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PubMed2004

Role of anti-PF4/heparin antibodies in recurrent thrombotic events after acute coronary syndromes.

We postulated that patients with recent acute coronary syndromes and antibodies to the platelet factor 4/heparin complex would have an increased risk of myocardial infarction (MI), even in the absence of thrombocytopenia. We analyzed sera from patients enrolled in the placebo/unfractionated heparin arm of the GUSTO IV-ACS trial who had a high likelihood of prior heparin exposure. We selected 109 patients without thrombocytopenia with the 30-day primary endpoint (death, MI, or revascularization) and 109 age-, gender-, and race-matched controls who did not achieve the primary endpoint. Twenty-three of 218 patients (10.6%) had anti-PF4/heparin antibodies. Patients with anti-PF4/heparin were more likely to have death or MI (30.4% vs. 11.3%, p = 0.011) or MI (21.7% vs. 6.2%, p = 0.008) than patients who were negative for the antibody. Antibody-positive patients had higher levels of sVCAM-1 (892 +/- 263 microg/L vs. 780 +/- 228 microg/L; p = 0.04) and sICAM-1 (246 +/- 50 microg/L vs. 222 +/- 71 microg/L; p = 0.02) than antibody-negative patients. In a multiple logistic regression model that included inflammatory markers and clinical risk factors, antibodies to PF4/heparin were a strong predictor of 30-day MI (odds ratio, 9.0; 95% confidence intervals, 2.1 to 38.6; p < 0.01), with IL-6 being the only other predictor (odds ratio, 1.1; 95% confidence intervals, 1.0 to 1.2; p = 0.03). Antibodies to the platelet factor 4/heparin complex are a novel, independent predictor of MI at 30 days in patients presenting with acute coronary ischemic syndromes. Antibodies to PF4/heparin are a stronger predictor of MI than clinical characteristics or inflammation markers.

Abciximab↗

PubMed2004

A critical evaluation of assays for detecting antibodies to the heparin-PF4 complex.

Heparin-induced thrombocytopenia (HIT) is a potentially catastrophic complication of heparin therapy. The syndrome is the result of the production of an antibody to the complex that forms between heparin and platelet factor 4 (H-PF4) released from activated platelets. IgG antibodies bind to platelet Fc receptors and cause platelet activation, resulting in thrombocytopenia and greatly increased risk of thrombosis. Tests for the H-PF4 antibody can be classified into functional assays (which rely on the demonstration of platelet activation) and immunoassays (which detect the presence of an antibody without regard for its functional ability). The functional assays have a greater specificity for clinical HIT, but require normal donor platelets and are relatively un-standardized. The immunoassays have the advantage of better standardization and do not require normal platelets, but may give positive results in the absence of clinical HIT. The choice of test is usually dictated by what is possible for a given laboratory in terms of instrumentation, expertise, and interest. For most institutions this will be a commercially available enzyme-linked immunosorbent assay. Although HIT is a true clinicopathological syndrome, there are several reasons why its diagnosis still rests primarily on clinical grounds. First, laboratory tests may not be available locally. Second, they may not be available in a sufficiently timely manner. Finally, available tests are not completely sensitive or specific for the condition. There is, therefore, a continuing need to develop more rapid testing strategies with greater specificity for clinical HIT.

Blood Chemical Analysis↗

PubMed1997

Absence of cross-reactivity of SR90107A/ORG31540 pentasaccharide with antibodies to heparin-PF4 complexes developed in heparin-induced thrombocytopenia.

New carbohydrate-based anticoagulants devoid of the side effects of unfractionated heparin are currently under development and show a major potential for patients with heparin-induced thrombocytopenia (HIT) who still require efficient antithrombotic therapy. As HIT is usually associated with antibodies to heparin-platelet factor 4 (H-PF4) complexes, cross-reactivity of the heparin pentasaccharide SR90107A/ORG31540 was tested in the presence of PF4 with the plasma from 49 patients with HIT. No cross-reactivity was observed whatever the pentasaccharide concentrations. Although more extensive studies are required for excluding its total absence of immunogenicity and pathogenicity, this pentasaccharide is a candidate for use in emergency situations in patients with HIT.

Autoantibodies↗

PubMed1980

Effect of prenatal drug administration on maternal and neonatal platelet aggregation and PF4 release.

Release of platelet antiheparin activity (platelet factor 4, PF4) induced by collagen and l-epinephrine, is normal in newborn infants without antenatal drug exposure. In contrast, PF4 release in platelets of infants of mothers with membrane-stabilizing drug ingestion is decreased to a greater extent than in their respective mothers. Platelet aggregation gives a qualitative indication of response. Platelets of mothers with antenatal drug exposure and those of their infants showed only a one-wave response to adenosine diphosphate, while platelets of these same mothers still showed a two-wave aggregation response to l-epinephrine. In contrast, platelets of all neonates lacked epinephrine-induced aggregation response, even when washed and resuspended in adult plasma. Our studies show that prenatal drugs have an effect on the platelet release mechanism in both mothers and their exposed infants; but the effect on the epinephrine-induced platelet response is less in mothers. Newborn infants have different aggregation and platelet release response to epinephrine which suggests that platelet aggregation and the release reaction can occur independently of each other.

Adenosine Diphosphate↗

PubMed2006

Pf4-Cre transgenic mice allow the generation of lineage-restricted gene knockouts for studying megakaryocyte and platelet function in vivo.

To generate transgenic mice that express Cre-recombinase exclusively in the megakaryocytic lineage, we modified a mouse bacterial artificial chromosome (BAC) clone by homologous recombination and replaced the first exon of the platelet factor 4 (Pf4), also called CXCL4, with a codon-improved Cre cDNA. Several strains expressing the transgene were obtained and one strain, Q3, was studied in detail. Crossing Q3 mice with the ROSA26-lacZ reporter strain showed that Cre-recombinase activity was confined to megakaryocytes. These results were further verified by crossing the Q3 mice with a strain containing loxP-flanked integrin beta1. Excision of this conditional allele in megakaryocytes was complete at the DNA level, and platelets were virtually devoid of the integrin beta1 protein. The Pf4-Cre transgenic strain will be a valuable tool to study megakaryopoiesis, platelet formation, and platelet function.

Animals↗

PubMed1985

beta-thromboglobulin (beta-TG) and platelet factor 4 (PF4) in obstetrical cases.

The plasma levels of beta-Thromboglobulin (beta-TG) and Platelet Factor 4 (PF4) were measured in patients during the normal obstetrical period and in pre-eclampsia. A significant increase was observed in the two proteins with respect to the non-pregnant control group but no difference was seen between pregnancy and puerperium in either the normal or pre-eclamptic cases. The one significant variation in the concentration of the two proteins was a sharp rise during parturition. There was no correlation between beta-TG, PF4 and either the platelet count or creatinine but urea and uric acid did show a slight correlation with the two platelet proteins.

Adult↗

PubMed1984

Clearance and in vivo release by heparin of human platelet factor 4 (PF4) in the rabbit.

13 male New Zealand rabbits were injected with two different doses (25 micrograms/Kg and 100 micrograms/Kg) of human platelet factor 4 antigen (PF4). The disappearance of the protein was extremely fast with an half-life for the fast component of 1.07 +/- 0.16 and 1.76 +/- 0.11 min respectively. The half-life for the slow component, detectable only with the highest dosage, was 18.8 min. The administration of 2500 I.U. of heparin 30 min after PF4 administration induced a partial release of the injected protein and its clearance from plasma was slow, with half-life of 23.3 +/- 5.9 min and 30.9 +/- 2.19 min respectively.

Animals↗

PubMed2004

Incidence of heparin-PF4 complex antibody formation and heparin-induced thrombocytopenia in acute coronary syndrome.

A multicenter prospective study on the rate of seroconversion of antibodies to heparin-PF4 complexes (heparin-induced thrombocytopenia [HIT] antibodies) during and after heparin treatment for 4 weeks was carried out in Japanese patients with acute coronary syndrome (ACS). A total of 254 ACS patients treated with heparin were enrolled consecutively from 12 facilities of cardiology. Two patients with preexisting HIT antibodies were excluded from the analysis. The total seroconversion rate for four weeks during and after heparin treatment was 8.7% (n=22, 95% confidence interval [CI]: 5.9-13.1), including values of 3.2% (n=8) at the end of heparin infusion and 5.5% (n=14) at 4 weeks. Among 22 seroconverted patients, four developed HIT and two of the four had the complication of thrombosis. The incidence of HIT was 1.6% (n=4, 95% CI: 0.04-3.1). The risk for thromboembolic development was higher in the seroconverted patients (odds ratio, 17.4, 95% CI: 5.2-58.4, p<0.0001) than nonconverted patients. An analysis of factors affecting the seroconversion rate was carried out. The seroconversion rate for ACS patients who underwent percutaneous coronary intervention (PCI; n=163) was 12.3%, significantly higher than the 2.3% in patients who did not undergo PCI (n=89), leading to an odds ratio of 6.1 (95% CI: 1.4-26.7, p=0.009). A significant odds ratio was obtained for each factor affecting the seroconversion: 3.5 (95% CI: 1.3-9.9, p=0.014) for more than 5 days of heparin infusion, 3.0 (95% CI: 1.2-7.6, p=0.035) for a thrombotic history and 2.7 (95% CI: 1.1-6.8, p=0.039) for hyperlipidemia. No other factor, including age or diabetes mellitus, contributed to the seroconversion. Therefore, PCI, duration of heparin treatment and thrombotic history facilitated the seroconversion in ACS patients. PCI patients treated for more than 5 days with heparin showed a maximal seroconversion rate of 18.3% (95% CI: 13.8-22.2). This high rate in PCI patients did not interact with age, type of underlying disease of unstable angina or myocardial infarction or thrombotic history. In conclusion, ACS patients demonstrating seroconversion are at risk of thromboembolic development due to the likelihood of immunomediated endothelial dysfunction. The increase in the rate of seroconversion in ACS patients would be affected by factors such as PCI with mechanical stress, longer duration of heparin treatment, thrombotic history and presence of hyperlipidemia. If PCI is undertaken with heparin anticoagulation for more than 5 days, seroconversion would easily occur, and the seroconverted patients could subsequently suffer from HIT.

Acute Disease↗

PubMed2006

Incidence and clinical significance of anti-PF4/heparin antibodies of the IgG, IgM, and IgA class in 755 consecutive patient samples referred for diagnostic testing for heparin-induced thrombocytopenia.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is usually caused by anti-platelet factor 4 (PF4)/heparin antibodies, leading to intravascular platelet activation. These antibodies can be detected by PF4/polyanion antigen assays or platelet activation assays. While antigen assays are very sensitive and recognize immunoglobulin (Ig)G, IgA, and IgM antibodies, the role of IgM and IgA HIT-antibodies is debated. Platelet activation assays recognize IgG and are more specific for clinical HIT. METHODS: We analyzed sera from 755 consecutive patients referred for diagnostic testing for HIT using a PF4/heparin enzyme-linked immunosorbent assay (ELISA) for IgG, IgA, and IgM and by the heparin-induced platelet activation (HIPA) test. Clinical information was provided by the treating physicians. RESULTS: A total of 108 of 755 (14.3%) patients tested positive, 105 (13.9%) in the PF4/heparin IgG/A/M ELISA [28 (26.7%) only for IgM/A]; 53 (7.0%) sera were positive in the HIPA, of those 50 tested also positive in the ELISA. In 77 patients sufficient clinical information was provided. Available clinical information for 17 of the 28 patients who had only IgM and/or IgA detected showed plausible alternative (non-HIT) explanations in four of seven who had thromboembolic complications and in nine of 10 who had isolated HIT. CONCLUSION: Detection of IgG, IgM and IgA class antibodies by PF4/heparin ELISA yields a positive test result about twice as often as does a platelet activation assay, with only a minority of the additional patients detected likely having HIT. Thus, there is a potential for considerable over-diagnosis of HIT by laboratories that utilize only an ELISA for diagnostic testing.

Antibodies↗

PubMed2003

[Inhibition of tumor angiogenesis in nude mice by adenovirus-mediated PF4 p17-70 cDNA transfection].

OBJECTIVE: To investigate the in vivo effect of modified platelet factor 4 (PF4)-p17-70 cDNA on tumor angiogenesis in nude mice. METHODS: The p17-70 cDNA was cloned into the AdEasy system to transfect packing cell line 293 and produce viral particles encoding p17-70cDNA (Ad p17-70). The integration of p17-70 cDNA was confirmed by RT-PCR and the P17-40 peptide Western blot. The biological activity of purified recombinant adenovirus was determined by umbilical veinal endothelial cell proliferation assay in vitro and in vivo tumor angiogenesis suppression of nude mice bearing human head and neck carcinoma. RESULTS: p17-70 significantly inhibited in vitro proliferation of endothelial cells being 58% lower than that of empty vector and reduced tumor volume in vivo. The tumor mass was (0.086 +/- 0.054) g, (0.171 +/- 0.076) g and (0.195 +/- 0.067) g, the tumor volume was (16.7 +/- 5.2) mm(3), (36.5 +/- 23.7) mm(3) and (41.5 +/- 12.2) mm(3) in p17-70 cDNA transfected group, empty vector group and PBS group, respectively. Immunohistochemical staining demonstrated a decreased number of blood vessels in the tumors. CONCLUSION: P17-70 peptide mediated by adenoviral vector could inhibit the endothelial proliferation in vitro and the tumor growth in vivo.

Adenoviridae↗

PubMed1980

Platelet proteins (beta-TG and PF4) in atherosclerosis and related diseases.

The mean plasma concentrations of beta-TG and PF4 were significantly elevated in patients with diabetes mellitus, peripheral vascular disease and coronary artery disease reflecting enhanced in vivo platelet activity in some of these patients. No correlations could be observed between state of metabolic control and concentrations of platelet specific proteins in diabetic subjects. High mean beta-TG levels were noticed in diabetic patients with increasing severity of retinopathy. Raised beta-TG values decreased significantly after two weeks of treatment with dipyridamole in 10 type-I diabetics. In patients with peripheral vascular disease the WU-test, but not the ADP- or collagen induced platelet aggregation was significantly different between patients and controls, but there were no correlations between the mentioned platelet function tests.

Arteriosclerosis↗

PubMedDate not supplied

Platelet factor 4 (PF4) in septicaemia.

The plasma concentrations of platelet factor 4 were measured in ten patients with septicaemia. In the acute phase the platelet factor 4 values were elevated (27.1 +/- 20.1 ng/ml; mean +/- SD; normal values 4.7 +/- 1.2 ng/ml), and declined significantly after treatment with antibiotics and surgical therapy, respectively (10.6 +/- 7.3 ng/ml; p less than 0.005). The determination of prothrombin time, fibrinopeptide A, AT III and platelet counts demonstrated a coagulation disorder in the acute phase of septicaemia in all patients; a thrombocytopenia (less than 100,000/mm3) was observed in three cases. We suggest that the measurement of platelet factor 4 concentration could be useful as an in vivo indicator and as a follow-up parameter of increased platelet activation.

Adult↗

PubMed1972