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PubMed1988

A predictive test for adverse reactions to contrast media. Preliminary results.

In a prospective study, whole blood samples drawn from patients prior to their being injected with contrast media were incubated with zymosan to activate the complement cascade. The samples were tested for various analytes, including C3a, thromboxane B2 (TxB2), beta thromboglobulin and platelet factor 4 (PF4). Of 207 patients receiving contrast media, only eight experienced reactions, which were mild. Levels of the platelet constituents were generally elevated in these patients. Specificity and sensitivity were 89% and 83%, respectively, for the combined TxB2 and PF4 radioimmunoassay data. Using the Wilcoxon-Mann-Whitney rank sum test, both PF4 and TxB2 were collected with RCM reactions at the R less than .05 level. Although preliminary, the results suggest that RCM reactions are predictable by the in vitro test procedures described.

Complement Activation↗

PubMed2002

Insights from mouse models of heparin-induced thrombocytopenia and thrombosis.

Heparin-induced thrombocytopenia/thrombosis (HIT/T) is the most frequent cause of drug-induced antibody-mediated thrombocytopenia, a common cause of life-and limb-threatening platelet activation and thrombosis. Although antibodies to heparin-platelet factor 4 (PF4) complexes are found in essentially all patients with HIT/T, it is unclear how antibody formation is initiated, why only a small subset of these antibodies cause disease, or the mechanism by which they initiate thrombosis. The recent development of a transgenic mouse model of HIT/T showed, for the first time in vivo, that heparin, PF4, antibodies to the heparin-PF4 complex, and Fc gamma RIIA are necessary and sufficient to recapitulate the severe thrombocytopenia and thrombosis seen in patients. This model can be expanded to systematically study individual factors important to HIT/T development in vivo, to determine their contribution to the spectrum of human disease. Several recent papers have examined the role of other contributors, such as monocyte tissue factor, endothelial cell activation, and leukocyte-platelet aggregates in the pathogenesis of the disease. Mouse models will provide a means to test new diagnostic and therapeutic approaches.

Animals↗

PubMed1984

Platelet and other tests followed sequentially for 14 days after operation.

Nineteen patients were studied twice before and sequentially from 1 h to 14 days after operations lasting about 1 h. Eighteen tests were carried out, ideally on all the nine occasions blood collections were planned. Only significant changes are summarized. Immediately after the operation the plasma PF4 and beta TG were raised in parallel suggesting some platelet 'release' had occurred. At this time platelet aggregation to ADP and collagen had decreased by 57% to 64% and the plasma cyclic AMP had doubled. Next day these abnormalities had returned towards normal. By day 2 the fibrinogen and the heparin neutralizing activity were maximal; they returned towards normal by day 14. On day 14, when presumably all platelets present at operation had been removed the new platelets were 53% more numerous and 9.5% smaller; they contained 23% less PF4 and 42% less serotonin and 5-HT uptake was decreased, but the total amount of 5-HT and PF4 in the circulation probably remained constant. In summary these operations transitorily upset platelet function for a few hours and the platelets formed postoperatively were abnormal.

Adult↗

PubMed1983

Platelet concentrates stored at 22 degrees C need oxygen. The significance of plastics in platelet preservation.

Platelet concentrates prepared by platelet apheresis were stored in plastic blood bags with different gas permeability properties. Inadequate oxygen supply gave an insufficient adenosine triphosphate (ATP) regeneration and a compensatory increase in glycolysis and lactic acid production, giving a rapidly falling pH. At pH below 6.0 the glycolysis was inhibited, oxygen consumption ceased, and ATP dropped towards depletion. Adequate oxygen supply kept the lactic acid production low with small pH changes only, and allowed a sufficient ATP regeneration. The release of alpha-granular platelet Factor 4 (PF4) was almost total at pH below 6.0, while at intact metabolic function there was a slow release of PF4. Platelet preservation is enhanced by the use of blood bags with adequate gas exchange properties. In our study one polyvinyl chloride plastic (PVC) bag gave poor results, while another PVC bag and a polyolefin bag showed intact metabolism for 5 days and a moderate release of PF4.

Adenosine Triphosphate↗

PubMed1994

Adsorption of anaphylatoxins and platelet-specific proteins by filtration of platelet concentrates with a polyester leukocyte reduction filter.

Anaphylatoxins generated during storage of platelet concentrates (PCs) may potentially have side effects on platelet transfusion. We evaluated the anaphylatoxin-scavenging abilities of white blood cell reduction filters. Among the commercially available filters for PCs, one made with polyester fiber (PL50) dramatically adsorbed C3a and C4a anaphylatoxins to the respective mean level of 1,721-208 ng/ml and 1,240-141 ng/ml in 3-day-old PCs. C3a and C4a were measured as the native and des Arg form of each complement by radioimmunoassay. C3a and C4a anaphylatoxins in the supernatant plasma fraction from 3-day-old PC again decreased from 1,136 to 114 ng/ml and from 1,086 to 65 ng/ml, respectively. The filter also adsorbed 85% of platelet factor 4 (PF4) and 31% of beta-thromboglobulin (beta-TG), which had been released from platelets into the plasma during storage. The plasma levels of adhesive proteins such as fibronectin, fibrinogen, and von Willebrand factor, and plasma lactate dehydrogenase activity did not decrease after filtration. Another polyester filter (PL5A), on the other hand, significantly increased C3a and C4a levels with filtration. In addition, there was no PF4 adsorption ability during the filtration. The filters for red cells (RC50, BPF4, and R500A) had no anaphylatoxin adsorption capabilities. The observed specific adsorption of anaphylatoxins might be attributed to the electrostatic force between the positively charged anaphylatoxins with high pI and the possibly negatively charged filter membranes. Since PF4 and beta-TG have positively charged moieties in the C-terminal position, the same adsorption mechanism might operate.(ABSTRACT TRUNCATED AT 250 WORDS)

Adsorption↗

PubMed2005

Management of liver transplantation in a patient with a history of heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is an adverse immune-mediated drug reaction in which antibodies are generated usually towards complexes of the soluble platelet protein platelet-factor-4 (PF4) and heparin. The resulting immune complexes activate platelets intravascularly, which increases the generation of thrombin. Therefore, HIT is strongly associated with thrombosis and heparin is thought to be contraindicated. As HIT antibodies decline rapidly in titre, short-term re-exposure to heparin is feasible in special situations. We report an uneventful liver transplantation of a heparinized donor in a patient with a 20-month history of HIT. Before, 2, 5, 12 and 25 days after transplantation, the patient's blood was drawn for analysis of heparin-induced antibodies by a functional assay (HIPA) and by an antigen assay (PF4-heparin/ELISA). Lepirudin was used for postoperative anticoagulation. Apart from hepatic artery bleeding, the clinical course was uncomplicated, neither thrombocytopenia nor thromboembolic complications occurred. Weak heparin-induced platelet activation, caused by pre-existing HIT antibodies was detected before and 12 days after transplantation by the HIPA test; moreover borderline amounts of anti-PF4-heparin antibodies were found. Twenty months after an episode of HIT, a patient may receive an organ from a heparin-treated donor without risk of thrombocytopenia or thromboembolic complications. Avoidance of heparin for postoperative anticoagulation is recommended.

Adult↗

PubMed1992

Investigation of how different filters affect some biochemical properties of stored platelet concentrates.

The aim of the present study was to investigate how four different filters, i.e. Imugard IG500 (Terumo, Japan), Miropore (Miramed, Italy), Pall P1-100 (Pall, USA) and Sepacell P1-10A (Asahi, Japan) affect some biochemical properties of platelet concentrates. The work was conducted using 42 pairs of platelet concentrates. After 2 days of storage, one of the preparations was filtered and the other served as an unfiltered control. Immediately after filtration, determination of the platelet count, desarginated activated complement factor 3 (C3a des arg) and the extracellular and total concentrations of platelet factor 4 (PF4) and lactate dehydrogenase (LDH) were carried out on both these platelet concentrates. After an additional storage period of 3 d, extracellular concentrations of PF4 and LDH were determined on both concentrates. A significant decrease of extracellular PF4 concentration was found immediately after filtration when Pall P1-100 and Imugard IG500 were used. During the 3-d storage after filtration, the concentrates filtered with Imugard IG500 and Pall P1-100 demonstrated significantly higher platelet lysis as compared to the unfiltered controls. It is concluded that the present work demonstrates storage instability after filtration with Imugard IG500 and Pall P1-100. Therefore, platelet concentrates filtered with these filters would not appear to be suitable for storage.

Blood Platelets↗

PubMed1978

Platelet factor 4: an inhibitor of collagenase.

Human platelet factor 4 (PF4) is known to bind to heparin and inhibit its anticoagulant effect. This factor also inhibits the enzyme collagenase derived from cultured human skin and collagenase extracted from human granulocytes. The addition of heparin to the PF4-collagenase assay system has no effect on the observed inhibition of collagenase. Thus PF4 inhibits collagenase, in addition to neutralizing heparin.

Blood Coagulation Factors↗

PubMed1991

Transcriptional regulation of the rat platelet factor 4 gene: interaction between an enhancer/silencer domain and the GATA site.

We used various segments of the 5' upstream region of the rat platelet factor 4 (PF4) gene coupled to the human growth hormone gene and heterologous promoters to identify domains which are critical for tissue-specific expression. Transient expression experiments with rat bone marrow cells and other cell lines revealed a complex interplay between a core promoter domain from -97 to the transcriptional start site and an enhancer/silencer domain from -448 to -112. The core promoter contains a GATA site at -31 to -28 whose mutation to TATA or AATA decreases tissue specificity and moderately affects expression in megakaryocytes as well as a positively acting subdomain from -97 to -83 whose removal decreases overall transcription without affecting tissue specificity. The enhancer/silencer domain possesses three positively acting subdomains from -380 to -362, -270 to -257, and -137 to -120 as well as a negatively acting subdomain at -184 to -151 which is able to reduce overall transcription but has no effect on tissue specificity. The subdomain from -380 to -362 is most critical in restricting gene expression driven either by the PF4 promoter or by a heterologous promoter to the megakaryocytic lineage. The subdomains from -270 to -257 and -137 to -120 function together with the subdomain from -380 to -362 to somewhat increase tissue specificity. Simultaneous mutation of the GATA site and deletion of either the whole enhancer/silencer domain or the subdomain from -380 to -362 or -137 to -120 reduce transcription in megakaryocytes by 10- to 30-fold. On the basis of the above-described results, we propose that the megakaryocyte-specific enhancer/silencer domain and the GATA site are responsible for high-level expression of the PF4 gene in a lineage-specific manner.

Animals↗

PubMed1994

Platelet secretion from dense and alpha-granules in vitro in migraine with or without aura.

Several studies in vivo indicate platelet activation in migraine, as reflected by increased plasma concentrations of platelet secretory products. In vitro data on platelet secretion are scant, which prompted an investigation into agonist-induced platelet aggregation and secretion in platelets from patients with migraine. Sixty two patients with migraine with aura (MA) and 41 with migraine without aura (MwA) were studied during a headache-free phase, together with 26 healthy controls. Platelet aggregation and secretion in platelet-rich plasma were induced by collagen and platelet activating factor (PAF). Serotonin was measured by high performance liquid chromatography and platelet factor 4 (PF4) with an enzyme immunoassay kit. There were no significant aberrations in platelet aggregation in those with migraine compared with healthy controls. The platelet PF4 secretion induced by PAF (1.0 and 0.1 microM) was increased in MwA (p < 0.05, p < 0.0001) compared with controls, and there was a similar trend in MA (NS, p < 0.01). By contrast, the PF4 secretion induced by collagen (0.5 and 2.0 micrograms/ml) was reduced in MA (p < 0.01 and p < 0.05). Further, the MA group exhibited increased basal intraplatelet serotonin concentrations (p < 0.0001) and increased serotonin secretion induced by both concentrations of collagen (p < 0.0001) and PAF (p < 0.001). The data indicate an abnormal platelet a-granule secretion in those with migraine, and focus attention on PAF as a possible factor contributing to the platelet activation associated with migraine. The increased platelet content and secretion of serotonin was specific to MA, and may reflect different serotonin turnover in the two clinical migraine types.

Adolescent↗

PubMed1977

Function of human platelets during extracorporeal circulation.

The interaction between human platelets and nonbiologic surfaces was studied during in vitro recirculation of 500 ml of fresh, heparinized human blood in four different perfusion circuits. Circuits differed in surface area (0.1 m2 or 0.9 m2) and in surface composition. No important differences were observed between standard silicone-rubber and filler-free, silicone-rubber surfaces. Platelet counts decreased to 85% of control in 0.1- m2 circuits, but retained normal sensitivity to aggregating agents and released only small amounts of platelet factor 4 (PF4). In contrast, platelet counts in 0.9-m2 circuits decreased to 20% of control within 2 min and platelet sensitivity was depressed out of proportion to the fall in platelet count. Plasma PF4 progressively increased and platelet PF4 content progressively decreased during 6 h of recirculation. The results indicate that human platelets may exist in three conditions during extracorporeal circulation. Some platelets are unaltered, some are less sensitive to aggregating agents, and others have undergone extensive release. The ratio of blood volume to surface area appears to be an important determinant of platelet-surface interaction.

Adenosine Diphosphate↗

PubMed1995

Chemokine gene expression in anti-glomerular basement membrane antibody glomerulonephritis.

Chemokines may be important in the pathogenesis of glomerular leukocyte infiltration in antiglomerular basement membrane (GBM) antibody (Ab) glomerulonephritis (GN). We studied the expression of the C-C chemokines [macrophage inflammatory protein (MIP)-1 alpha, monocyte chemotactic protein (MCP)-1, and RANTES] and C-X-C chemokines [platelet factor 4 (PF4), interferon-inducible protein of 10 kDa (IP-10), MIP-2, and cytokine-induced neutrophil chemoattractant (CINC)] at 30 min, 3, 6, 9, 15, and 24 h after induction of heterologous-phase anti-GBM Ab GN in Lewis rats. There was a rapid induction of CINC, MIP-2, MCP-1, and MIP-1 alpha mRNAs in the glomeruli of nephritic rats 30 min after administration of the anti-GBM Ab, whereas increases in PF4 and IP-10 mRNAs were not seen until 3 h. The mRNA expression of PF4, MIP-1 alpha, MIP-2, and IP-10 peaked at 3 h, whereas CINC and MCP-1 peaked at 6 and 15 h, respectively. By comparison, the expression of RANTES mRNA in rats with anti-GBM Ab GN did not differ from those of control rats. These changes in chemokine gene expression were associated with glomerular polymorphonuclear leukocytes (PMN) and monocyte/macrophage infiltration which peaked at 3 h (20.8 +/- 11.1 PMN/glomerulus) and 24 h (8.2 +/- 1.0 ED-1 cells/glomerulus), respectively. The administration of dexamethasone suppressed glomerular chemokine mRNA expression (60-98%) at both 3 and 15 h, which was associated with a 50-100% reduction in glomerular PMN and monocyte/macrophage infiltration, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Heparin-induced thrombocytopenia: pathophysiology and new treatment options.

Heparin induced thrombocytopenia (HIT) is a severe complication of heparin therapy. It is generally accompanied by a paradoxical decrease in platelets leading to activation of platelets and of the coagulation system. HIT type I is a mild, transient, non-immune disorder. HIT type II is an immune-mediated reaction towards neo-antigen on PF4, which is platelet factor 4 (PF4) that is exposed upon binding to heparins. A low sulfated octasaccharide is required for binding to PF4. The generated immunoglobulines bridge platelets by binding to the FcgRIIa-receptor. In patients with HIT type II heparin/LMW-heparin has to be discontinued immediately upon clinical suspicion. Diagnosis can be confirmed by laboratory tests. As patients are at high risk for or because they have developed thromboembolism, anticoagulation is mandatory, despite thrombocytopenia. Treatment options are danaparoid, r-hirudin, bivalirudin, argatroban, dextransulfate, and dermatansulfate. In future, fondaparinux and ximelagatran may be considered for treatment.

Anticoagulants↗

PubMed2006

Pseudo-pulmonary embolism as a sign of acute heparin-induced thrombocytopenia in hemodialysis patients: safety of resuming heparin after disappearance of HIT antibodies.

Heparin-induced thrombocytopenia (HIT) is a syndrome caused by platelet-activating antibodies that recognize complexes of platelet factor 4 (PF4) and heparin. Thrombocytopenia is the most common clinical feature of HIT. HIT can be considered as a hypercoagulable state, with a high risk of thrombosis. Another feature of HIT is an acute systemic reaction that characteristically begins 5-30 min after receiving an intravenous bolus of unfractionated heparin, such as is commonly given for hemodialysis (HD). Here we present 4 patients who developed acute HIT at or near the start of their chronic HD. All patients were anticoagulated with the low-molecular-weight heparin, nadroparin, for HD. Three of our patients underwent surgery approximately 1-2 weeks before developing HIT. All patients presented with an acute systemic reaction during HD. All patients were treated and further dialyzed with lepirudin. Under this treatment we observed a quick recovery of the platelet count, and patients remained symptom-free. Antibodies against the PF4-heparin complex were detected with a combination of a 'quick test' and an enzyme-linked immunosorbent assay test. The likelihood of having HIT previous to the detection of antibodies was estimated with the pre-test probability score criteria. The tests for PF4-heparin antibodies remained positive for an average of 165 days. Three patients underwent a rechallenge with nadroparin after disappearance of the HIT antibodies in their serum. All 3 remained symptomless when they were further hemodialyzed on nadroparin. Our observations indicate that nadroparin can be successfully reintroduced for HD anticoagulation once the patient's HIT antibodies have disappeared.

Aged↗

PubMed1991

Abnormal levels of platelet-specific proteins and mitogenic activity in myeloproliferative disease.

It has been postulated that platelet-derived growth factor and platelet factor 4 (PF4) are involved in the imbalance of the mechanism of medullar stroma maintenance which triggers off the bone marrow myelofibrotic process. In this work we compare the PF4 and the beta-thromboglobulin (beta-TG) and mitogenic activity in platelet-poor plasma (PPP) and platelet extracts (PE) from patients with myeloproliferative disorders (MPD) with those of secondary thrombocytosis (ST) and normal volunteers. Statistically significant differences were found between MPD and ST patients or controls, but none between ST and controls in all the parameters studied. Maximal differences in platelet-derived factors (PDFs) between MPD and control groups were found in polycythemia vera patients. However, the relationship between the presence of myelofibrosis and abnormal levels of beta-TG, PF4 and mitogenic activity in PPP and PE was only observed in patients with agnogenic myeloid metaplasia (AMM). These results show that PDFs are specifically decreased in MPD platelets. Furthermore, no statistical correlation was found between PDFs and the number of platelets. However, other unknown factors or conditions would be necessary to develop myelofibrosis in MPD, which is present in AMM.

Adult↗

PubMed1976

Dose-dependent influence of acetylsalicyclic acid on platelet functions and plasmatic coagulation factors.

Lysine salt of acetylsalicylic acid (ASA) was given to ten patients by intravenous infusion. Blood samples taken at intervals during the infusion permitted the examination of the influence of the dose of ASA on platelet functions. Aggregation was significantly reduced when 50 mg ASA had entered circulation, while a diminution of PF3 and PF4 availability could only be demonstrated when the dose had reached 500 and 200 mg, respectively. In order to exclude a longer latency time for the diminution of PF3 and pf4 availability, a second series of ten patients received intravenous injections of 100 and 300 mg ASA, respectively. From these patients, blood was taken 1 h after the injection. The decrease of PF3 and PF4 availability in these cases was comparable to the results of the first group. In a third series of patients, a daily intravenous dose of 2,000 mg ASA was given. In these cases, a moderate decrease of factors II, VII, IX and X was observed. Since the appearance of a PIVKA effect could also be demonstrated, vitamin K antagonism was assumed when a high dose of AS

Adult↗

PubMed1977

Studies on the chemistry of human platelet factor 4.

The chemical characteristics of several PF4 preparations have been examined by gel electrophoresis, amino acid analysis and NH2-terminal amino acid sequence determination. Preparations of PF4 from gel filtration and from affinity chromatography appeared identical. A single NH2-terminal sequence was determined as follows: NH2-Glu-Ala-Glu-Glu-Asp-Gly-Asp-Leu-Gin-SCMCys-Leu-SCMCys-Val-Lys-Thr-Thr-Ser-Gln-Val-Arg-. The molecular weight of the PF4 subunits, which seem to be identical, was 7,100 based on the recovery of NH2-terminal glutamic acid.

Amino Acid Sequence↗

PubMed1981

Plasma concentration of platelet-specific proteins and fibrinopeptide A in patients with artificial heart valves.

beta-Thromboglobulin (beta TG), platelet factor 4 (PF4), fibrinopeptide A (FPA), lactic dehydrogenase (LDH), and platelet count were evaluated in patients with bioprostheses and prosthetic heart valves. beta TG and PF4 were significantly elevated in both patient groups (p less than 0.001), whereas FPA was normal. There was no significantly difference in plasma concentrations of beta TG and PF4 between patients with prosthetic heart valves and bioprostheses. LDH levels were significantly (p less than 0.001) higher and platelet count lower (p less than 0.001) in patients with prosthetic cardiac valves. The data indicate that bioprostheses do not cause haemolysis or activation of the coagulation system. The findings that the plasma concentration of platelet-specific proteins were elevated, support the assumption that both types of valves cause platelet damage.

Adult↗