key: cord-0682383-1lys4lpa
authors: Chan, Meng; Zhao, Xinyang; Zheng, X. Long
title: Low ADAMTS‐13 predicts adverse outcomes in hospitalized patients with suspected heparin‐induced thrombocytopenia
date: 2021-09-16
journal: Res Pract Thromb Haemost
DOI: 10.1002/rth2.12581
sha: 277ce8d58c94c54af7612bdc122d29002b8c70ef
doc_id: 682383
cord_uid: 1lys4lpa

BACKGROUND: Heparin‐induced thrombocytopenia (HIT) is a life‐threatening thrombotic complication after heparin exposure. However, the role of ADAMTS‐13 and von Willebrand factor (VWF) in the disease process and outcomes of HIT is not known. OBJECTIVE: To determine the potential role of ADAMTS‐13 and VWF in hospitalized patients suspected with HIT. METHODS: Associations of the HIT tests, ADAMTS‐13 activity, and VWF antigen or activity with other clinical parameters and outcomes in the patients suspected with HIT were determined. RESULTS: Of 261 patients, 87 (33.3%) were positive and 174 (66.7%) were negative for a HIT antibody determined by an enzyme immunoassay (EIA). Of these 87 EIA+ patients, 31 (35.6%) were also positive but 56 (64.4%) were negative for serotonin‐releasing assay (SRA). There was no statistically significant difference among all three groups (i.e., EIA–, EIA+/SRA+, and EIA+/SRA–) as to their demographic features, reasons for admission to the hospital, type of procedures performed, and in‐hospital mortality. Compared to those in the healthy controls, plasma ADAMTS‐13 activity in patients suspected with HIT was significantly lower but plasma VWF antigen (VWFAg) and activity (VWFAc) in these patients were significantly higher. While there was no statistically significant difference among all three groups regarding plasma levels of ADAMTS‐13 activity, VWFAg, and VWFAc, plasma levels of ADAMTS‐13 activity <50% or the low ratios of ADAMTS‐13 activity to VWFAg (or VWFAc) are highly predictive for a 90‐day mortality rate, particularly in the EIA+SRA+ group. CONCLUSIONS: These results demonstrate that relative deficiency of plasma ADAMTS‐13 activity in hospitalized patients suspected with HIT is common, which may contribute at least in part to the adverse outcomes in this patient population, particularly in those with true HIT.

• Heparin-induced thrombocytopenia (HIT) is a life-threatening thrombotic complication.

• The role of ADAMTS-13 and von Willebrand factor (VWF) in patients with suspected HIT is not known.

• We show that low ADAMTS-13 and high VWF are prevalent in hospitalized patients with suspected HIT.

• We conclude that relative deficiency of ADAMTS-13 activity may be a risk factor for mortality in these patients.

Heparin-induced thrombocytopenia (HIT) is a potentially lifethreatening complication after exposure to heparin, characterized by thrombocytopenia and potential catastrophic thrombosis. 1,2 HIT is primarily caused by the formation of antibodies that target platelet factor 4 (PF4)/heparin complexes (e.g., the HIT antibodies), which may activate platelets and coagulation cascade, resulting in arterial and venous thromboses. [3] [4] [5] [6] [7] Approximately 30% to 50% of patients with HIT may develop thrombosis [8] [9] [10] [11] [12] with an estimated mortality rate of 5% to 10%. [12] [13] [14] Venous thromboembolism is 2 to 5 times more prevalent than arterial thrombosis in patients with HIT. 9, 11, 13 This includes deep vein thrombosis (DVT) and pulmonary embolism (PE). Arterial thrombosis, including ischemic stroke, myocardial infarction, and peripheral arterial occlusion, may also occur. 9, 11, [15] [16] [17] Rarely, bilateral adrenal hemorrhage, 18 skin necrosis, 19, 20 venous gangrene, 21 and thrombosis in a grafted vessel 22 

Clinical diagnosis of HIT requires a high index of suspicion based on clinical information, followed by laboratory tests, such as enzyme immunoassay (EIA) and serotonin-releasing assay (SRA). The 4T score (i.e., thrombocytopenia, time to platelet falls, thrombosis, and no other causes of thrombocytopenia) has been the widely used to predict the pretest probability of HIT. 23 The higher the scores are, the more likely the patient may have a HIT. 24 A more complex HIT expert probability (HEP) score was also developed on the basis of broad expert opinions, which was considered to have a higher of interobserver's agreement and correlated better with the results of the laboratory tests for HIT. 25 Regardless of what tests are used for diagnosis of HIT, clinical presentations and outcomes are not always correlated with the HIT test results, suggesting that additional factors may contribute to the pathogenesis of thrombotic events, organ damage, and outcomes.

ADAMTS-13, a plasma metalloprotease, plays a critical role in regulating hemostasis and preventing unwanted thrombosis. 26 It does so through proteolytic cleavage of von Willebrand factor (VWF), which is synthesized and released from activated or injured endothelium. 27 Severe deficiency of plasma ADAMTS-13, primarily resulting from acquired autoantibodies against ADAMTS-13, leads to thrombotic thrombocytopenic purpura (TTP), a potentially fatal blood disorder. 28 Relative deficiency of plasma ADAMTS-13 has been observed in patients with acute cerebral infarction, 29, 30 myocardial infarction, 31,32 malignant malaria, 33, 34 preeclampsia, 35, 36 acute traumatic brain injury, or multiple site injury, 37, 38 as well as in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. [39] [40] [41] However, the role of ADAMTS-13 in pathogenesis, disease progression, and outcome in patients with suspected HIT has not been systematically determined. The present study aims to determine the associations among plasma levels of ADAMTS-13 activity, VWF antigen, VWF activity, and other clinical factors or laboratory parameters, and in particular the role of ADAMTS-13 and VWF in predicting in-hospital mortality in patients with suspected HIT.

Center and the University of Alabama at Birmingham approved the study protocol. The subjects were identified from the list of patients who were tested for HIT antibody (ie, the anti-PF4/heparin complex IgG) in the special coagulation laboratory. Residual plasma after HIT tests was stored at −80℃ as part of biorepository for quality assurance and research. Informed consent was waived for the use of retrospective samples and other clinical and laboratory information extracted from electronic medical record. Control samples were collected from local volunteers who did not have any acute illness, with age, sex, and race background matched. Whole blood was collected and anticoagulated with sodium citrate the same way as did the samples for all other coagulation tests.

The demographic information including age, sex, race, reasons for admission to hospital (e.g., infection, surgery, nonsurgery, and trauma, etc.), death in hospital, length of stay, and other clinical conditions (e.g., acute or exacerbated renal failure, heart failure, liver failure, and respiratory failure; sepsis and bleeding; etc.), comorbidities (e.g., hypertension, diabetes, hyperlipidemia, coronary heart disease, valvular heart disease, congestive heart failure, chronic obstructive pulmonary disease (COPD), institutional lung disease, connective tissue disease, cirrhosis, stroke, malignancy, etc.), and procedures performed during hospitalization (e.g., intra-aortic balloon pump/ ventricular assistant device, extracorporeal membrane oxygenation [ECMO] , etc.). The data related to heparin usage and changing of platelet count, as well as form of heparins (unfractionated vs lowmolecular-weight heparin), route of heparin administration (e.g., intravenous or subcutaneous), timing of thrombocytopenia occurred in relation to heparin exposure, nadir of platelet count, percentage of platelet count falling, and venous or arterial embolic events that were discovered or progressed after exposure to heparin that were considered the results of HIT, and alternative anticoagulants (e.g., direct thrombin inhibitor, factor X inhibitors, etc.). The 4T 23 and HEP scores 25 were determined for each patient. Additionally, plasma samples from healthy individuals were collected for negative controls.

An EIA (i.e., the Asserachrom HPIA IgG, #00624) was used to determine the IgG antibodies against PF4/heparin complexes according to manufacturer's recommendations (Stago, Parsippany, NJ, USA).

An optical density (OD) value >0.5 was defined as positive, and an OD <0.5 was negative. The HIT EIA test was performed in the Clinical Laboratory Improvement Amendments-certified special coagulation laboratory that serves patient care. All EIA+ samples were sent to a reference lab (Versiti, Milwaukee, WI, USA) for the SRA.

Plasma ADATMS-13 activity was determined using our in-house rFRETS-VWF73 assay as previously described. 42, 43 Plasma ADAMTS-13 antigen was determined using ELISA 44 

Plasma VWF antigen (VWFAg) and collagen-binding activity (VWFAc) were determined with the in-house ELISA-based assays as previously described. 44, 45 

The categorical variables of sex, race, mortality, reasons for admission, comorbidity, procedures, special clinical conditions, administered heparin products, administration route, alternative anticoagulants, time for heparin exposure, thromboembolic events before and after heparin exposure, and 4T score graded by risk were expressed as number (%) and compared by chi-square. The normally distributed quantitative data of age, 4T score, and HEP score were expressed as mean with standard deviation (SD) and compared using one-way analysis of variance (ANOVA) for more than three groups and Student t test for two groups, while nonnormally contributed data of length of stay, percentage of platelet falling, time of platelet falling, nadir value of platelet, and HIT antibody OD were expressed as median and interquartile range (IQR) and were compared by Kruskal-Wallis one-way ANOVA test for more than three groups or Mann-Whitney U test for two groups. Analysis of consistency between 4T score and HEP score was carried out by linear regression. A P < 0.05 and <0.01 was considered to be statistically significant and highly significant, respectively. All the statistical analyses were performed using SPSS Of 87 EIA+ patients, 31 (35.6%) were also SRA+, and 56 (64%) were SRA-( Table 1 ). As also shown in Table 1 , there was no statistically significant difference in the demographic features (e.g., age, sex, and race), the reasons for admission, in-hospital mortality, and the type of procedure performed among all three patient groups (ie, EIA+/ SRA-, EIA+/SRA+, and EIA-). Additionally, there was no statistically significant difference in term of acute events occurring after admission including acute respiratory failure, liver failure, sepsis, bleeding, and so on, except for acute heart failure (P = 0.01) and renal failure (P = 0.002). In terms of comorbidities, all three groups of patients exhibited a similar incidence rate. These include hypertension, diabetes mellitus, cardiovascular disease, valvular heart disease, arrhythmia, peripheral vascular disease, cerebral vascular disease, COPD/bronchitis, obesity, liver disease/cirrhosis, malignancy, connective tissue disease, and recent/chronic infections. Again, fewer patients had congestive heart failure in the EIA+/SRA+ group than in the EIA+/SRA-and EIA-groups (P = 0.03). While in-hospital mortality rate was similar in all three patient groups, more time in the hospital (P = 0.005) or fewer percentage of patients staying in hospital for <30 days (P = 0.002) in the EIA+ group, regardless of the SRA results, than in the EIA-group (P = 0.005) was observed (Table 1 ).

Clinical diagnosis of HIT relies on a high index of suspicion based on thrombocytopenia, timing of platelet count fall, thrombosis or other sequalae, and no other causes for thrombocytopenia (i.e., the 4T score). 23, 46 In our cohort of patients, the nadir of platelet count Note: a-b indicates that the difference was significant (P < 0.05). However, the differences between a-a, b-b, a-c, and b-c were not statistically significant (P > 0.05).

Abbreviations: COPD, chronic obstructive pulmonary disease; CTD, connective tissue disease; ECMO, extracorporeal membrane oxygenation. EIA, enzyme immunoassay; IABP, intra-aortic balloon pump; IQR, interquartile range; SD, standard deviation; SRA, serotonin-releasing assay; VAD, ventricular assistant device.

IQR) in the EIA+/SRA+ group (5; 4.5-6.0) than in the EIA+/SRA-(4.0; 2.3-4.0) and EIA-(3.0; 2.0-4.0) groups (P < 0.001). When the 4T score was stratified as low (0-3), medium (4) (5) , and high (6) (7) (8) , the percentage of patients with a high-risk score in the EIA+/SRA+ group (35.5%) was significantly higher than that in the EIA+/SRA-(17.9%) and EIA-(2.9%) groups, respectively (P < 0.001; Table 2 and Figure 1A) . A similar result was obtained with the HEP score.

The HEP score (mean ±SD) in EIA+/SRA+ group (5.6 ± 3.1) was significantly higher than that in the EIA+/SRA-(3.6 ± 3.2) and EIA-

There was no statistically significant difference in both 4T and HEP scores between the EIA+/SRA+ group and the EIA+/SRA-group (Table 2 and Figure 1B ). Spearman correlation analysis demonstrated a strong correlation between 4T score and HEP score with a Spearman correlation coefficient of 0.71 for all patients assessed ( Figure S1 ), suggesting that both scoring systems have similar predictive value for the probability of HIT. Relative risk based on 4T score 

None, n (%) 4(12.9) a 29(51. Note: Here, the differences between a-b, b-c, and a-c were statistically significant (P < 0.05) while the differences between a-a, b-b, a-ab, and b-ab were not statistically significant (P > 0.05).

Abbreviations: AMI, acute myocardial infarction; DVT, deep vein thrombosis; HEP, HIT expert probability; HIT Ab, heparin-induced thrombocytopenia anti-PF4/heparin IgG; IQR, interquartile range; IV, intravenous; OD, optical density; PE, pulmonary embolism; UFH, unfractionated heparin. more frequently seen in the EIA+/SRA+ group than in the EIA+/ SRA-and EIA-patients. However, PE (P = 0.06) and ventricular or aortic thrombosis (P = 0.40), although rare, in all three groups had a similar incidence rate (Table 2 ). Figure 2A) . Conversely, plasma levels of VWFAg ( Figure 2B ) and VWFAc ( Figure 2C ) in all patients with clinically suspected HIT were dramatically increased compared with those in the healthy controls. Again, there was no statistically significant difference in plasma levels of VWFAg and VWFAc among three patient groups (P > 0.05) ( Table 3) (Table 3 and Figure 2D ). Similarly, lower ratios of ADAMTS-13 activity to VWF activity were observed among three patient groups compared with that in the healthy controls (Table 3 and Figure 2E ). There was no statistically significant difference in the ratios of VWFAc to VWFAg among patient groups or between patients and healthy controls (Table 3 and Figure 2F ). These results demonstrate for the first time a high prevalence of relative deficiency of plasma ADAMTS-13 activity in all hospitalized patients with suspected HIT.

To assess the role of ADAMTS-13 and VWF in the disease pro- (Table 1 ). These results suggest that having a positive HIT test may require change in the management strategy, resulting in an increased usage of hospital resource.

To determine if the ratio of ADAMTS-13 to VWF would be more sensitive for prediction of mortality, the Kaplan-Meier analysis was performed in each patient group. As shown, the ratio of plasma ADAMTS-13 activity to VWFAg at less than the 50th percentile was 

To determine the mechanism underlying low ADAMTS-13 activity in patients with suspected HIT, we determined plasma ADAMTS-13 antigen by ELISA in the same patient samples. Spearman correlation coefficient (r) demonstrated that plasma ADAMTS-13 activity was positively Note: All data are presented as the median (interquartile range). Here, the differences between a-b, b-c, a-c, or ab-c were statistically significant (P < 0.05), while the differences between a-ab and b-ab were not statistically significant (P ≥ 0.05).

Abbreviations: EIA, enzyme immunoassay; SRA, serotonin-releasing assay; VWF, von Willebrand factor; VWFAc, von Willebrand factor activity; VWFAg, von Willebrand factor antigen. (Table 4 ). These results suggest that in rare situations the reduction of plasma ADAMTS-13 activity may also result from autoantibodies against ADAMTS-13.

To determine the potential cause of low plasma ADAMTS-13 activity and other clinical factors contributing to mortality, we per- Table 6 ). These results suggest that the causes of death in these patients may be multifactorial, but each may contribute to the mortality independently.

Finally, logistic regression analysis revealed that EIA+/SRA-or EIA+/SRA+, thrombosis before heparin use, respiratory failure, and chronic cardiovascular disease were associated with an increased probability of thrombotic events after heparin exposure (Table 7) .

HIT is a life-threatening thromboembolic complication after heparin exposure. Clinical and laboratory diagnosis, as well as management of HIT remain to be challenging. Over-and underdiagnosis Note: Odds ratio (OR)s of all the binary variances were compared by "yes" to "no". Note: ORs of all the binary variances were compared by "yes" to "no."

Abbreviations: CI, confidence interval; OR, odds ratio; PLT, platelet.

preeclampsia, 35,60-62 and sepsis, [63] [64] [65] as well as severe SARS-CoV-2

infection. [39] [40] [41] 66, 67 Consistent with such a notion, low plasma ADAMTS-13 activity or reduced ratio of ADAMTS-13 activity to VWF antigen or activity is prevalent in our patients with suspected HIT; this may be primarily caused by congestive heart failure, pulmonary embolism, and sepsis, resulting in reduced synthesis and increased consumption of ADAMTS-13. In some cases, low ADAMTS-13 activity may be the result of IgG autoantibodies against ADAMTS-13 that binds ADAMTS-13 and accelerates clearance of immune complexes from circulation.

Most importantly, our Kaplan-Meier survival analysis demonstrates that patients with low ADAMTS-13 activity (<50th percentile) or low ratio of ADAMTS-13 activity to VWF (antigen or activity) exhibits a dramatically reduced survival probability within 90 days of follow-up, regardless of HIT test results, although the predictive value in the EIA+/SRA+ patients is clearly better. This is further supported by the multivariant analysis demonstrating that low ADAMTS-13 activity is an independent factor contributing to the 90-day mortality rate.

There may be certain limitations related to this study. While the control and patient samples were collected and stored at −80°C without repeated freezing and thawing before this analysis, the patient samples were stored longer than the control samples. Fortunately, both VWF and ADAMTS-13 in plasma are stable under such a storage condition. The other limitations include the retrospective nature of patient data collection and potential interassay variability of the HIT EIA test.

Nevertheless, our results demonstrate that while other clinical factors may contribute to the mortality, low levels of plasma ADAMTS-13 activity and high levels of plasma VWF, resulting in relative deficiency of ADAMTS-13 function, appear to be highly predictive for adverse outcomes in hospitalized patients with suspected HIT. Our findings suggest a possible interventional strategy with ADAMTS-13 supplementation to improve the survival rate in this patient population should future prospective studies confirms these findings.

The authors thank Laura Taylor and other staff in the coagulation laboratory at the University of Alabama at Birmingham for the biorepository of HIT test samples. The study is partially supported by the grants from National Heart, Lung, and Blood Institute (HL126724 and HL144552).

XLZ is a consultant for Alexion, Sanofi-Genzyme, and Takeda. XLZ is also a speaker for Alexion and Sanofi-Genzyme and cofounder of

Clotsolution. MC has no conflict of interest to disclose. 

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von Willebrand factor/ ADAMTS13 axis and venous thromboembolism in moderate-tosevere COVID-19 patients

ADAMTS13 activity to von Willebrand factor antigen ratio predicts acute kidney injury in patients with COVID-19: Evidence of SARS-CoV-2 induced secondary thrombotic microangiopathy

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Additional supporting information may be found online in the Supporting Information section