High Prevalence of Antibodies to the Heparin-Platelet Factor 4 Complex in Hemodialysis Patients.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4119-4119
Author(s):  
Marc Carrier ◽  
Greg Knoll ◽  
Michael Kovacs ◽  
Marc A. Rodger
Keyword(s):  
Unfractionated Heparin ◽  
Vascular Access ◽  
Arterial Thrombosis ◽  
Heparin Therapy ◽  
Small Sample ◽  
Platelet Factor 4 ◽  
Platelet Factor ◽  
High Prevalence ◽  
Thrombotic Complications ◽  
Small Sample Sizes

Abstract Heparin-induced thrombocytopenia is a serious complication of systemic heparin therapy. Patients with this disorder develop antibodies to the heparin-platelet factor 4 (H-PF4) complex. Patients with H-PF4 antibodies are at higher risk of venous and arterial thrombosis independently of the platelet count. Hemodialysis (HD) patients are repeatedly exposed to heparin to prevent thrombosis of the extra-corporeal circuit. However, thrombosis remains a frequent complication of vascular access, which accounts for up to 20% of all hospitalization in HD patients. Studies to date on H-PF4 antibody and vascular access thrombosis in HD patients have produced conflicting data but have been limited by small sample sizes. We sough to determine the prevalence of H-PF4 antibodies in a large cohort of HD patients and the correlation with vascular access thrombosis. Pre-dialysis blood samples were drawn on 419 HD patients; 107 cases with access thrombosis and 312 controls that never had access thrombosis. H-PF4 antibodies were measured twice using an ELISA (GTI PF4 Enhanced, GTI Diagnostics). The average of the two measurements was used in this analysis. All patients received unfractionated heparin while on dialysis. The mean age was 64 16 yrs with 62% male patients. Antibodies to H-PF4 were positive in 54 (12.9%) patients. H-PF4 antibodies were present in 10 (10.5%) of patients with confirmed access thrombosis and in 44 (15.1%) of controls. Hemodialysis with repeated exposure to systemic unfractionated heparin is associated with a high prevalence of H-PF4 antibodies. Although H-PF4 antibodies contribute to hypercoagulability leading to thrombotic complications, our results are not supporting a correlation between H-PF4 antibodies and vascular access thrombosis. Given the potential for venous and arterial thrombosis and the implications of our findings further investigations are needed in this population.

Thrombotic Biomarker Profiling Of Plasma Samples From Patients Undergoing Bypass Surgery Using Protein Chip Array

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3579-3579
Author(s):  
Jeanine M. Walenga ◽  
Takefumi Matsuo ◽  
Keiko Wanaka ◽  
Josephine Cunanan ◽  
Debra Hoppensteadt ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Bypass Surgery ◽  
Protein Chip ◽  
Platelet Factor 4 ◽  
Plasma Samples ◽  
Elisa Method ◽  
Platelet Factor ◽  
High Prevalence ◽  
Inflammatory Processes ◽  
Thrombotic Complications

Abstract Introduction Cardiovascular bypass surgical procedures, such as the coronary bypass procedure (CAP), patients are exposed to large doses of heparin and protamine sulfate. There is a high prevalence of anti-heparin platelet factor-4 antibodies in these patients. Although a fraction of these patients develop HIT syndrome, the role of circulating anti-heparin platelet factor-4 antibodies is not clear. Some of these patients may be at a high risk for post-surgical thrombotic complications. Such thrombogenic mediators as the microparticle and tissue factor, may also be up regulated in these patients. Inflammatory processes may also contribute to the overall post-thrombotic complications. The relevance of thrombotic mediators and inflammatory processes remains to be further explored in these patients. Recently protein chip array approach using SELDI/TOF mass spectrometry methods have been employed to identify the unique biomarker in various diseases. The purpose of this study was to determine the protein chip array profile and quantification of various mediators of thrombotic activation in patients who have undergone bypass surgery. Materials & Methods Plasma samples from 79 patients were collected immediately prior to and two weeks after the CAP. Protein chip array profiling was carried out on a SELDI/TOF mass spectrometric method (PCS4000, BioRad, Richmond, CA) employing a gold chip array in the molecular weight range of 3000-150,000. The intensity of unique peaks was also calculated in terms of relative intensities. Microparticles were measured using a functional method (Hyphen Biomedical, France) and tissue factor antigen levels were measured using an ELISA method. The anti-heparin platelet factor-4 antibodies were also measured using a commercially available ELISA method (Genprobe, Wisconsin). Results Of the 79 patients, 20 showed a unique biomarker peak around 11-12kDa in the pre-op samples, which was absent from normal controls. 77 of the patients showed this unique biomarker peak at one week, whereas only 48 patients exhibited at two weeks after surgery. The relative intensity of the 11.6kDa biomarker was much higher at one week (6-fold) and was decreased at two weeks (3-fold). In addition to this unique peak, other biomarker peaks were noted at 15.1 and 15.8kDa. However, these peaks were not changed at different time points. In comparison to the normal, the microparticle levels were higher at the baseline sample (10.1±3.2nM) and increased to 19.3±6.1 and 24.5±8.1nM. Similarly, the tissue factor levels were increased at three weeks’ time period. The anti-heparin platelet factor-4 titer rose 28% from the baseline at week one and 33% at week two. Conclusions The results on the biomarker profile are consistent to the earlier finding, where the presence of a unique biomarker in the range of 11-12kDa have been reported in patients with high prevalence of anti-heparin platelet factor-4 antibody. The increased level of microparticles and tissue factor at post-surgical periods of one week and two weeks suggest endogenous activation of thrombogenic mechanisms, which appears proportional to the up regulation of the anti-heparin platelet factor-4 antibodies. Thus, this data indicates that the non-functional anti-heparin platelet factor-4 antibodies may result in the activation of cellular processes leading to thrombogenesis. Further characterization of the unique biomarkers identified in these patients may be useful in understanding of the pathogenesis of inflammatory processes and their relevance to thrombogenesis in CABG patients. Clinical Implications These results indicate that the nonfunctional anti-heparin platelet factor 4 antibodies are capable of mediating inflammatory and thrombotic responses without symptomatic thrombocytopenia. Therefore, the measurement of these antibodies along with inflammatory and thrombogenic mediators may be helpful in the diagnostic and prognostic management of these patients. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Assessment of HIT Antibody Complex in Hip Fracture Patients Receiving Enoxaparin or Unfractionated Heparin

2011 ◽  
Vol 17 (6) ◽  
pp. 567-571
Author(s):  
Justin W. Griffin ◽  
William J. Hopkinson ◽  
Michael R. Lassen ◽  
Indermohan Thethi ◽  
Evangelos Litinas ◽  
...  
Keyword(s):  
Hip Fracture ◽  
Elderly Patients ◽  
Unfractionated Heparin ◽  
Standard Of Care ◽  
The Elderly ◽  
Enzyme Linked Immunosorbent Assay ◽  
Platelet Factor ◽  
Surgical Fixation ◽  
Thrombotic Complications ◽  
Antibody Complex

Thromboembolic disease is a common complication of hip fracture in the elderly. Anticoagulants represent a standard of care in preventing postoperative thrombotic complications following surgical fixation. We asked whether levels of antibody to heparin–platelet factor 4 (PF4) complex were differentially present in unfractionated heparin (UFH) versus Enoxaparin, following hip fracture and whether one particular subtype of antibodies was more prevalent. Plasma samples from elderly patients sustaining a hip fracture treated with either enoxaparin or UFH were collected pre- and postoperatively and analyzed using enzyme-linked immunosorbent assay (ELISA) sandwich method for the prevalence of antiheparin-PF4 antibodies and later subtyped. The prevalence of antiheparin-PF4 antibodies was higher in the UFH group especially on postoperative day 7. Patients treated with UFH showed a greater prevalence of antiheparin-PF4 antibodies and a greater prevalence of immunoglobulin G (IgG) subtype. Heparin and enoxaparin are capable of generating heparin-induced thrombocytopenia (HIT) antibodies in elderly patients undergoing orthopedic surgery but perhaps not to the same extent. When comparing low-molecular-weight heparin (LMWH) with UFH, the incidence of new antiheparin-PF4 antibody production is higher in patients treated with UFH.

scholarly journals Sleep Spindle Characteristics in Children with Neurodevelopmental Disorders and Their Relation to Cognition

2016 ◽  
Vol 2016 ◽  
pp. 1-27 ◽  
Author(s):  
Reut Gruber ◽  
Merrill S. Wise
Keyword(s):  
Cognitive Function ◽  
Neurodevelopmental Disorders ◽  
Sleep Problems ◽  
Small Sample ◽  
Future Research ◽  
Sleep Spindles ◽  
Sleep Spindle ◽  
High Prevalence ◽  
Future Research Directions ◽  
Small Sample Sizes

Empirical evidence indicates that sleep spindles facilitate neuroplasticity and “off-line” processing during sleep, which supports learning, memory consolidation, and intellectual performance. Children with neurodevelopmental disorders (NDDs) exhibit characteristics that may increase both the risk for and vulnerability to abnormal spindle generation. Despite the high prevalence of sleep problems and cognitive deficits in children with NDD, only a few studies have examined the putative association between spindle characteristics and cognitive function. This paper reviews the literature regarding sleep spindle characteristics in children with NDD and their relation to cognition in light of what is known in typically developing children and based on the available evidence regarding children with NDD. We integrate available data, identify gaps in understanding, and recommend future research directions. Collectively, studies are limited by small sample sizes, heterogeneous populations with multiple comorbidities, and nonstandardized methods for collecting and analyzing findings. These limitations notwithstanding, the evidence suggests that future studies should examine associations between sleep spindle characteristics and cognitive function in children with and without NDD, and preliminary findings raise the intriguing question of whether enhancement or manipulation of sleep spindles could improve sleep-dependent memory and other aspects of cognitive function in this population.

Effect of fondaparinux on platelet activation in the presence of heparin-dependent antibodies: a blinded comparative multicenter study with unfractionated heparin

Blood ◽  
2005 ◽  
Vol 105 (1) ◽  
pp. 139-144 ◽  
Author(s):  
Pierre Savi ◽  
Beng H. Chong ◽  
Andreas Greinacher ◽  
Yves Gruel ◽  
John G. Kelton ◽  
...  
Keyword(s):  
Unfractionated Heparin ◽  
Factor Xa ◽  
Annexin V ◽  
Heparin Therapy ◽  
Cross Reactivity ◽  
Serotonin Release ◽  
Aggregation Assay ◽  
Platelet Factor ◽  
Platelet Aggregation Assay ◽  
History Of

Abstract Heparin-induced thrombocytopenia (HIT) is a complication of heparin therapy caused by antibodies against a complex of platelet factor 4 and heparin. Fondaparinux (Arixtra) is a new synthetic selective factor Xa inhibitor. We performed a serologic study to determine the cross-reactivity of HIT sera with fondaparinux. Using a prospective, blinded study design, 39 clinically and serologically confirmed sera from patients with HIT and 15 control sera were sent to 3 different laboratories, each of which specialized in a particular HIT assay. These include the serotonin release assay, heparin-induced platelet agglutination assay, and platelet aggregation assay. Two of 82 assays (2.4%) performed in the presence of control sera were positive, both with unfractionated heparin. In the presence of HIT sera, 75 of 94 (79.8%) evaluable assays were positive with unfractionated heparin; fondaparinux was significantly (P < .001) less reactive than unfractionated heparin, only 3 of 91 evaluable assays (3.3%) being positive. Using flow cytometry, unlike unfractionated heparin, fondaparinux did not induce the binding of PAC1 and anti-CD62 monoclonal antibodies or of annexin V to platelets with HIT sera. Together, these results suggest that fondaparinux is nonreactive to HIT sera and raise the possibility that the drug may be used for prophylaxis and treatment of thrombosis in patients with a history of HIT.

scholarly journals Heparin Re-Exposure in Patients with Heparin-Induced Thrombocytopenia (HIT)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4265-4265 ◽  
Author(s):  
Prajwal Dhakal ◽  
Vijaya R. Bhatt
Keyword(s):  
Conflicts Of Interest ◽  
Small Sample Size ◽  
Small Sample ◽  
Platelet Factor 4 ◽  
Systemic Review ◽  
Enzyme Linked Immunosorbent Assay ◽  
Platelet Factor ◽  
Platelet Recovery ◽  
Risk Of Recurrence ◽  
History Of

Abstract Introduction Patients with a history of HIT, who require cardiopulmonary bypass (CPB), have limited anticoagulation options. Unfractionated heparin (UFH) is preferred by surgeons during CPB because of their extensive experience, short half-life of the drug, and the availability of protamine sulfate to reverse its effect. However, heparin re-challenge may be associated with a risk of recurrence of HIT. A number of instances of successful heparin re-exposure during CPB have been reported in HIT patients. However, small sample size of these reports and a lack of systemic review have prevented better understanding of the potential complications. The objective of this study was to determine the safety of heparin re-exposure in HIT patients and various strategies utilized to reduce the recurrence of HIT. Methods Using several search terms, all cases of heparin re-exposure in HIT patients published and indexed in English language in Pubmed by June 2014 were reviewed. The bibliography of each relevant article was searched for additional related reports. The diagnosis of HIT was based on the clinical probability or 4T scoring system and laboratory tests. The exposure to either UFH or low molecular weight heparin (LMWH) in patients with a history of HIT was considered a re-exposure. In two cases, heparin was used multiple times for repeated cardiovascular surgeries after an initial diagnosis of HIT. Each re-exposure was determined as a different instance of re-exposure during analysis. Results A total of 136 patients with a history of HIT had 141 instances of heparin re-exposure. Median age was 56 years (6 weeks -87 yrs) and 67% were males. Regarding the original HIT diagnosis, UFH (98%) and nadroparin (2%) were the causative agents. Thrombotic complications occurred in 23%. The pretest probability score was high in 79% and moderate in 21%. Platelet aggregation studies (66%), enzyme linked immunosorbent assay (ELISA)/enzyme immunoassay (EIA) (20%), serotonin release assay (SRA) (2%), and both SRA and EIA (12%) were performed for diagnosis. Cardiac (76%) and vascular surgeries (11%) were the most common indications for heparin re-exposure. Although 67% were re-exposed to heparin after 3 months of HIT diagnosis, 11%, 8% and 15% were re-exposed within 1 week, between 1 week to 1 month, and 1 month to 3 months of HIT diagnosis respectively. Anti-platelet factor 4/heparin antibodies were positive in 63% before re-exposure. UFH (93%) or LMWH (7%) were the utilized agents during re-exposure. Sixteen patients (11%) underwent plasmapheresis to lower the level of anti-platelet factor 4/heparin antibodies before the re-exposure. Non-heparin anticoagulants such as bivalirudin, fondaparinux, danaparoid, r-hirudin, argatroban, lepirudin, and warfarin were used singly or in combination after the exposure in 63% of patients. With heparin re-exposure, 4.2% had complications, which included recurrence of HIT (2.1%), and bleeding (2.1%). Among the patients with HIT recurrence (n=3), one patient was re-exposed to UFH within a week of HIT diagnosis and shortly after platelet recovery with LMWH (Intensive Care Med. 1991;17(3):185-6.). The other two patients were initially diagnosed with HIT more than 5 years back and tested negative for anti-platelet factor 4/heparin antibody prior to heparin re-exposure. Conclusion A review of the published reports indicates that intra-operative heparin re-exposure in patients with HIT has a small risk of developing thrombocytopenia or recurrence of HIT. The use of pre-exposure plasmapheresis in patients with positive anti-platelet factor 4/heparin antibody and post-exposure non-heparin anticoagulants may have reduced the risk of recurrence of HIT. Given several limitations of such retrospective review, prospective studies are needed to validate these results. Disclosures No relevant conflicts of interest to declare.

scholarly journals Anti-Platelet Factor 4 Antibodies Causing VITT do not Cross-React with SARS-CoV-2 Spike Protein

Blood ◽  
2021 ◽  
Author(s):  
Andreas Greinacher ◽  
Kathleen Selleng ◽  
Julia Mayerle ◽  
Raghavendra Palankar ◽  
Jan Wesche ◽  
...  
Keyword(s):  
Adverse Effect ◽  
Platelet Activation ◽  
3D Modelling ◽  
Platelet Factor 4 ◽  
Spike Protein ◽  
Severe Adverse Effect ◽  
In Silico Prediction ◽  
Platelet Factor ◽  
Prediction Tools ◽  
Thrombotic Complications

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a severe adverse effect of ChAdOx1 nCoV-19 COVID-19 vaccine (Vaxzevria) and COVID-19 vaccine Janssen (Ad26.COV2.S), and associated with unusual thrombosis. VITT is caused by anti-platelet factor 4 (PF4) antibodies activating platelets through their FcgRIIa receptors. Antibodies activating platelets through FcgRIIa receptors have also been identified in COVID-19 patients. These findings raise concern that vaccination-induced antibodies against anti-SARS-CoV-2 spike protein cause thrombosis by cross-reacting with PF4. Immunogenic epitopes of PF4 and SARS-CoV-2 spike protein were compared using in-silico prediction tools and 3D-modelling. The SARS-CoV-2 spike protein and PF4 share at least one similar epitope. Reactivity of purified anti-PF4 antibodies from patients with VITT was tested against recombinant SARS-CoV-2 spike protein. However, none of the affinity-purified anti-PF4 antibodies from 14 VITT patients cross-reacted with SARS-CoV-2 spike protein. Sera from 222 PCR-confirmed COVID-19 patients from five European centers were tested by PF4/heparin ELISA and PF4-dependent platelet activation assays. We found anti-PF4 antibodies in 19 of 222 (8.6%) COVID-19 patient sera. However, only four showed weak to moderate platelet activation in the presence of PF4, and none of these patients developed thrombotic complications. Among 10 of 222 (4.5%) COVID-19 patients with thrombosis, none showed PF4-dependent platelet-activating antibodies. In conclusion, antibodies against PF4 induced by vaccination do not cross-react with the SARS-CoV-2 spike protein, indicating that the intended vaccine-induced immune response against SARS-CoV-2 spike protein is not the trigger of VITT. PF4-reactive antibodies found in COVID-19 patients of the present study were not associated with thrombotic complications.

scholarly journals Heparin induced thrombocytopenia type ii and myocardial infarction: Two case reports

2004 ◽  
Vol 132 (1-2) ◽  
pp. 33-37 ◽  
Author(s):  
Nebojsa Antonijevic ◽  
Milica Stanojevic ◽  
Jovan Perunicic ◽  
Milan Djokic ◽  
Danijela Mikovic ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heparin Therapy ◽  
Platelet Factor 4 ◽  
Cardiac Insufficiency ◽  
Inferior Wall ◽  
Type Ii ◽  
Platelet Factor ◽  
Heparin Induced Thrombocytopenia ◽  
Skin Changes ◽  
Therapeutic Measures

Heparin-induced thrombocytopenia (HIT) type II is an acquired thrombophylic state and life-threatening immune complication of a heparin treatment mainly clinically manifested by marked thrombocytopenia, frequently by arterial and venous thrombosis, and sometimes by skin changes. Functional assay as heparin aggregation test and 14C-serotonin release assays are used in diagnostics as well as antigen assays of which detection tests for heparin-platelet factor 4 antibodies are most frequently used. Considering the fact that there is no single reliable assays for HIT II detection available, sometimes it is necessary to combine both of the above-mentioned types of assays. We present the case of a 57-year-old patient with an acute anterior myocardial infarction with cardiac insufficiency of III and IV degree according to Killip, recurrent ventricular fibrillation and diabetes mellitus type II developing thrombocytopenia to 37x10 9/l accompanied with typical skin changes. The diagnosis was confirmed by the heparin aggregation test. The second patient aged 70 undergoing the treatment for anteroseptal myocardial infarction and reinfarction of the inferior wall complicated by a cardiogenic shock and acute right bundle branch block developed thrombocytopenia 59x10 9/I on the third day of the heparin therapy, with the remark that he had received a heparin therapy during the first infarction as well. Antibodies against heparin-platelet factor 4 were detected by particle gel ID-HPF4 immunoassay. In both patients, the disease had a lethal outcome despite all then available therapeutic measures applied. Further on we discuss advantages of certain types of tests, a therapy doctrine, need for urgent therapeutic measures, inclusive of the administration of anitithrombins, avoidance of harmful procedures like low-molecular-weight heparins administration and prophylactic platelet transfusion as well as preventive measures.

scholarly journals Heparin Induced Thrombocytopenia in Patients with COVID-19

2021 ◽  
Author(s):  
Surbhi Warrior ◽  
Elizabeth Behrens ◽  
Sefer Gezer ◽  
Parameswaran Venugopal ◽  
Shivi Jain
Keyword(s):  
Mortality Rate ◽  
General Population ◽  
Small Sample Size ◽  
Small Sample ◽  
Platelet Factor 4 ◽  
Thromboembolic Events ◽  
Platelet Factor ◽  
Heparin Induced Thrombocytopenia ◽  
Confirmatory Testing ◽  
Increased Risk

Abstract Background Acute respiratory and renal failure as well as systemic coagulopathy are critical aspects of the morbidity and mortality in patients with COVID-19. Heparin Induced Thrombocytopenia (HIT) occurs when IgG antibodies form against platelet factor 4-Heparin complex, resulting in platelet activation and removal, leading to a prothrombotic state. Studies have shown that only 6% who are investigated serologically for HIT actually have the diagnosis. Methods A retrospective analysis was performed on all COVID-19 positive patients hospitalized between March and June 2020. Patients with suspicion for HIT were tested for HIT antibodies with IgG-specific platelet factor 4(PF4)-dependent enzyme immunoassay (EIA). Confirmatory testing with serotonin release assay (SRA) and heparin-induced platelet aggregation were used in cases with intermediate or low optical density (OD) with EIA positivity (EIA+). Due to rarity of disease, a through literature review on HIT in COVID-19 patients was also analyzed. Results Incidence of EIA + in COVID-19 patients was 0.6%, significantly higher than in the general population 0.2% (p < 0.0001). The incidence of thromboembolic events in EIA + patients was 87.5%, significantly higher than the rate of 10.90% in all COVID-19 patients (p < 0.0001). The mortality rate in EIA + patients was 50%, significantly greater than the mortality rate of 12% in all hospitalized COVID-19 patients (p = 0.0011). Serological confirmation of HIT diagnosis was 37.5% which is significantly higher than confirmation of HIT in nonCOVID-19 patients 6% (p < 0.0001). Of 39 HIT antibody positive patients in the literature, 23.07% had positive confirmatory testing (6 SRA, 3 HIPAA) which is significantly higher than 5.6% in the general population (p = 0.00001). The incidence of thrombosis in EIA + COVID-19 patients in the literature was 56.4% which is significantly higher than reported rates of thrombotic events in in all COVID-19 patients in the literature at 4.8%1 (p = 0.00001). Conclusion Our study indicates incidence of HIT is higher in the COVID-19 population. This can be attributed to the cytokine storm and severe sepsis seen in critically ill COVID-19 patients. Our study also suggests that development of HIT can contribute to increased risk for thromboembolic events as well as mortality of COVID-19 patients, however, our study is limited due to small sample size.

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