honneur de diriger cette thèse. Vous m’avez soutenue, guidée tout au long
de ce travail et toujours su me redonner la motivation dans les moments difficiles.
Je n'aurai pas assez de place sur ces quelques lignes pour vous exprimer ma plus profonde
reconnaissance pour la qualité et quantité de travail que vous avez fournie pour m'aider dans
cette thèse. Cela a été un plaisir de travailler avec vous. Je vous remercie.
Madame la Professeur Catherine Guidon
Vous me faites l’honneur d’apporter votre expérience à la critique de ce travail en siégeant
dans mon jury de thèse. Je vous prie de bien vouloir accepter ma respectueuse considération.
Monsieur le Docteur Adrien GENIN
Vous me faites l’honneur de juger ce travail. Veuillez trouver ici l’expression de mes
sentiments respectueux.
Monsieur le Docteur Pierre Suchon
Je vous remercie d’avoir accepté de participer au jury de cette thèse, recevez à cette occasion
mes sincères remerciements
A Monsieur le Professeur Pierre-Emmanuel MORANGE
Je vous remercie pour vos précieux conseils et votre bienveillance. Soyez assurée de mon
gratitude et de mon profond respect.
À L’équipe de laboratoire d’hémostase à TOURS
Un grand merci pour votre aide qui a contribué à la réalisation de ce travail.
À mes nouveaux collègues
Guenièvre et Océane, j’ai hâte de commencer ma carrière à vos côtés... Nous les trois on fera
une équipe de choc !
À ma mère
L’épaule qui m’a toujours soutenue, rassurée, consolée et surtout écoutée dans tous mes
« états ». Maman, je ne sais pas comment quelques mots peuvent suffire pour décrire l’amour
que j’ai envers toi ou comment je pourrais résumer ton soutien toute ma vie !!
À mon père
Mon exemple, même si tu n’es plus là avec moi physiquement, tu seras toujours avec moi
dans mon cœur… tu m’as toujours suivi et porté pas à pas dans toutes ces longues études et as
toujours su trouver les mots pour me booster, « ton future est en danger !! », je t’aime papa !
A mon amour
Merci chéri pour tout ce que tu fais pour moi:
Ce n’était pas facile ces dernières années !!
Mais tu l’as rendu facile en étant toujours là pour moi quoiqu’il arrive,
quand je te raconte
mes soucis, tu m’écoutes et me remontes le moral. Quand je suis triste et que je perds
confiance en moi, tu m’encourages et me pousses à aller de l’avant. Je ne sais pas ce que
je ferais sans toi dans ma vie. Merci !
A Sally et Hicham
Mes rayons de soleil, mes deux pépites, merci de m’avoir laissé travailler !! Vos éclats de rire
sont si précieux. Je vous aime d’un amour incroyable.
À mes supers sœurs et frères
Mes superhéros « Tammy, Rami, Sima, Husam et Hazem », votre soutien constant et vos
encouragements m’ont aidé tout au long de ma vie.
À ma grand-mère
Tu me manques beaucoup, j’espère que tu es fier de moi et j’aurais aimé partager avec toi ce
moment final de mon parcours.
À mes neveux et nièces
Nour, Eamon, Layla and Riana… Pour toutes les bêtises et l’affection que l’on partage.
À Nicolas
Mon co-interne préféré ... Écrire cette thèse était beaucoup plus facile avec nos pauses café !
Je te souhaite que le bonheur dans ta vie et dans ta nouvelle aventure à Tours.
À tous mes praticiens
Qui ont su m’apporter leur passion de la biologie, et tous les autres médecins croisés durant
mes stages qui ont su me guider et me faire devenir celle que je suis aujourd’hui.
À Maryline et Tony
Journal of Thrombosis and Thrombolysis
Clinical Validation of Immunoassay HemosIL® AcuStar HIT-IgG (PF4-H) in the
diagnosis of Heparin-induced thrombocytopenia
--Manuscript
Draft--Manuscript Number:
Full Title: Clinical Validation of Immunoassay HemosIL® AcuStar HIT-IgG (PF4-H) in the
diagnosis of Heparin-induced thrombocytopenia
Article Type: Original Article/Investigation
Keywords: Heparin induced thrombocytopenia, 4T score, Heparin, Immunoassay,
Chemiluminescent.
Corresponding Author: Laurence Camoin-Jau, PhD, MD
IHU Mediterranee Infection
Marseille, Provence-Alpes-Côte d'Azu FRANCE Corresponding Author Secondary
Information:
Corresponding Author's Institution: IHU Mediterranee Infection Corresponding Author's Secondary
Institution:
First Author: Zeina Marashi-Sabouni
First Author Secondary Information:
Order of Authors: Zeina Marashi-Sabouni
Caroline Vayne, PhD, MD Manal Ibrahim-Kosta, MD Catherine Guidon, MD, PhD Anderson Loudoun, MD, PhD Eve Anne Guery, MD
Pierre-Emmanuel Morange, MD, PhD Laurence Camoin-Jau, PhD, MD Order of Authors Secondary Information:
Funding Information:
1
Clinical Validation of Immunoassay HemosIL
®AcuStar HIT-IgG
(PF4-H) in the diagnosis of Heparin-induced thrombocytopenia
Zeina Marashi-Sabouni
1, Caroline Vayne
2-3,Manal Ibrahim-Kosta
1-4, Catherine Guidon
5,
Anderson Loundou
6, Eve Anne Guery
2, Pierre-Emmanuel Morange
1-4, Laurence Camoin-Jau
1-7
1. Laboratoire d'Hématologie, La Timone Hospital, APHM, boulevard Jean- Moulin, 13005
Marseille, France.
2. Service d’Hématologie Hémostase, Hôpital Trousseau, CHU de Tours. 37044 Tours, France
3. EA7501 GICC, Université de Tours. Tours, France.
4. Aix Marseille Univ, INSERM, INRAE, C2VN, Marseille, France,
5.
Department of Anaesthesiology and Critical Care Medicine, University Hospital Timone,
Marseille, France
6. Biostatistic and Public Health Department, La Timone Hospital, Marseille, France
7. Aix Marseille Univ, IRD, APHM, MEPHI, IHU Méditerranée infection, Marseille, France
Corresponding author
Laurence Camoin-Jau
Service d’Hématologie Biologique CHU Timone
264 Rue Saint Pierre
13385 Marseille cedex 05, France Courriel : laurence.camoin@ap-hm.fr
Word counts: 3464 words
2
Abstract: Introduction:
Heparin induced thrombocytopenia (HIT) is a life and limb-threatening complication of heparin exposure. The misdiagnosis of the disease can have major consequences on the patients. The objective of this study was to evaluate a diagnostic strategy that combines the 4Ts score, with the result of HemosIL® AcuStar HIT-IgG (PF4-H) to confirm the diagnosis of HIT.
Methods:
Citrated plasmas from 1300 patients with suspicion of HIT were analyzed with a fully automated quantitative chemiluminescent immunoassay (HemosIL® AcuStar HIT-IgG (PF4/H)). If the IgG anti-PF4/H antibodies were positive (cut-off, 1 U/mL), HIT diagnosis was confirmed using functional tests.
Results:
In total 1300 samples of consecutive patients were enrolled; 94 (7.2%) gave positive results in HemosIL® AcuStar-IgG. HIT was diagnosed in 65 out of these patients corresponding to a prevalence of 5%. Using ROC curve analysis, patients were divided into three groups according to their titer of antibodies.
Higher values of the IgG (PF4-H) were associated with increased probability of HIT, and the diagnostic specificity was greatly increased by using the combination of a 4Ts score > 3 and a positive titer 3.25 U/mL. Importantly, the diagnostic specificity is 100% when the titer is > 12.40 U/mL.
Conclusion:
We demonstrated that higher values of Anti PF4/H Antibodies were associated with a high probability of having HIT. A titer of HemosIL® IgG (PF4-H) > 12.40 U/mL has a specificity of 100% which should no require a functional test to confirm the diagnosis of HIT.
3
Abbreviations
ECC : extracorporeal circulation
ECMO : extracorporeal membrane oxygenation; HIT : heparin induced thrombocytopenia UFH : unfractioned heparin
LMWH : low molecular weight heparin PF4 : platelet factor 4
4
Highlights
Heparin-induced thrombocytopenia (HIT) is a severe drug reaction associating the drop of platelet’s count with a high risk of thrombosis, caused by platelet-activating antibodies against Platelet Factor 4 (PF4) / heparin (H) complexes.
Many immunoassays commercially are available with a large heterogeneity of positive predictive value and negative predictive value.
The AcuStar IgG anti PF4/H is a rapid chemiluminescent immunoassay allowing detection of Anti PF4/H antibodies in less than one hour.
Higher values of the HemosIL® AcuStar HIT-IgG (PF4-H) were associated with increased probability
5
Introduction
Heparin-induced thrombocytopenia (HIT) is a severe, sometimes fatal drug reaction associating the drop of platelet’s count with a high risk of thrombosis, caused by platelet-activating antibodies against Platelet Factor 4 (PF4) / heparin (H) complexes (1-2). HIT is a clinical pathological disorder where the prognosis depends on the early recognition of HIT and stopping the heparin as soon as suspected (3). It is a paradoxical disease, while the anticoagulant is administered to prevent thrombosis, yet the major clinical event is an increased risk of thrombosis. The diagnosis is based on both clinical assessment (the 4Ts score or The HIT Expert Probability (HEP) (2) (4) and the demonstration in vitro of the presence of platelet factor 4 (PF4) / heparin (H) antibodies with a positive functional activity. Misdiagnosis of HIT can be fatal and false positive HIT diagnosis can have serious clinical and financial implications such as the use of direct thrombin inhibitors (DITs) which in turn may result in higher hemorrhagic risk and wasted drug cost.
Since no single laboratory test is available with 100% sensitivity and specificity, the results of the laboratory tests should always be interpreted with the clinical context. Many immunoassays commercially are available. More recently, the AcuStar IgG anti PF4/H, a rapid chemiluminescent immunoassay, allowing detection of Anti PF4/H antibodies in less than one hour has been developed. These different tests have a heterogeneity of positive predictive value (PPV) and negative predictive value (NPV) (5-6). The specificity and PPV of immunological assays are usually lower in comparison to the functional assays as they also detect non pathogenic antibodies (1) (3). According to recommendations, functional assays are necessary to confirm HIT diagnosis and have acceptable sensitivity and specificity for HIT. The serotonin release assay is considered as the gold standard with high sensitivity and specificity while platelet aggregometry has poor sensitivity but rather good specificity (7-8). Unfortunately, these functional assays are not immediately available. However, immunoassays with better specificity are needed in order to minimize the switch to non-heparinic anticoagulation, as these are more difficult to manage and much more expensive. (9-10). Regarding available ELISA tests, several algorithms regarding the strength of optical density (OD) and the probability of HIT (11-13), have been proposed. There is a limited data in the literature regarding the interpretation of chemiluminescent immunoassayy results.
The aim of this work is to assess a diagnostic strategy that combines the 4Ts score, with the result of HemosIL® AcuStar HIT-IgG (PF4-H) to confirm the diagnosis of Heparin-induced thrombocytopenia.
Materials and methods
Study design
This monocentric retrospective study was carried out in the “Assistance Publique-Hôpitaux de Marseille- La Timone”, between October 2016 and the end of October 2019 and concerned all the hospitalized patients with clinical suspicion of HIT and all the external demands. All patients included were treated with unfractionated heparin (UFH) and /or low-molecular-weight heparin (LMWH). In this study and as the American Society of Hematologica 2018 (14) recommends, patients who received a combination of UFH and LMWH, were considered to belong to the UFH group (14). The exclusion criteria included unjustified requests because of no
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anticoagulant administrated, or the use of anticoagulants non associated with a risk of HIT as fondaparinux or danaparoide sodium (Fig 1 supp).All clinical history information and heparin therapy were carefully recorded for each patient using the hospital data base. The probability of pre-test HIT (low, intermediate or high) was estimated using the 4Ts score (14-16). The medical history of each patient was extensively analyzed. The 4Ts score were independently assessed by two experimented investigators (LCJ and CG), unaware of the results of the laboratory assays. Drugs associated with thrombocytopenia were defined according to Arepally et al (1) (15). 30 patients had no 4Ts score evaluation (external demands).
“Confirmed HIT” patients were defined as patients whose plasma sample tested positive in both AcuStar IgG anti PF4/H and a functional assay (SRA or a platelet aggregation assay). Patients are also considered positive when their clinical course and platelet count were considered consistent with HIT, either by thorough investigation (4Ts score ≥ 4 points) or by upon case review in rare cases with low score (3). All other patients were classified as “HIT negative”.
Immunoassay HemosIL® AcuStar HIT-IgG (PF4-H)
Blood samples were collected into 3.2% sodium citrate. After centrifugation, plasma samples were frozen at -80°C until further testing. All the citrated plasmas were analyzed with fully automated quantitative chemiluminescent immunoassay (HemosIL® AcuStar HIT-IgG (PF4-H) per manufacturer’s instructions (6). All patients, even with a low 4Ts score were tested. The manufacturer suggests that results equal or higher than 1.00 U/mL indicate the presence of HIT antibodies (PF4/H+ Ab) (6). Accordingly, when an antibody titer over or equal to 1 U/mL (fixed by the manufacturer), a functional confirmation (assay platelet aggregation test and, or serotonin-release assay [SRA]) were performed (14).
Heparin-induced Light Transmission Aggregation (LTA)
Heparin-induced light transmission aggregation (LTA) was performed on plasma with suspected heparin responsible for thrombocytopenia, according to Minet et al, (17), using Aggregometer APACT 4004 Labitec (LAbor BioMedical Technologies GmbH, Ahrensburg, Germany). Plasma rich-platelets (PRP) of four healthy donors were prepared and were tested in parallel. PRP of each donor was incubated with diseased plasma in the presence of low concentration of heparin (1 IU/mL). If this test was positive, the same technique was performed with 0.9% NaCl instead of heparin. If the second test was also positive, this was interpreted as a non-specific reaction and the heparin was not responsible of the aggregation. However, if the test with the NaCl was negative, the PRP was incubated with diseased plasma in the presence of high concentration of heparin (100 IU/mL). The endpoint used for our study was the percentage of aggregation. The result was considered positive when complete (non reversible) platelet aggregation, performed with two different healthy donors, occurred with intensity greater than 20% in the presence of low heparin concentration and was inhibited by the high concentration of UFH (18).
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Serotonin release assays
Conventional SRA was performed as previously described (19) with minor modifications. Platelets from healthy donors were selected per their good responsiveness to known HIT plasma samples, and labelled with 14C-serotonin (14C-5HT, Perkin Elmer, Villebon-sur-Yvette, France) for 45 min at 37°C (14.8 kBq/ml PRP).
After washing, 75 µl of labelled platelets suspended at 300 x 109/L in Tyrode buffer with 3 mmol/l calcium were
incubated for 1 hour at room temperature with 20 µl tested sample and 5 µl unfractionated heparin at 0, 0.1, 0.5 or 10 IU/ml (final concentrations). The release reaction was terminated with PBS-EDTA (0.1 mol/l) and platelets were then centrifuged. The radioactivity in the supernatants was then counted by Liquid Scintillation Counting (LSC; Perkin Elmer) and expressed as percentage release of serotonin (%) by comparison with the total radioactivity in the platelet preparation.
PF4-SRA was performed as previously described (20) with addition of 10 µg/mL of exogenous human PF4 (Hyphen BioMed, Neuville-sur-Oise, France) pre-incubated for 10 minutes with platelets before testing. Regardless of the assay performed (conventional SRA or PF4-SRA), the test result was considered positive with a release of 14C-serotonin ≥ 20% measured at 0, 0.1 or 0.5 IU/ml of heparin, and complete inhibition at 10 IU/ml
(14C-serotonin < 20% or ≥50% inhibition).
Statistical analysis
Statistical analysis was performed using IBM SPSS Statistics version 20.0 (IBM SPSS Inc., Chicago, IL, USA). Data are expressed as mean ± the standard deviation or median with interquartile range. Two groups were compared using the Chi square or Fisher's exact test for categorical characteristics, and using the student t-test or Mann-Whitney U test for continuous ones, as appropriate. To compare more than two independent samples, the analysis of variance (ANOVA) were used or the non-parametric Kruskal-Wallis test. The cut-off points were calculated by selecting the point on the ROC curve that maximized both sensitivity (Se) and specificity (Sp). Negative predictive value (NPV), positive predictive value (PPV), and accuracy were provided with their 95% confidence intervals. A two-sided p value of less than 0.05 was considered statistically significant.
Results
1. Demographic data
Characteristics of the study population are presented in Table 1. A total of 1300 patients, were included in this study. Among them 766 (58.9%) were men. The mean age was 64.8 years. 59.2% of patients received UFH and 40% LMWH. For both treatments, two thirds of the patients were hospitalized in medical departments. 10 patients (0.8%) the type of heparin administrated was not known (lack of information transmitted from external hospitals).
725 (55.8%) of all patients have a low score (≤ 3), 506 (38.9%) an intermediate score (4-5) and 39 (3%) of patients a high score (6-8).
The mean 4Ts score was 3.2 ± 1.47, the mean duration of the heparin treatment was 11.54 days and 82 patients had a thrombotic event (6.3%).
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2. Results of immunoassay HemosIL® AcuStar HIT-IgG (PF4-H)
The AcuStar assays with the insert cut-off of 1.0 U/mL were negative in 1206 of 1300 patients (92.8%) and positive in 94 patients (7.2%) (Table 1).
The negative patients were mainly treated by LMWH and had an increased prevalence of active cancer (p= 0.02). Only 15 patients had a high 4Ts score (Figure 2). Among these 15 patients, 12 (80%) had presented thrombotic events and 12 (80%) were under UFH.
The positive patients were mainly treated with UFH 84% vs 15.9% for LMWH treatment (p<0.001). Among them, 59.5% were treated for medical indications. Positive patients more often underwent Extracorporeal Circulation (ECC) and hemodialysis (p<0.001). 17 patients had a low 4Ts score with 12 patients treated by UFH (70.6%), 7 underwent ECC (41.2%) and 10 (58.8%) had evidence of infection.
There were no significant differences in terms of Extracorporeal membrane oxygenation (ECMO), infection or positive blood culture between the two groups. As expected, Intermediate and high 4Ts score were significantly more common in patients with positive anti PF4/H antibodies (p<0.001) (Table 1) (Figure 1).
3. Confirmation of HIT Diagnosis
Functional tests were performed only on patients with PF4/H positive immunoassays (n=94).
“HIT Confirmed” patients were defined as patients whose plasma was tested positive with AcuStar IgG anti PF4/H and/or a functional assay (SRA or an aggregation assay) together with clinical profiles consistent with a true HIT.
All the 94 positive immunoassay patients were tested with an aggregation assay except for 3 patients (96.8%). When LTA results were positive, patients were considered HIT positive and a SRA assay was not performed (n= 28, 29.8%). Therefore, 63 samples were tested with SRA (67%), 34 patients were SRA positive (36.2%) and 29 (30.8%) were SRA negative. The three patients who had not had any functional test (external demands with no sufficient plasma) were clinically diagnosed (3.2%). The diagnosis of HIT was confirmed in 65 (69.1%).
For both negative and positive HIT groups, the UFH was more often used than LMWH (p<0.001), but no significant difference can be detected in terms of heparin’s indication. Regarding the 4Ts score, when HIT tested negative, 48.2% patients had a low score (≤3). By opposite, in positive HIT group, only 4.6% patients had a low score (p<0.001). No significant difference was observed in case of an intermediate score. Significantly more patients (n=23) with high score were in the HIT positive group (35.4%) with 1 being in the negative HIT group (3.5%), (p<0.001). Hemodialysis was more common in HIT negative patients (p = 0.043) which indicates the effect of this situation in testing false positive Anti PF4/H antibodies. No significant difference in infection rates was observed (p= 0.179) (Table 2).
The mean value (SD) of Anti PF4/H antibodies in negative HIT group was 3.67 3.41 with extreme values between [1.07 – 12.38], while in positive HIT group was 23.9 39.7 [1.2 – 240]. (p<0.001).
4. Performance of 4Ts score:
Among 1300 study participants, 30 patients had no 4Ts score evaluation (external demands). HIT was confirmed in 3 out of 725 with a low 4Ts score (0.4%), 39 of 506 with an intermediate 4Ts score (7.7%), and 23 of 39 with
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a high 4Ts score (58.9%). The best calculated sensitivity and specificity for 4Ts score was observed with score > 3, the sensitivity was 95.08 (CI: 86.3 – 99.0%) and specificity was 50.00% (CI: 30.6 – 69.4%).
5. Performance of HemosIL® AcuStar Anti PF4/H:
According to HIT confirmed diagnosis, we determined the optimal thresholds for AcuStar HIT-IgG (PF4-H), using ROC curve analyses. At the optimal cut-off 3.25 U/mL, we noted that the sensitivity was 83.61 (CI: 71.9 – 91.8%) and specificity was 67.86 (CI: 47.6 – 84.1%). Another threshold of 12.40 U/mL was evaluated. The sensitivity was 40.98 (CI: 28.6-54.3%) and specificity was 100.00 (CI: 87.7 – 100.0%).
Based on the work provided by Warkentin et al (21) where results were classified as negative (0.00 - 0.99 U/mL), weak positive (1.00 - 4.99 U/mL), positive (5.00 - 19.99 U/mL) and strong positive ( 20.00 U/mL). The same approach was done with our thresholds using ROC curve analysis. Overall, we divided our patients with confirmed HIT diagnosis into three subgroups, according to anti PF4/H Ab titer: weak positive titer (1- 3.24 U/mL), positive titer (3.25 - 12.40 U/mL) and strong positive titer (> 12.40 U/mL) (Fig 2). For all the three subgroups, UFH was more often used. Whatever the value of anti PF4/H Ab was, no difference was detected between the three subgroups with respect to type of heparin and indication of treatment. Generally, more than 50% of all subgroups had an intermediate score. Significantly hemodialysis and infection were more prevalent in the weak positive titer compared to higher titers (Table 1 supp).
HIT diagnosis was confirmed in all patients with strong positive titer (>12.40 U/mL) (n=26, 27.6% of our 94 positive antibodies), likewise we had less false positive HIT diagnosis in patients with weak positive titer (1- 3.24 U/mL) (n= 18, 62% of total weak positive titer and 19.1% of all positive anti PF4/H Ab patients).
6. Performance of HemosIL® AcuStar Anti PF4/H and score 4Ts combined:
Using the threshold of 3.25 U/mL found in our study combined with a 4Ts score > 3, the sensitivity was 78.46% (95% CI: 67.03 - 86.71) and specificity 75.86% (95% CI: 57.89 - 87.78%), VPP was 87.93% (95% CI: 77.12 - 94.03%) and VPN was 61.11% (95% CI: 44.86 - 75.22%).
Discussion:
Higher values of the HemosIL® AcuStar HIT-IgG (PF4-H) were associated with increased probability of HIT,
and the diagnostic specificity was greatly increased by using the combination of the 4Ts score > 3 and a positive titer 3.25 U/mL, (sensitivity = 78.46% and specificity = 75.86%). A strong positive titer (>12.40 U/mL) confirmed the diagnosis of HIT in our study (with a specificity of 100%).
Our study was performed on a tertiary hospital and all patients suggestive of HIT were consecutively included. Among the 1300 consecutive patients enrolled, 94 patients (7.2%) were positive with Immunoassay HemosIL® AcuStar HIT-IgG (PF4-H), (1 U/mL), which is lower compared to the enzyme-linked immunosorbent assays (ELISA) with comparable populations (approximately 15%) (22-23).
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The clinical characteristics of our studied population are as expected regarding our recruitment (3) (24-25). Patients with positive titers of PF4/H Antibodies were mainly treated with UFH compared to LMWH treatment (84% vs 15.9% respectively, p<0.001) and significantly more patients underwent ECC and hemodialysis (p<0.001), whereas in the negative group more patients had active cancer (p= 0.02). There were no significant differences in terms of ECMO, infection or positive blood culture between the two groups.
Respecting ASH guidelines, functional test was performed only in patients with positive PF4/ Heparin Ab. Serotonin-release assay and/or PAT were performed for 96.8% of positive antibodies’ patients (no plasma was available for 3 patients). SRA is considered to be the current gold standard (26), but has certain limitations regarding its complexity and accessibility. LTA, despite its low sensitivity has a 100% specificity (7-8). Thus, in our study, a positive aggregation assay LTA is considered as a positive HIT without the need to perform a SRA assay. Using the threshold of AcuStar HIT-IgG (PF4-H) at 1 U/ml, the incidence of HIT- confirmed patients in our study (based on a positive functional test or clinical assessment) was 5% (65 of 1300), which is consistent with findings observed in patients treated with heparin and suspected of HIT, where HIT ranges from 0.1% to 5.0% (27-31).
As proposed by Warkentin et al (21), our population was divided according to the titer of anti-PF4/heparin Ab, and we fixed three cut-offs using ROC curve analyses (1-3.24 U/mL, 3.25-12.40 U/mL and >12.40 U/mL). All patients with a strong positive titer (>12.40 U/mL) had a confirmed HIT. Our threshold was lower than the threshold fixed by Warkentin et al, ( 20 U/mL). Interestingly, we have more real negative HIT patients (62%) with weak positive titer (1- 3.24 U/mL) than Warkentin (21). Then, the same analysis was performed but this time using the 3 cut-offs proposed by Warkentin (21) (1 - 4.99 U/mL, 5 - 19.99 U/mL and 20.00 U/mL). In the first subgroup 50% of our patients were negative HIT. Therefore, by using our cut-offs, we might increase the probability of excluding HIT in patients with low value of anti-PF4/H antibodies (< 3.24 U/mL). Moreover, our data allowed confirmation of HIT in specimens with a cut-off of anti-PF4/H antibodies at 12.4, which is lower than the value proposed by Warkentin ( 20.00 U/mL), since we did not find any negative patients in this group. Similarly, the probability of a positive HIT increases with the titer of anti-PF4/heparin Ab as previously described with Elisa assay (11) (32).
The ASH guideline 2018 recommends against HIT laboratory testing (strong recommendation) in case of suspected HIT and a low probability 4Ts score. Several assessment studies evaluated the diagnostic accuracy of the 4Ts score (33-35) (4) and a meta-analysis implied a high NPV (99.8%; 95% CI: 97-100%) (14). In our study 3 out of 725 patients with a low (0-3) 4Ts score (0.4 %) were diagnosed with HIT (based on a positive SRA). These cases were carefully re calculated by an expert hematologist and all three were validated as low score. Thus, the NPV for the 4Ts score in our study was lower, at 94.31% (95% CI: 92.8-95.5%). Various studieshave shown a minimal sensitivity than described in the aforementioned meta-analysis(14), (sensitivity 81.3%; 95% CI: 67.7, 94.8%; specificity 63.8%; 95% CI: 59.6-68.0%) (36). Consequently, and due to difficulties in calculating the 4Ts score in clinical practice, some authors have come to the conclusion that a low 4T’s score (≤3) alone is inadequate to exclude HIT in clinical practice (37-38). This is consistent with our results. 15 patients had a high 4Ts score with negative anti PF4/H antibodies. Functional tests were undertaken for all of them and were all considered negative. These results reveal the difficulties in performing 4Ts score in
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patients with complex medical history and is consistent with the findings of Cuker et al (14) and Pischco et al (39).
Interestingly, when combining the 4Ts score and the titer of Anti PF4/heparin Ab, we observed a significant increase of specificity and sensitivity compared to 4T score alone or immunoassay alone. This underlined the complexity to confirm a HIT diagnosis notably in patients admitted in UCI. We were unable to perform functional assays in all patients. However, in our population, the performance of this combination was inferior to these described by Warkentin (21). We might explain this discrepancy by the high prevalence of patients admitted in ICU in our cohort (26.5%).
Our findings above suggest that neither the 4Ts score alone, nor the laboratory assays can correctly diagnose HIT, so in order to avoid the risk of misdiagnosis of HIT we propose a diagnostic algorithm that can help improve the diagnostic accuracy of HIT. (Fig 3).
Limitations:
We are aware that our study has several limitations. First, it is a retrospective study and clinical information and few biological results were not always available but we tried to overcome this obstacle by affecting an extensive research for every case. Second, patients with negative antibodies (<1 U/mL) were not tested with a functional test, based on data published by Legnani et al. (6) explaining the high sensitivity and negative predictive values at 100% of the HemosIL® AcuStar.
Third, we could not perform the functional assay to confirm the presence of HIT in 3 patients with positive Anti PF4/H Antibodies, because there was no remaining plasma available, but these patients were studied carefully and we were able to classify them considering their clinical course.
Conclusion:
There is a significant correlation between higher values of Anti PF4/H Antibodies and the probability of having HIT. The diagnostic specificity was greatly increased by using the combination between the 4Ts score > 3 and a positive Anti PF4/H Ab titer 3.25 U/mL.
A titer of HemosIL® AcuStar HIT-IgG (PF4-H) > 12.40 U/mL have a specificity of 100%, and thus, a combination of clinical evaluation and laboratory testing will best ensure the accuracy of diagnosis of HIT.
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Acknowledgment:
We would like to show our gratitude to our laboratory technicians in La Timone Hospital for assistance with
HemosIL® AcuStar HIT-IgG (PF4-H).
The authors would like to thank Pr Claire Pouplard for her help and critical reading.
Conflict of interest: none declared. Author contributions:
Z M-S, C V, M I-K and EA G: substantial contribution to carrying out experiments, Z M-S, C V, P-EM and LC-J : substantial contribution to result analysis, A L : statistical analysis, Z M-S, CV, P-E M and L C-LC-J substantial contribution to manuscript writing.
