Frequency and Clinical Impact of Platelet Factor 4-Specific Antibodies in Patients Undergoing Extracorporeal Membrane Oxygenation

2019 ◽  
Vol 119 (07) ◽  
pp. 1138-1146 ◽  
Author(s):  
Caroline Vayne ◽  
Marc-Antoine May ◽  
Thierry Bourguignon ◽  
Eric Lemoine ◽  
Eve-Anne Guery ◽  
...  
Keyword(s):  
Platelet Count ◽  
Extracorporeal Membrane Oxygenation ◽  
Serotonin Release ◽  
Clinical Impact ◽  
Platelet Factor 4 ◽  
Ecmo Circuit ◽  
Platelet Factor ◽  
Specific Antibodies ◽  
Release Assay ◽  
Specific Igg

Introduction/Objectives Extracorporeal membrane oxygenation (ECMO) provides circulatory support in patients with severe heart failure, but the frequent use of unfractionated heparin exposes patients to high risk of heparin-induced thrombocytopenia (HIT). We prospectively evaluated the development and clinical impact of platelet factor 4 (PF4)-specific antibodies (Abs) during ECMO and whether specific biological characteristics could predict HIT. Materials and Methods From 2014 to 2018, we studied 57 adults who underwent an ECMO for at least 5 days. The plasma samples collected daily were tested for PF4-specific Abs using immunoassays to detect immunoglobulin (Ig) G, A, and M isotypes or only IgG. Serotonin release assay was performed without and with PF4 to detect pathogenic Abs. Results Twenty-nine patients (50%) were positive for PF4-specific Abs (IgG, A, M), with IgG in 17/57 (30%) and 16 of them (94%) were immunized within 10 days. PF4-specific IgG Abs did not affect the clinical or biological course of most patients. HIT was suspected in only two patients with ECMO circuit dysfunction and unexpected platelet count decrease after day 5. High levels of PF4-specific IgG were detected in both patients, and HIT was confirmed by a serotonin release assay, which was also more sensitive when exogenous PF4 was present. Conclusion PF4-specific Abs are common during ECMO but are mostly non-pathogenic and not associated with a less favorable prognosis. However, an abnormal platelet count evolution, in particular if associated with ECMO circuit dysfunction, should prompt the search for pathogenic PF4-specific IgG.

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

2020 ◽  
Author(s):  
Theodore E. Warkentin ◽  
Maureen A. Smythe ◽  
Mona A. Ali ◽  
Naveed Aslam ◽  
Jo‐Ann I. Sheppard ◽  
...  
Keyword(s):  
Enzyme Immunoassay ◽  
Serotonin Release ◽  
Platelet Factor 4 ◽  
Platelet Factor ◽  
Release Assay

Pathophysiology of Heparin-Induced Thrombocytopenia

2000 ◽  
Vol 124 (11) ◽  
pp. 1657-1666 ◽  
Author(s):  
Fabrizio Fabris ◽  
Sarfraz Ahmad ◽  
Giuseppe Cella ◽  
Walter P. Jeske ◽  
Jeanine M. Walenga ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Serotonin Release ◽  
Platelet Factor 4 ◽  
Thrombin Inhibitors ◽  
Platelet Factor ◽  
Cellular Activation ◽  
Heparin Induced Thrombocytopenia ◽  
New Information ◽  
Study Selection ◽  
Release Assay

Abstract Objective.—This review of heparin-induced thrombocytopenia (HIT), the most frequent and dangerous side effect of heparin exposure, covers the epidemiology, pathophysiology, clinical presentation, diagnosis, and treatment of this disease syndrome. Data Sources and Study Selection.—Current consensus of opinion is given based on literature reports, as well as new information where available. A comprehensive analysis of the reasons for discrepancies in incidence numbers is given. The currently known mechanism is that HIT is mediated by an antibody to the complex of heparin–platelet factor 4, which binds to the Fc receptor on platelets. New evidence suggests a functional heterogeneity in the anti-heparin-platelet factor 4 antibodies generated to heparin, and a “superactive” heparin-platelet factor 4 antibody that does not require the presence of heparin to promote platelet activation or aggregation has been identified. Up-regulation of cell adhesion molecules and inflammatory markers, as well as preactivation of platelets/endothelial cells/leukocytes, are also considered to be related to the pathophysiology of HIT. Issues related to the specificity of currently available and new laboratory assays that support a clinical diagnosis are addressed in relation to the serotonin-release assay. Past experience with various anticoagulant treatments is reviewed with a focus on the recent successes of thrombin inhibitors and platelet GPIIb/IIIa inhibitors to combat the platelet activation and severe thrombotic episodes associated with HIT. Conclusions.—The pathophysiology of HIT is multifactorial. However, the primary factor in the mediation of the cellular activation is due to the generation of an antibody to the heparin-platelet factor 4 complex. This review is written as a reference for HIT research.

Antibodies to the Platelet Factor 4-Heparin Complex and Mortality in Chronic Hemodialysis Patients.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 274-274
Author(s):  
Marc Carrier ◽  
Greg A. Knoll ◽  
Dean Fergusson ◽  
Steven Doucette ◽  
Michael J. Kovacs ◽  
...  
Keyword(s):  
Cardiovascular Events ◽  
Hemodialysis Patients ◽  
Serotonin Release ◽  
Chronic Hemodialysis ◽  
Platelet Factor 4 ◽  
Elisa Assay ◽  
Platelet Factor ◽  
Risk Of Death ◽  
Asymptomatic Patients ◽  
Release Assay

Abstract Background: Heparin-induced thrombocytopenia is a serious complication of heparin therapy that can lead to thromboembolism, cardiovascular events or death. Patients with this disorder develop antibodies to the platelet factor 4-heparin (PF4-H) complex. Hemodialysis patients are repeatedly exposed to heparin and are at risk for developing PF4-H antibodies. The clinical impact of asymptomatic PF4-H antibodies in patients on chronic hemodialysis is not known. Objective: To determine the association between asymptomatic PF4-H antibodies and mortality in a cohort of chronic hemodialysis patients repeatedly exposed to heparin. Methods: Pre-dialysis blood samples were drawn from 419 asymptomatic patients. All patients received unfractionated heparin (Baxter) while on dialysis. All samples were screened for PF4-H antibodies using an ELISA assay (GTI PF4 Enhanced, GTI Diagnostics). All positive and indeterminate samples were then tested using an IgG-specific PF4-H ELISA assay and a platelet serotonin-release assay. Participants were then followed up prospectively for thromboembolic events, cardiovascular events, or death. Results: During a median follow-up of 2.5 years there were 129 deaths. After controlling for important potential confounding variables, the relative risk of death was 2.92 (95% CI: 1.18-7.25; P= 0.02) in patients with IgG-specific PF4-H antibodies and 4.08 (95% CI: 1.26–13.2; P= 0.02) in patients with IgG-specific antibodies and an indeterminate serotonin-release assay. Conclusions: PF4-H antibody formation is associated with increased all-cause mortality in patients on chronic hemodialysis. Further investigation is needed to determine if anticoagulation with alternative agents would improve survival in this population.

Prevalence of Heparin-Dependent Platelet Antibodies in Children after Cardiopulmonary Bypass Surgery.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3019-3019
Author(s):  
Rowena C. Punzalan ◽  
Sheila J. Hanson ◽  
Nancy Ghanayem ◽  
Brian R. Curtis ◽  
Kathleen Murkowski ◽  
...  
Keyword(s):  
Cardiopulmonary Bypass ◽  
Unfractionated Heparin ◽  
Pediatric Intensive Care ◽  
Serotonin Release ◽  
Platelet Factor 4 ◽  
Enzyme Linked Immunosorbent Assay ◽  
Platelet Factor ◽  
Heparin Induced Thrombocytopenia ◽  
Platelet Antibodies ◽  
Release Assay

Abstract Heparin is used during cardiopulmonary bypass (CPB) surgery in children. Upon exposure to heparin, heparin-dependent platelet antibodies (HDPA) may form against complexes of platelet factor 4 and heparin on platelet surfaces. Heparin-induced thrombocytopenia (HIT) or heparin-induced thrombocytopenia and thrombosis (HITT) may then ensue. Among adult CPB patients, up to 50% demonstrate HDPA, although only 2% develop HIT and 1% develop HITT. In previous studies done among non-CPB newborns and pediatric intensive care patients, the incidence of HDPA has been zero to minimal. Objective: To determine prevalence of HDPA among children undergoing CPB who are exposed to unfractionated heparin for >120 hours after CPB. Methods: We designed a prospective pilot study. All patients ≤ 12 years old who were to receive heparin during CPB were eligible. The presence of HDPA was assessed by heparin-platelet factor 4 enzyme-linked immunosorbent assay (ELISA); positive and equivocal results were confirmed by serotonin release assay. Blood samples were obtained at the time of cessation of heparin or after 10 days on heparin, whichever came first. Results: Thirty patients were enrolled: 15 were aged 2–19 days (median 6 days); 15 were aged 1.2 to 50 months (median 4.5 months). One patient had borderline positive and 1 had positive results by heparin-platelet factor 4 ELISA; both had negative results by serotonin release assay; neither developed clots. Eighteen patients developed thrombocytopenia, which is common after CPB, including the 2 with equivocal results by ELISA. Six patients, all with negative ELISAs, developed symptomatic thromboses. Conclusion: There were no HDPA identified among children who received unfractionated heparin for CPB. The specificity of heparin-platelet factor 4 ELISA among children should be assessed.

scholarly journals Heparin-Induced Thrombocytopenia Testing: ELISA Based Anti-Platelet Factor 4 Polyspecific and IgG-Specific Antibody Detection Assays Compared to the Unfractionated Heparin Serotonin Release Assay

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3209-3209
Author(s):  
Edward C.C. Wong ◽  
Laura A. Worfolk ◽  
Caixia Bi ◽  
Lina J. Noh ◽  
Andrew Espinoza ◽  
...  
Keyword(s):  
Unfractionated Heparin ◽  
Specific Antibody ◽  
Serotonin Release ◽  
Test Results ◽  
Platelet Factor ◽  
Heparin Induced Thrombocytopenia ◽  
Specific Antibodies ◽  
Functional Assays ◽  
Antibody Assays ◽  
Release Assay

Abstract Introduction: Antibodies that cause heparin-induced thrombocytopenia (HIT) can be detected with either antigenic or functional assays. Previously, it has been shown that antigenic (ELISA based) assays that detect anti-platelet factor 4 (anti-PF4) IgG, IgM, or IgA (polyspecific) antibodies are more sensitive but less specific than functional assays such as the unfractionated serotonin release assay (UFH SRA), and that the use of anti-PF4 assays that detect IgG antibodies only, would increase the specificity but decrease the sensitivity of these assays for the detection of HIT antibodies that are prothrombotic (associated with positive functional assay). To date large epidemiologic studies have not confirm these findings. To evaluate the relative performance of anti-PF4 polyspecific and IgG-specific antibodies in their ability to detect prothrombotic HIT antibodies, we evaluated results of non-reflexive HIT panels that contained either anti-PF4 polyspecific or IgG-specific assays and unfractionated heparin serotonin release assays over an eight-year period at a U.S. reference laboratory. Methods: Test results for 2 HIT detection panels were compared: 1 panel had UFH SRA plus the polyspecific PF4 ENHANCED® assay (GTI Diagnostics, Waukesha, WI) and 1 panel had UFH SRA plus the IgG-specific Zymutest HIA IgG assay (Hyphen Biomed, France). Test results were from the last 4 years of use for each panel (2009 to 2012 for the polyspecific panel; 2017 to 2020 for the IgG-specific panel). UFH SRA was performed as described by Sheridan et al, (1986) with positivity defined as ≥20% serotonin release by low dose UFH and >50% suppression of release at high dose (100 U/mL) UFH. For each year and assay, test results were stratified by optical density (OD) results, and the percent of results positive by UFH SRA was determined for each OD range. Median yearly UFH SRA positivity rates for each OD interval were compared for anti-PF4 polyspecific vs IgG-specific antibody assays using non-parametric statistical testing, Mann-Whitney U test, two-tailed, with significance defined as <0.05. Results: HIT panels with either ELISA based assays detecting either anti-PF4 polyspecific or IgG specific antibodies demonstrated increasing UFH SRA positivity rates as OD increased. Approximately 50% UFH SRA positivity occurred when OD was in the 2.000 to range. No significant differences in SRA positivity were seen at any positive OD interval when comparing anti-PF4 polyspecific vs IgG-specific assays. A small but significant difference was seen when OD results were considered This observation may have been due to a in the review process (2017-2020): when a UFH SRA result was positive with a negative OD result, repeat UFH SRA testing was performed. Conclusions: Our study demonstrates that the correlations of UFH SRA positivity and OD measurements are similar for anti-PF4 IgG-specific and polyspecific antibody assays. These results suggest the assay types may perform similarly for the detection of HIT and importantly provide important predictive information as to when an optical density value will lead to a positive UFH SRA result. Figure 1 Figure 1. Disclosures Wong: Quest Diagnostics: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Worfolk: Quest Diagnostics: Current Employment. Bi: Quest Diagnostics: Current Employment. Noh: Quest Diagnostics: Current Employment. Espinoza: Quest Diagnostics: Current Employment. Wu: Quest Diagnostics: Current Employment. Sahud: Quest Diagnostics: Current Employment. Racke: Quest Diagnostics: Current Employment. Dlott: Quest Diagnostics: Current Employment.

Platelet factor-4 concentration in adult veno-arterial ECMO patients

Perfusion ◽  
2020 ◽  
pp. 026765912096510
Author(s):  
Michael Mazzeffi ◽  
Madeline Clark ◽  
Alison Grazioli ◽  
Colleen Dugan ◽  
Raymond Rector ◽  
...  
Keyword(s):  
Antibody Formation ◽  
Critical Factor ◽  
Epidemiologic Studies ◽  
Serotonin Release ◽  
Platelet Factor 4 ◽  
Platelet Factor ◽  
Heparin Induced Thrombocytopenia ◽  
Release Assay ◽  
Va Ecmo ◽  
Control Plasma

Background: Heparin induced thrombocytopenia (HIT) is reported at a variable rate in extracorporeal membrane oxygenation (ECMO) patients. A critical factor impacting platelet factor-4 (PF4)-heparin antibody formation is plasma PF4 concentration. We hypothesized that PF4 concentration would be increased during veno-arterial (VA) ECMO. Methods: Plasma PF4 concentration was measured during the first 5 ECMO days in 20 VA ECMO patients and 10 control plasma samples. PF4-heparin ratios were estimated using an assumed heparin concentration of 0.4 IU/mL. This correlates with an activated partial thromboplastin time of 60 to 80 seconds, which is the anticoagulation target in our center. Results: Twenty VA ECMO patients were enrolled, 10 of which had pulmonary embolism. Median PF4 concentration was 0.03 µg/mL [0.01, 0.13] in control plasma. Median PF4 concentration was 0.21 µg/mL [0.12, 0.34] on ECMO day 1 or 2, 0.16 µg/mL [0.09, 0.25] on ECMO day 3, and 0.12 µg/mL [0.09, 0.22] on ECMO day 5. Estimated median PF4-heparin ratios were 0.04, 0.03, and 0.02 respectively. Two patients (10%) developed HIT that was confirmed by serotonin release assay. PF4 concentration did not differ significantly in these patients compared to non-HIT patients (p = 0.37). No patient had an estimated PF4-heparin ratio between 0.7 and 1.4, which is the reported optimal range for PF4-heparin antibody formation. Conclusion: Our data suggest that PF4 concentration is mildly elevated during VA ECMO compared to control plasma. Estimated PF4-heparin ratios were not optimal for HIT antibody formation. These data support epidemiologic studies where HIT incidence is low during VA ECMO.

scholarly journals False-Negative Platelet Factor 4 Antibodies and Serotonin Release Assay and the Utility of Repeat Testing in the Diagnosis of Heparin-Induced Thrombocytopenia and Thrombosis

2019 ◽  
Vol 2019 ◽  
pp. 1-4 ◽  
Author(s):  
Tarig Omer ◽  
Naresh Mullaguri ◽  
Pravin George ◽  
Christopher R. Newey
Keyword(s):  
False Negative ◽  
Serotonin Release ◽  
Clinical Suspicion ◽  
Platelet Factor 4 ◽  
Platelet Factor ◽  
Heparin Induced Thrombocytopenia ◽  
Repeat Testing ◽  
Tandem Occlusion ◽  
Release Assay ◽  
The Right

Objective. To report a case of false-negative serological tests in the diagnosis of heparin-induced thrombocytopenia (HIT) followed by a brief review of the literature on this topic. Case Presentation. A 75-year-old Caucasian female patient was admitted with a traumatic right ankle fracture that required open reduction and internal fixation. Despite postoperative subcutaneous heparin chemoprophylaxis, she developed deep vein thrombosis (DVT) and pulmonary embolism (PE) on day 4 and subsequently started on continuous heparin infusion. On day 5, she suffered a stroke from a complete occlusion of the right common carotid artery with tandem occlusion of the right middle cerebral artery. She underwent successful thrombectomy of both arteries. The proposed stroke mechanism was paradoxical embolism through a patent foramen ovale. Over the next few days, thrombocytopenia was noted, the heparin drip was stopped, and HIT antibodies (antibodies targeting the complex of platelet factor 4 and heparin; PF4-H AB) and serotonin release assay (SRA) tests were sent. Because of the suspicion for HIT, she was started on bivalirudin with subsequent improvement in platelet count. Initial PF4-H AB and SRA tests were negative, bivalirudin was stopped, and heparin was restarted. Subsequently, her platelets trended down, again raising clinical suspicion of HIT. Repeat PF4-H AB and SRA testing resulted positive. Conclusions. A positive SRA in the appropriate context is considered for the diagnosis of heparin-induced thrombocytopenia. This case report highlights that false-negative serological evaluation is possible early in the course of the disease. Repeat testing is recommended in patients with high clinical suspicion.

scholarly journals Heparin-induced thrombocytopenia in patients on extracorporeal membrane oxygenation and the role of a heparin-bonded circuit

Perfusion ◽  
2019 ◽  
Vol 34 (7) ◽  
pp. 584-589 ◽  
Author(s):  
Dirk Pabst ◽  
Jacqueline B Boone ◽  
Behzad Soleimani ◽  
Christoph E Brehm
Keyword(s):  
Overall Survival ◽  
Platelet Count ◽  
Retrospective Study ◽  
Extracorporeal Membrane Oxygenation ◽  
Serotonin Release ◽  
Single Center ◽  
Heparin Induced Thrombocytopenia ◽  
Membrane Oxygenation ◽  
Release Assay

Background: In patients supported with extracorporeal membrane oxygenation, and who develop heparin-induced thrombocytopenia, there is no clear evidence to support changing to a non-heparin-coated extracorporeal membrane oxygenation circuit. Our goal was to evaluate clinical outcomes of patients who were continued on heparin-bonded circuits despite diagnosed heparin-induced thrombocytopenia. Methods: We completed a single-center retrospective study of all patients who underwent extracorporeal membrane oxygenation support from July 2008 to July 2017 and were tested heparin-induced thrombocytopenia positive while on extracorporeal membrane oxygenation support. After diagnosis of heparin-induced thrombocytopenia, mean platelet count (k/µL) was measured on consecutive days for 14 days. Results: Out of 455 patients, 14 (3.1%) had a diagnosis of heparin-induced thrombocytopenia by serotonin release assay and systemic heparin treatment was discontinued in every case. In total, 11 of the heparin-induced thrombocytopenia patients (78.6%) survived to discharge. The overall survival of all 455 extracorporeal membrane oxygenation patients was 54.1%. Platelets counts after discontinuation of systemic heparin in the heparin-induced thrombocytopenia patients increased from a mean of 59.8 k/µL at time of heparin-induced thrombocytopenia diagnosis to a mean of 280.2 k/µL at 14 days after discontinuation of heparin despite continuation of the heparin-bonded circuit. Platelet count increased in heparin-induced thrombocytopenia patients on extracorporeal membrane oxygenation support after discontinuation of systemic heparin even if maintained on the heparin-bonded circuit. Conclusion: Discontinuation of systemic heparin but continuation of heparin-coated extracorporeal membrane oxygenation circuits appeared to be an appropriate response for our extracorporeal membrane oxygenation–supported patients who developed heparin-induced thrombocytopenia. Survival in this group was not significantly different to those patients on extracorporeal membrane oxygenation without heparin-induced thrombocytopenia. Larger studies should evaluate the safety of heparin-bonded extracorporeal membrane oxygenation systems in heparin-induced thrombocytopenia patients.

Platelet-Activating Anti-Platelet Factor 4/Polyanion Antibodies without Preceding Heparin Therapy: A Transient Autoimmune Disorder Resembling Heparin-Induced Thrombocytopenia (“Spontaneous HIT”).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1047-1047 ◽  
Author(s):  
Theodore E. Warkentin ◽  
Richard M. Jay ◽  
Michael Makris ◽  
John G. Kelton
Keyword(s):  
Immune Response ◽  
Platelet Count ◽  
Systemic Reaction ◽  
Autoimmune Disorder ◽  
Serotonin Release ◽  
Acute Illness ◽  
Platelet Factor 4 ◽  
Platelet Factor ◽  
Heparin Induced Thrombocytopenia ◽  
Heparin Administration

Abstract Heparin-induced thrombocytopenia (HIT) is a prothrombotic disorder with autoimmune features: its target antigen is a “self” protein, platelet factor 4 (PF4), that is conformationally modified in the presence of heparin or certain other polyanions. A central dogma in HIT is that the antibodies are invariably triggered by treatment with heparin. We report four patients who developed an acute illness strongly resembling immune HIT despite the absence of any preceding heparin administration [Table 1]. Various inflammatory or invasive events were documented during the two-week period prior to each patient’s acute illness, suggesting that factors other than heparin can trigger an immune response against PF4/polyanion complexes. Following onset of their HIT-like illness, three of the patients received unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) to treat proven or suspected thrombosis, which precipitated abrupt platelet count falls in all. Serum from all four patients contained antibodies serologically indistinguishable from those causing HIT, namely platelet-activating immunoglobulin G (IgG) recognizing PF4 bound to heparin or polyvinyl sulfonate [Table 2]. Two patients died from thrombosis; in the two survivors, antibodies became undetectable during follow-up, consistent with the transient nature of the anti-PF4/heparin immune response reported in HIT. Conclusion: These four patient cases suggest that on rare occasions a transient prothrombotic autoimmune disorder strongly resembling immune HIT can occur, “spontaneous HIT”. Table 1. Clinical features: 4 patients with “spontaneous HIT” Case Age M/F Platelet count nadir (× 10^9^/L) Sequelae Event(s) in preceding two weeks * UFH or LMWH were only given for proven or suspected thrombosis after “spontaneous HIT” disorder was established; DIC = disseminated intravascular coagulation 1 69 M 17 (no heparin given) Limb artery thromboses (amputations); pulmonary embolism; DIC; fatal myocardial infarction Ampicillin (sore tooth); corticosteroid injection into wrist 2 40 F 175 (pre-UFH*); 59 (post-UFH*) Stroke; limb artery thrombosis (amputation) Incision & draining procedures (recurrent groin cyst) 3 69 F 33 (pre-UFH*); 11 (post-UFH*) Bilateral adrenal infarction; digital infarcts; deep-vein thrombosis; DIC Knee replacement surgery 4 24 F 301 (pre-LMWH*); 62 (post-LMWH*) Acute systemic reaction after LMWH Pneumonia Table 2. Serologic features: 4 patients with “spontaneous HIT” Case Maximum serotonin release (0.1-0.3 U/mL UFH) (N<10%) Serotonin release (Fc receptor-blocking monoclonal antibody) Serotonin release (100 U/mL UFH) Anti-PF4/H ELISA (IgG) (N<0.450 OD U)* Anti-PF4/polyanion ELISA, GTI (N<0.400 OD U)* * >80% inhibition in presence of 100 U/mL UFH was seen with all 4 blood samples and in both ELISAs (not shown) 1 99% 1% 0% 2.028 2.722 2 95% 0% 0% 2.909 2.284 3 100% 0% 0% 1.888 2.950 4 80% 0% 0% 1.866 2.622

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