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PubMed1982

Complement, coagulation and fibrinolytic parameters in hereditary angioedema (HAE).

The intrinsic clotting, the kinin generating and the fibrinolytic systems were investigated in 10 patients with hereditary angioedema (HAE), 10 patients with chronic urticaria and 18 healthy volunteers. In spite of the fact that patients suffering from HAE severely lack C1 INH, neither the intrinsic coagulation nor the fibrinolytic systems are impaired. There was a slight decrease of plasma kallikrein--as already known--and moreover a greater decrease in HMW-kininogen, and increase in Factor XII levels. Furthermore, activation of pre-kallikrein was delayed in these patients. These findings make it apparent that lowered HMW-kininogen levels compensate the lack of C1 INH, thus preventing an enhanced activation of the intrinsic clotting and the fibrinolytic systems.

Angioedema↗
PubMed1980

[Blood coagulation changes in hypo- and hypertensive neurocirculatory dystonia under the influence of physical load].

The coagulogram, factor XII and fibrinolytic activity of blood were studied in 90 patients with hypotension, 30 patients with hypertension and in 23 healthy individuals under the effect of physical exercise on a bicycle ergometer. In patients with hypotension, the initial moderate increase in the blood coagulative properties was attended by intensification of the anticoagulation system. Physical exercise revealed the predominance of the coagulation system over the anticoagulation system in patients with hypotension. Analysis of the clinical course of hypotension showed a tendency towards hypercoagulation in the crisis, labile and transitory forms of the disease. A permanently low BP does not induce marked deviations in the blood system.

Adolescent↗
PubMed1994

Anaphylactoid reactions during hemodialysis.

Taken together, with the wide-spread use of ACE-inhibitors within the dialysis population, a novel type of hypersensitivity reaction has been recognized, which may occur not only during hemodialysis but also during other forms of extracorporeal therapy. From the data available today, it seems that such reactions are triggered by negatively charged biomaterials which are capable to activate factor XII, leading among others to the generation of bradykinin. Normally this kinin is rapidly degraded by the serine proteinase kininase II. Thus, in the absence of ACE inhibitors plasma bradykinin levels increase only moderately during dialysis with AN69 membranes and clinically most patients are free of symptoms. However, once kininase II, which is identical with converting enzyme, is blocked by ACE inhibitors, plasma levels may increase more than 100-fold and patients will suffer from severe anaphylaxis. Based on our present knowledge, the consequences for clinical medicine are straightforward. It is mandatory to avoid the combination of negatively charged membranes or other biomaterials with ACE inhibitor therapy. As there are many different membranes available, this should be no unsurmountable problem in the setting of clinical hemodialysis.

Anaphylaxis↗
PubMed1993

The role of endotoxin immunity, neutrophil degranulation and contact activation in the pathogenesis of post-operative organ dysfunction.

Gut mucosal hypoperfusion is associated with a poor outcome following major surgery but the pathogenetic mechanisms remain poorly understood. We have examined the relationship between gut mucosal hypoperfusion, endotoxin core antibodies (EndoCAb), neutrophil elastase alpha-1 antitrypsin complexes (NE) and components of the contact system during elective major surgery. Of the 26 patients studied 16 developed gut mucosal hypoperfusion (pHi < 7.32) by the end of surgery; of these four developed multiple organ failure (MOF) and three subsequently died. In this group there was a significant rise in NE (P < 0.005) and significant reductions in components of the contact system (factor XII, antithrombin III, prekallikrein and C1-inhibitor; P < 0.001) from immediately before surgery to 24 h later. Ten patients maintained gut mucosal perfusion (pHi > or = 7.32); none of these developed life threatening complications. In this group there was no significant increase in NE and, although there were significant reductions in some components of the contact system (P < 0.01), levels of C1-INH were not reduced. All patients demonstrated a significant reduction in both IgG and IgM EndoCAbs (P < or = 0.005) indicating exposure to endotoxin. However, the group that maintained gut mucosal perfusion had significantly higher IgG EndoCAb levels at baseline and 24 h (P < or = 0.005). These data suggest that all patients were exposed to endotoxin and that high levels of anti-endotoxin antibodies may contribute to the prevention of endotoxin-induced contact activation, neutrophil degranulation and gut mucosal hypoperfusion occurring during major surgery and thus reduce the likelihood of the development of post-operative MOF.

Adult↗
PubMed1993

Activation of the zymogen of hepatocyte growth factor activator by thrombin.

Hepatocyte growth factor activator (HGF activator) is a serine protease which converts single-chain HGF to the active two-chain form. HGF activator purified from human serum has a molecular mass of 34 kDa and consists of two chains held together by a disulfide bond. The nucleotide sequence of HGF activator cDNA shows that HGF activator is derived from the COOH-terminal region of a precursor of 655 amino acids by proteolytic cleavage of the bonds between Arg372 and Val373 and between Arg407 and Ile408 and that the precursor consists of multiple domains homologous to those observed in blood coagulation factor XII. In this study, we identified the precursor of HGF activator in human plasma using an enzyme-linked immunosorbent assay system. The precursor was purified from plasma by a five-step procedure. The purified precursor did not activate single-chain HGF. The precursor was efficiently cleaved in vitro by thrombin, at the bond between Arg407 and Ile408, in the presence of negatively charged substances. The cleaved precursor activated single-chain HGF. These findings led us to conclude that HGF activator is present in plasma as an inactive zymogen and that the zymogen is activated by the cleavage of the bond between Arg407 and Ile408 by thrombin. Characteristic structural domains in the NH2-terminal region of the zymogen may be involved in the binding of the zymogen to negatively charged substances, which stimulates the activation of the zymogen by thrombin.

Amino Acid Sequence↗
PubMed1994

Administration of gamma interferon in human subjects decreases plasminogen activation and fibrinolysis without influencing C1 inhibitor.

Recombinant gamma interferon (rHuIFN-gamma) has been recognized to increase mRNA and protein levels of C1 inhibitor (C1 INH) in various human cells. Further, when administered to patients with colon cancer, it increased plasma C1 INH levels. A prospective trial was initiated to determine whether rHuIFN-gamma could elevate plasma C1 INH levels in six normal volunteers and two patients with type I angioedema. After 1 month of observation of plasma C1 INH levels, rHuIFN-gamma was administered subcutaneously at 25 micrograms/M2 daily for 4 consecutive days. All healthy volunteers and patients experienced local erythema, headache, myalgias, and chills during the administration of rHuIFN-gamma. C1 INH, prekallikrein, high-molecular-weight kininogen, and factor XII levels in plasma were not influenced by the rHuIFN-gamma administration. One patient with hereditary angioedema (HAE) had an attack of angioedema 3 days after completion of rHuIFN-gamma therapy. During the attack, circulating cleaved high-molecular-weight kininogen, kallikrein-alpha 2-macroglobulin complexes, and an altered 50 kd form of kallikrein were detected in the patient's plasma. Additional studies showed that rHuIFN-gamma treatment resulted in decreased total fibrinolytic activity. It was found that immediately after rHuIFN-gamma treatment, tissue plasminogen activator activity and antigen levels were not significantly decreased in volunteers. Plasminogen activator inhibitor levels rose significantly, but this activity was not due to plasminogen activator inhibitor-1 antigen, whose value significantly fell. These data suggest that rHuIFN-gamma may stimulate the expression of another plasminogen activator inhibitor.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1997

[Hypercoagulable state in Duchenne muscular dystrophy].

Pulmonary and cerebral infarctions have come to be noticed as life-threatening complications of Duchenne muscular dystrophy (DMD). In order to elucidate the underlying mechanism of hypercoagulable state, was studied following markers of coagulation and fiblinolysis in 69 DMD and 50 control patients showing no signs of thrombosis: prothrombin time, activated partial thrombin time, thrombotest, fibrinogen, fibrinogen degradation product, thrombin-antithrombin III complex (TAT), alpha 2-plasmin inhibitor plasmin complex (PIC), D-dimer, protein C activity, protein S, antithrombin III, XII factor, thrombomodulin and plasminogen activity. 66 out of 69 patients (96%) showed abnormal results in more than one of these studies, among which abnormally low thrombotest (78%), high TAT (61%) and high PIC (40.3%), were very frequently observed. The results were not correlated to the age, the activity of daily living and the respiratory of cardiac functions. Significantly smaller number of the control patients suffering from other neuromuscular diseases showed abnormal results, while the ambulatory DMD patients not infrequently showed hypercoagulable state. These results strongly suggest that unknown inherent factor(s) as well as inevitable immobilization and cardiac dysfunction play(s) an important role in the development of hypercoagulable state in this intractable disorder.

Adolescent↗
PubMed1998

Lack of clinically significant contact system activation during platelet concentrate filtration by leukocyte removal filters.

When blood (plasma) contacts certain foreign surfaces, factor XII can activate and trigger a series of reactions leading to cleavage of kininogens with subsequent release of bradykinin. In this study, we investigated two different widely used leukocyte removal filters, Pall PXL8K (A) and Asahi PLS-5A (B), to test whether clinically significant contact activation occurred during leukodepletion of platelet-rich plasma (PRP). Kininogens were measured by particle concentration fluorescence immunoassay (PCFIA), which can detect cleavage of high and low molecular weight kininogens (HK and LK), the parent molecules of bradykinin, to determine if contact activation had occurred. A slight, nonsignificant decrease in HK and LK was observed with filter A after the first 5 mL was filtered that returned to prefiltration levels by the end of the filtration. Specific TotK (the combined measurement of HK and LK heavy chains divided by plasma protein concentration) showed a small, significant decrease with filter A after the first 5 mL of platelet concentrates was filtered that returned to prefiltration levels by the end of the filtration. There were no significant increases or decreases in the cleaved kininogen index (CKI), an index of HK proteolytic activation or HK and LK destruction (with release of bradykinin). These data suggest that small amounts of both HK and LK initially adsorb to filter A and then desorb, primarily intact. These data also indicate that no significant contact activation, as measured by PCFIA, occurs during leukodepletion of platelet concentrates with either filter A or B.

Blood Platelets↗
PubMed1988

Mechanism of transient adsorption of fibrinogen from plasma to solid surfaces: role of the contact and fibrinolytic systems.

The transient detection of fibrinogen on surfaces has been described (Vroman effect) and high-mol-wt kininogen (HK) has been shown to play a role in this reaction. In this study, we attempted to identify the form of HK responsible for preventing detection of the fibrinogen initially adsorbed from plasma to various artificial surfaces and to determine if other plasma components were involved. We compared 125I-fibrinogen adsorption in the presence of normal plasma to plasma deficient in specific proteins. On all surfaces tested, we found that fibrinogen was displaced from the surface. The extent of displacement was greatly reduced, however, but not eliminated in HK-deficient plasma. Factor XII-deficient plasma also showed reduced fibrinogen displacement. These data indicate that HK can actually displace fibrinogen; however, factor XII, or a factor XII-mediated reaction also appears to be necessary for this displacement to occur. Furthermore, when normal plasma was first subjected to extensive contact activation by dextran sulfate, during which the HK was extensively degraded to components smaller than the light chain (as assessed by Western blotting), we observed greatly reduced displacement of fibrinogen. Extensive contact activation of Factor XI-deficient plasma failed to show low-mol-wt derivatives, however, and displacement of fibrinogen was similar to normal plasma that had not undergone extensive activation. These data indicate that HKa (active cofactor produced during contact activation by factor XIIa or kallikrein) is primarily responsible for displacing fibrinogen, and that HKi (inactive cofactor generated by factor XIa) cannot displace fibrinogen. The fibrinogen from all plasma samples looked similar by Western blot analysis, suggesting that fibrinogenolysis was not a component of the Vroman effect. In addition, experiments performed with plasma prechromatographed on lysine agarose showed that a lysine-agarose adsorbable protein may be minimally involved in fibrinogen desorption and a synergism may exist between HK and that protein.

Adsorption↗
PubMed1986

Neurophysiological variables and fibrinolysis in insulin-dependent diabetes treated with an aldose reductase inhibitor or placebo. A double-blind randomized study.

In a double-blind study we randomized insulin-dependent diabetics (n = 19) into a group (n = 12) given daily 250 mg Sorbinil, a potent aldose reductase inhibitor reported to ameliorate diabetic neuropathy, and another group (n = 7) given placebo for 1 year. Objective, neurophysiological variables (biothesiometry, electromyography, nyctometri) were followed throughout the study and correlated with fibrinolytic variables in blood. We found that Sorbinil did not improve any of the selected neurophysiological variables. Neither did Sorbinil induce marked changes in the fibrinolytic activities of the extrinsic, tissue-type plasminogen activator (t-PA), or in the intrinsic factor XII-dependent or factor XII-independent (urokinase-like) plasminogen activator systems. We found no effect of Sorbinil on the activity of the fast-reacting inhibitor (PA-I) of plasminogen activator. Levels of PA-I in plasma influence the amounts of t-PA precipitated in euglobulins.

Aldehyde Reductase↗
PubMed1986

Purified plasma factor XIIa aggregates human neutrophils and causes degranulation.

Plasma kallikrein has been shown to aggregate human neutrophils and release human neutrophil elastase. However, neutrophils resuspended in factor XII-deficient plasma released only 30% of the elastase compared with normal plasma. Isolated human neutrophils were aggregated in a concentration-dependent fashion by 0.06 to 0.6 U/mL factor XIIa (0.022 to 0.22 mumol/L). Factor XIIa (0.1 to 1.0 U/mL) also induced neutrophil degranulation as evidenced by a concentration-dependent release of the specific granule protein, lactoferrin, and azurophilic granule protease, elastase. The release of neutrophil elastase was biphasic, reaching 40% of maximum at 15 seconds with maximal release by 90 minutes. The active site of factor XIIa was required, since the synthetic inhibitor, D-Pro-Phe-Arg-CH2Cl, which reacts with an essential histidine, and the natural plasma inhibitor, Cl-inhibitor, which interacts with the critical serine, both inhibit by more than 90% the release of elastase. The heavy chain is also required, since factor XII fragments failed to aggregate neutrophils or stimulate degranulation. Factor XIIa (0.6 U/mL) can completely correct the defect in elastase release evident in factor XII-deficient plasma. These studies demonstrate that factor XIIa, at concentrations potentially obtainable in plasma in disease states, can activate neutrophils, and thus may participate in the inflammatory response.

Cell Aggregation↗
PubMed1977

Generation of coagulation factors V, XI, and XII by the isolated rat liver.

When isolated rat livers were perfused with platelet-free erythrocytes suspended in Tyrode's solution containing 6% bovine serum albumin, the generation of factors V, XI, and XII was clearly demonstrable. On average, after 5 h of perfusion of a single liver, the concentrations in the perfusate (as a percentage of normal rat plasma) were about 6% for factor V, 8% for factor XI, and 5% for factor XII, compared with 20% for factor VII, which was used as the reference standard. When two livers were perfused, approximately twice these concentrations were achieved. When the properties of these factors in perfusate and plasma were compared, they agreed well except for differences in the celite adsorbability of factors XI and XII.

Aging↗
PubMed1995

In vitro contact phase activation with haemodialysis membranes: role of pharmaceutical agents.

Contact phase activation was investigated in vitro using flat sheet type of haemodialysis membranes, Cuprophan (Akzo, Faser, Germany) and AN69S (Hospal, France), and a negatively charged polyamide Ultipor NR 14225 membrane as a control. The investigation focussed on the determination of factor XII-like activity (FXIIA) as an indicator of contact phase activation in the supernatant phase and at the membrane surface after plasma-membrane contact using an incubation test cell. The findings were compared with the observations from a plasma-free system utilizing purified unactivated factor XII. The plasma FXIIA bound to the membrane surface was significantly different between the membranes, while the supernatant phase FXIIA exhibited no significant differences. In contrast, the plasma-free system exhibited significant differences in the supernatant FXIIA and membrane-bound FXIIA for all the materials used and the magnitude of the activity was significantly greater for negatively charged materials. This finding demonstrated the strong influence of the interaction of other plasma constituents on the membrane surface and as such the binding and subsequent activation of factor XII may be altered possibly due to competitive binding and steric hindrance. On the addition of anticoagulants such as heparin, low-molecular-weight heparin, citrate and hirudin, no significant differences were observed in plasma supernatant phase FXIIA. However, each anticoagulant appears to have a distinct influence on the magnitude of plasma membrane-bound FXIIA. On the addition of aprotinin (a kallikrein inhibitor), no significant differences were observed in the plasma supernatant FXIIA. In contrast, aprotinin appears to significantly reduce membrane-bound FXIIA on Cuprophan and polyamide NR, but significantly increase the magnitude of the membrane-bound FXIIA on AN69S.

Anticoagulants↗
PubMed1982

Effect of captopril on inactive renin and contact phase of coagulation system.

It has been suggested that a Factor XII-plasma Prekallikrein dependent pathway might play an important role in the activation of inactive renin. Since Captopril has the potential to affect the kinin-kallikrein system, we have studied in a group of 16 patients with essential hypertension its acute effect both on the levels of active, inactive and total renin, and on the contact phase of the coagulation system. Our results show that a single dose of Captopril (25 mg) induces a rapid and persistent increase of active and total renin, while inactive renin tends to decrease. Together with blood pressure, plasma Prekallikrein(PK), Factor XII(FXII) and Factor XI(FXI) concomitantly decrease, although not significantly, and their values seem to return to basal levels soonafter. However, no correlation was found at any time between the levels of any of these coagulation factors, including PK, and those of inactive, active or the ratio inactive/total renin. In spite of that, it is still possible that an activation of PK, which is likely to occur under Captopril administration, may affect at least the conversion of vessel-bound prorenin rather than the circulating form.

Adolescent↗
PubMed1986

Activation of intrinsic coagulation pathway in pre-eclampsia.

Disseminated intravascular coagulation, thrombocytopenia, consumption of factors VIII and II, and antithrombin deficiency have been previously demonstrated in pre-eclampsia. However, the precise mechanism responsible for initiation of disseminated intravascular coagulation has not been elucidated. The present study documents activation of the intrinsic coagulation pathway in a patient with severe pre-eclampsia. The studies revealed marked reductions of plasma coagulant activities of all intrinsic pathway factors, i.e., XII, XI, IX, and VIII. In addition, the ratio of plasma factor XII activity to antigen concentration was markedly abnormal, and plasma high-molecular-weight kininogen concentration was diminished. It is suggested that activation of the intrinsic coagulation pathway may be operative in the genesis of disseminated intravascular coagulation in pre-eclampsia.

Adult↗