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PubMed1980

Kinetics of activation of prekallikrein by prekallikrein activator.

A 28 000 molecular weight activator of prekallikrein was isolated from human plasma, and the kinetics of its enzymic activity toward prekallikrein was investigated. The activation follows Michaelis-Menten kinetics with a kcat of approximately 3 S(-1); Km is strongly dependent upon the ionic strength. Under suitable conditions the activation obeys first-order kinetics, and the first-order rate constant may be used to quantitate prekallikrein activator activity. Thus a two-stage assay, in which the first step involves the activation of prekallikrein by the activator and the second step quantitates the kallikrein generated, was developed to allow the measurement of prekallikrein activator in biologic samples. The prekallikrein activator content of therapeutic protein solutions, as determined by means of this assay, correlated well with the hypotensive activity of these solutions as determined in an animal model.

Enzyme Activation↗
PubMed1983

Benzyl p-guanidinothiobenzoate hydrochloride, a new active-site titrant for trypsin and trypsin-like enzymes.

Benzyl p-guanidinothiobenzoate hydrochloride was synthesized and demonstrated to be useful for active-site titration of bovine trypsin, bovine thrombin, human lung tryptase, bovine activated protein C, human Factor XIIa fragment and bovine Factor Xa beta. The titration is based on rapid formation of a stable acyl-enzyme with a stoichiometric release of benzyl thiol. Thiol production is measured quantitatively by including 4,4'-dithiodipyridine in the reaction mixture and measuring the increase in absorbance at 324 nm. Ellman's reagent has also been successfully employed, allowing measurement at 410 nm. Unlike p-nitrophenyl p'-guanidinobenzoate, the thioester titrant reacts slowly with chymotrypsin A alpha thus eliminating interference by this enzyme in most titrations. Advantages of this reagent as a titrant include: flexibility in detection of the released thiol, selectivity between trypsin and chymotrypsin-like enzymes, minimal pH-dependence of the epsilon of the absorbing species, relative stability of the reagent under titration conditions, and high epsilon at pH 7.2 with either 4,4'-dithiodipyridine or Ellman's reagent. The reagent should prove useful as an alternative to p-nitrophenyl p'-guanidinobenzoate hydrochloride for the determination of active-site concentrations of the enzymes employed, as well as of other related enzymes.

Animals↗
PubMed1998

Performance characteristics of a new synthetic APTT reagent.

Performance characteristics of a totally synthetic activated partial thromboplastin time (APTT) reagent, recently available commercially, were evaluated and compared with a rabbit-brain extracted reagent. We found that the synthetic reagent, Synthasil, returned significantly higher normal APTT values than the brain-extracted reagent, Thrombosil. APTT ratios (APTT patients/normal mean APTT), yielded by Synthasil were higher in the majority of patients receiving heparin therapy. Synthasil also returned longer APTT values than did Thrombosil on normal plasma spiked with heparin. On patients with lupus anticoagulants, APTTs assayed with Synthasil were generally longer than with Thrombosil. However, the differences disappeared when APTT values were converted to ratios. Factors XII-, XI-, IX- and VIII-deficient plasmas supplemented with normal plasma to yield activities of 2-50%, generally gave longer APTTs with Synthasil than with Thrombosil. However, this was not always the case on plasmas from haemophilias A and B patients. No reduction in Synthasil activity was noted after the reagent had been left at 24 degrees C for 28 days.

Coagulation Protein Disorders↗
PubMed2003

Inherited bleeding disorders in Indian women with menorrhagia.

In order to define the prevalence of haemostatic defects in women presenting with menorrhagia in our region, the coagulation data on women bleeders investigated in the Department of Haematology, AIIMS, were analysed. A total of 337 of the 2200 menorrhagic women investigated were characterized to have an inherited bleeding disorder; 221 of these 337 women presented with menorrhagia alone while 116 also had other associated bleeding manifestations as prolonged bleeding from injury site, ecchymotic patches in the skin, epistaxis, haematomas, haemarthroses and major bleeds like intracerebral bleeding. The tests performed included bleeding time (BT), platelet count, prothrombin time (PT), prothrombin consumption index (PCI), activated partial thromboplastin time (APTT), PF3 release with adenosine diphosphate (ADP) at 0 and 20 min, total PF3 assay and platelet Aggregation studies with collagen, ADP, adrenaline, arachidonic acid and ristocetin. Coagulation factor assays, von Willebrand antigen estimation, ristocetin cofactor assay and electron microscopy were performed wherever necessary. Inherited platelet dysfunction was seen in 283 (83.9%) of the patients. Amongst these, isolated PF3 availability defect was seen in 163 (48.4%) cases. Glanzman's thrombasthenia was seen in 30 (8.9%) patients, Storage pool disease in eight (2.4%) patients, arachidonic acid pathway defect in five (1.5%) patients and Bernard-Soulier Syndrome in six (1.8%) patients. In 71 (21.1%) patients, the platelet function defect could not be classified into any specific subtypes. Inherited defects of coagulation were observed in 54 (16%) of the cases. Amongst these, von Willebrand disease (vWD) was the most frequent being seen in 40 (11.9%) of the cases. Factor XIII deficiency was seen in one (0.3%), factor X deficiency in four (1.2%), factor VII deficiency in one (0.3%) and factor XII deficiency in one (0.3%) of the patients. It is concluded that although hereditary platelet function defects constitute a large majority of women bleeders in India but among the coagulation defects, vWD is the commonest as reported from the caucasian population. It is thus suggested that in women presenting with menorrhagia, screening tests for haemostasis especially for vWD and inherited platelet function defects must be performed.

Adolescent↗
PubMed2001

Bradykinin production during donor plasmapheresis procedures.

BACKGROUND AND OBJECTIVES: Extracorporeal circuits made of artificial substances may induce blood cells and humoral activation. Negatively charged surfaces may activate Factor XII and the prekallikrein-kinin cascade, resulting in bradykinin (BK) production. BK has been considered to be involved in severe hypotensive reactions occurring during therapeutic apheresis in patients taking angiotensin-converting enzyme (ACE) inhibitors or in those receiving platelet transfusion. In this study we investigated BK production during donor plasmapheresis procedures. PATIENTS AND METHODS: Eighteen volunteer donors entered the study protocol. Nine of them were taking ACE inhibitors. Their blood pressure (BP) was monitored both pre- and post-apheresis, and BK determination was carried out using a competitive enzyme immunoassay (EIA), in plasma samples collected both during and at completion of the procedure. In addition, a limited number of thawed plasma units were checked for BK. RESULTS: No side-effects were observed during the procedures. However, donors taking ACE inhibitors showed a higher variation of their systolic BP compared to those who were not taking ACE inhibitors, while diastolic BP percentage variations did not differ significantly between the two groups. The BK concentration was considerably higher in donors taking ACE inhibitors: 183 +/- 26 versus 82 +/- 6 ng/ml (P < 0.0001) after the first collection cycle and 142 +/- 20 versus 65 +/- 11 ng/ml (P < 0.0001) in the final samples. BK was also detected, at a lower concentration (15 ng/ml), in one out of four thawed plasma units obtained from donors taking ACE inhibitors and at 1 ng/ml in one out of two thawed plasma units from the control group. CONCLUSION: Donors taking ACE inhibitors and undergoing plasmapheresis showed higher levels of BK compared to the control group. Furthermore, the detection of BK in plasma units after a freeze-thaw procedure might explain the sudden hypotensive reaction occurring during therapeutic plasma exchange when plasmapheresis units are adopted as substitution fluids. Further investigations are needed to assess the real clinical importance of the presence of BK in plasma units.

Adult↗
PubMedDate not supplied

Plasma protein fraction. Product improvement studies.

The vasodilative effects associated with the use of sodium acetate have been reported in the literature. Preparations of plasma protein fraction (PPF) substantially free of this vasodilator were developed. This paper presents and discusses experimental work on the improved product.

Acetates↗
PubMed1997

Activation of the contact system by filtration of platelet concentrates with a negatively charged white cell-removal filter and measurement of venous blood bradykinin level in patients who received filtered platelets.

BACKGROUND: Several recent reports have described hypotensive transfusion reactions in patients receiving platelet concentrates (PCs) filtered through white cell-reduction filters. It is well known that a negatively charged surface activates the contact system, consisting of factor XII, prekallikrein, and high-molecular-weight kininogen. STUDY DESIGN AND METHODS: To clarify the mechanisms of these hypotensive reactions, the possibility that white cell-reduction filtration activates the contact system was examined. Venous blood plasma bradykinin levels were also measured in patients receiving PC transfusions through filters. RESULTS: None of the measured values were changed by filtration through a positively charged filter. However, filtration through a negatively charged filter resulted in a decrease in the amounts of prekallikrein and an increase in the amount of bradykinin generated, which indicated the activation of the contact system. The bradykinin level was inversely related to the activity of angiotensin-converting enzyme (ACE) in the PCs and was elevated by addition of an ACE inhibitor. Although the venous blood plasma bradykinin level did not change in two patients with a normal ACE activity during PC transfusion through the negatively charged filter, two patients who had decreased ACE activity, showed a significant increase in bradykinin during the transfusion. CONCLUSION: These results suggest that the generation of a large amount of bradykinin by filtration of PCs through a negatively charged filter might cause hypotensive reactions in patients with decreased ACE activity. The clinical significance of bradykinin generation requires further study.

Aged↗
PubMed2003

Assessment of the role of heparan sulfate in high molecular weight kininogen binding to human umbilical vein endothelial cells.

The assembly and activation of the kinin forming system components on human umbilical vein endothelial cells (HUVEC) have been studied in great detail. Proteins such as gC1qR, cytokeratin-1 and u-PAR have been identified to be responsible for Zn2+-dependent binding of high molecular weight kininogen (HK) to HUVEC. Heparan sulfate has also been shown to have a major role in Zn2+-dependent binding of HK to the endothelial cell line, Ea.hy 926. In this study, we have analyzed the possible contribution of heparan sulfate to high molecular weight kininogen binding to HUVEC using multiple approaches. The presence of heparan sulfate on HUVEC was analyzed by staining with an antibody specific for heparan sulfate. Incubation of the cells with bacterial heparinases removed the heparan sulfate from the cell surface to the level seen with a control antibody, however, the Zn2+-dependent binding of HK was not affected. Further, blocking of heparan sulfate with a specific antibody to heparan sulfate even after digestion with heparinases did not reduce HK binding whereas antibodies to the proteins gC1qR and cytokeratin-1 consistently reduced the binding of HK to the endothelial cells. The binding intensities of FITC-labeled HK were similar in heparinase-treated and -untreated HUVEC. The rate of kallikrein formation by the assembly of factor XII, HK and PK were similar in both heparinase-treated and non-treated HUVEC. All of these data indicate that heparan sulfate does not contribute significantly to HK binding to HUVEC.

Antibodies↗
PubMed2001

Recurrent pregnancy loss: etiology of thrombophilia.

Congenital and acquired thrombophilia are associated with an increased risk of pregnancy-associated venous thrombosis and fetal loss. Two hundred eighty-nine patients with a history of recurrent spontaneous abortion were subjected to screening examinations for the etiology of these abortions. Endocrine abnormality (28.0%), uterine abnormality (10.4%), autoimmune diseases (1.4%), antiphospholipid antibody syndrome (4.5%), and balanced type chromosome translocation (4.2%) were found as underlying causes of recurrent abortions, and the remaining 55.0% of the 289 patients were classified as having an unexplained etiology. Congenital thrombophilia such as protein C (PC) deficiency, protein S (PS) deficiency, antithrombin deficiency, and factor V Leiden mutation was not frequently detected; only one patient had PS deficiency. A reduced factor XII activity was found at a frequency of 4.2%. The frequency of methylene tetrahydrofolate reductase gene C677T mutation in recurrent aborters (0.38) was the same as that found in a fertile control group. Although the prevalence of anti-beta2-glycoprotein I antibody (abeta2-GPI) syndrome was very low (1.7%), patients with a high titer of immunoglobulin G (IgG) class abeta2-GPI, despite anticoagulation therapy, experienced severe fetomaternal complications in subsequent pregnancies. The rate (13.8%) of positive tests for serum IgA class abeta2-GPI in patients with unexplained etiology was higher than that in the controls (0%) (P < .05). We conclude that congenital thrombophilia is rare in Japanese patients who had experienced consecutive spontaneous abortions.

Abortion, Habitual↗
PubMed1985

In vitro coagulant and amidolytic methods for evaluating the activity of heparin and a low molecular weight derivative (PK 10169).

In summary, the following points have been presented. PK 10169 produced somewhat weaker effects on the coagulant tests in comparison to heparin in various whole blood and citrated plasma assays. In the synthetic substrate assays, PK 10169 produced a pronounced inhibition of various serine proteases in the AT III supplemented system. No significant inhibition was noted in the non-AT III systems. Preliminary data show that PK 10169-AT III complex is capable of producing direct inhibition of the generation of factors Xa and XIIa. In all platelet function tests studied, this agent failed to produce any modulating effects. PK 10169 did not produce an effect on the fibrinolytic system in vitro. However, analysis of blood samples obtained from animals treated in vivo with this agent suggests activation of fibrinolysis. Thus, the mechanism of action must involve certain cellular components or endogenous modulation of the heparin fraction. The newly developed FPA generation test can be modified by various activators or blood systems to mimic closely in vivo physiology. PK 10169 produces a dose response that is more sensitive and more global by this method than the amidolytic anti-Xa or anti-IIa. In contrast to heparin, larger amounts of platelet factor 4 and protamine sulfate are needed to neutralize the anti-Xa and anti-IIa actions of this agent. Additionally, the anti-IIa component is more susceptible to neutralization than the anti-Xa component. Our studies also suggest that PK 10169 is resistant to the action of certain heparin digestive systems, such as heparinase.

Antithrombin III↗
PubMed1985

In vivo studies on the binding of heparin and its fractions with platelet factor 4.

PF4 has a half-life in plasma of less than 3 minutes, and its rapid clearance appears to be a function of binding to the vascular endothelium. Once bound to the endothelium, PF4 can be released by heparin in a time-dependent manner; recovery is greater the sooner heparin is administered following PF4 infusion. This heparin-induced release of PF4 can be abolished if the heparin is first complexed with hexadimethrine bromide. Likewise, this heparin-induced release of PF4 is dependent upon the type of heparin used; low molecular weight heparin fractions and fragments do not cause the PF4 rebound seen with intact heparin. Thus, it would appear that low molecular weight forms of heparin are advantageous in that their in vivo administration would not be mediated by such platelet modulators as PF4.

Animals↗
PubMed1999

Treatment of hereditary and acquired thrombophilic disorders.

The treatment of hereditary and acquired thrombophilic disorders is based on an understanding of the disease pathophysiology, prevalence, associated morbidity and mortality, and available therapeutic options. Genetic mutations are identified that result in activated protein C (APC) resistance and hyperhomocyst(e)inemia. The underlying etiologies are less well-defined; however, the disorders of factor XII deficiency, dysfibrinogenemia, Wien-Penzing platelet defect, and sticky platelet syndrome (SPS) are treatable inherited thrombophilias. Antithrombin deficiency, protein C and protein S deficiencies, and plasminogen deficiency are disorders both inherited and acquired. Antiphospholipid antibodies, myeloproliferative syndromes, and Trousseau's syndrome are acquired. Treatment for acute arterial thrombosis or venous thromboembolism is the same or similar for all thrombophilic disorders. Long-term management is based on the risk of a primary or recurrent acute thrombotic event, compared with the risk of the proposed therapy. Few blinded, controlled studies are available to validate treatment recommendations. When long-term anticoagulation is advised, careful consideration should be given to the risk associated with therapy. Bleeding risk, variable efficacy, and the risk of cutaneous necrosis limit the use of warfarin. Fixed low-dose unfractionated porcine heparin and low-molecular-weight heparins (LMWH) offer significant advantages for long-term management. These recommendations are derived from an analysis of the pertinent medical literature and are expected to change with the progress of clinical and laboratory investigation.

Disease Management↗