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PubMed1985

Further studies on the hypercoagulable state of patients with Cushing's syndrome.

Factors XII, XI, IX and VIII, plasminogen and alpha 2-antiplasmin levels were found to be increased in a group of patients affected by Cushing's syndrome. High activity of these coagulation factors could be due to their increased release and synthesis mediated by cortisol. A significant correlation between the main arterial pressure and either factor VIII antigen, ristocetin cofactor or factor XII activity was found. Moreover a similar correlation between factor XII activity and either factor VIII antigen or ristocetin cofactor was seen. In conclusion, the presence of a hypercoagulable state in Cushing's syndrome seems confirmed. Synergic release of factor XII and factor VIII from endothelium could be due to high blood vessel tone secondary to hypercorticism. Finally, decreased fibrinolytic activity was suspected according to plasminogen and alpha 2-antiplasmin increase.

Blood Coagulation Disorders↗
PubMed1984

Prorenin-renin conversion by the contact activation system in human plasma: role of plasma protease inhibitors.

Acid-pretreated normal human plasma generates renin activity at 0 degree C and neutral pH by the activation of prorenin. The activation is caused by kallikrein generated from prekallikrein by activated factor XII. Nonacidified plasma also generates renin at 0 degree C, but at a lower rate (cold-promoted activation). In normal plasma, 14% +/- 1% of prorenin (mean +/- SEM, n = 30) was activated during incubation at 0 degree C for 7 days (range 6% to 26%). Cold-promoted activation of prorenin was within the normal range in plasma deficient in factor XI, X, IX, VIIIC, VII, V, prothrombin, or high mol wt kininogen. Cold-promoted activation of prorenin was less than or equal to 1% in plasma deficient in factor XII or prekallikrein. Reconstitution of these plasmas with highly purified factor XII or prekallikrein restored normal prorenin activation. Correction of high mol wt kininogen deficiency had no effect. Thus cold-promoted activation of prorenin depends on the presence of factor XII and prekallikrein, whereas the other clotting factors are not essential. The influence of the inhibitors C1 esterase-inhibitor, alpha 2-macroglobulin, antithrombin III, and alpha 1-antitrypsin on the activation of prorenin was studied in factor XII-deficient plasma from which one or more of these inhibitors had been selectively removed by immunoadsorption. Factor XII was subsequently added, and the generation of renin at 37 degrees C was observed after complete factor XII-high mol wt kininogen-mediated activation of prekallikrein induced by dextran sulfate. No activation of prorenin was observed at 37 degrees C after depletion of C1 esterase inhibitor, alpha 2-macroglobulin, antithrombin III, or alpha 1-antitrypsin. When prekallikrein was activated in plasma depleted of both C1 esterase-inhibitor and alpha 2-macroglobulin, 6% of prorenin was activated in 2 hours at 37 degrees C. After additional depletion of antithrombin III, the activation increased to 47%. These results indicate that the contact activation system is capable of activating prorenin in plasma at physiologic pH and temperature when the three most important kallikrein inhibitors, C1 esterase-inhibitor, alpha 2-macroglobulin, and antithrombin III, are absent.

Binding Sites↗
PubMed2002

Activation of the bradykinin-forming cascade on endothelial cells: a role for heat shock protein 90.

Bradykinin is a major mediator of swelling in C1 inhibitor deficiency as well as the angioedema seen with ACE inhibitors and may contribute to bronchial hyper-reactivity in asthma. Formation of bradykinin occurs in the fluid phase and along cell surfaces requiring interaction of Factor XII, prekallikrein and high molecular weight kininogen (HK). The mechanism by which initiation occurs is uncertain. Recent data suggest that activation of the kinin-forming cascade can occur on the surface of endothelial cells, even in the absence of Factor XII. We demonstrate herein that during a 2-h incubation time, plasma deficient in either Factor XII or high molecular weight kininogen (HK) fail to activate kinin-forming cascade as compared to normal plasma. With more prolonged incubation, Factor XII deficient plasma gradually activates and HK deficient plasma does not. Our data support both Factor XII-dependent (rapid) and Factor XII-independent (slow) mechanisms; the latter may require a cell-derived protein (possibly protease) to activate prekallikrein in the presence of zinc ion and HK. To further define this cellular factor, we demonstrated that both cytosolic and membrane fractions from endothelial cells possessed the ability to catalyze prekallikrein conversion to kallikrein in the presence of HK and zinc ion. We purified this factor from cytosol by affinity chromatography employing corn trypsin inhibitor (CTI) as ligand. The fractions with peak activity were subjected to SDS-PAGE analysis, ligand blotted with biotinylated CTI, and positive bands were sequenced. Heat shock protein 90 (Hsp90) was identified as one of the proteins. Zinc-dependent activation of the prekallikrein-HK complex on endothelial cells was inhibited upon the addition of polyclonal antibody to Hsp90 in a dose-dependent manner. Although the mechanism by which Hsp90 activates the kinin-forming cascade is not yet clear, this protein represents the cellular contribution to the reaction and may become the dominant mechanism in pathologic circumstances in which Hsp90 is highly expressed or secreted.

Amino Acid Sequence↗
PubMed1994

Activation of blood clotting factors by microbial proteinases.

There are very few reports on the involvement of bacterial proteinases on the blood clotting system using both human plasma and purified clotting factors. We studied whether microbial proteinases from the opportunistic pathogens Candida albicans, Pseudomonas aeruginosa and Serratia marcescens activate the blood clotting cascade by using normal human plasma, human plasmas deficient in clotting factor XII or X, and also by using purified clotting factors XII, X and prothrombin. All proteinases tested activated either clotting factor XII or prothrombin in vitro, thus resulting in generation of thrombin. Clotting factor X was converted to the active form (Xa) by both Candida and Pseudomonas proteinases, but not by Serratia proteinase. These results suggest that peripheral and systemic blood circulation may be impaired by activation of the blood clotting cascade by microbial infections, especially in septic patients, which would enhance disseminated intravascular coagulation and multi-organ failure.

Amino Acid Sequence↗
PubMed1998

Hemofiltration removes bradykinin generated in the priming blood in cardiopulmonary bypass during circulation.

After induction of hemofiltration for the hemic prime of a cardiopulmonary bypass, the initial drop in blood pressure disappears, and postoperative edema rarely occurs. We have suspected that bradykinin, a strong vasodilator generated through the activation of factor XII, prekallikrein, and high molecular weight kininogen was removed by ultrafiltration. We examined the changes in the activities of plasma-factor XII, prekallikrein, high molecular weight kininogen and in the levels of bradykinin in the priming blood using red cell concentrates before and after hemofiltration, and evaluated the effectiveness of hemofiltration. Ten circuits were used, and ten sets of blood samples were collected from red cell concentrates, the priming blood before hemofiltration, after hemofiltration, and the filtrate. During circulation in the circuit, factor XII, prekallikrein and high molecular weight kininogen were completely consumed and a large amount of bradykinin was generated, but it was filtered well by ultrafiltration. Factor XII, prekallikrein and high molecular weight kininogen could be activated through the dilution of red cell concentrates during the priming and contact with the circuits. Because bradykinin is the most potent vasodilator, increasing microvascular permeability and relating to several other inflammatory mediators, the removal of bradykinin generated from factor XII, prekallikrein and high molecular weight kininogen is very significant in the prevention of non-specific inflammatory reactions during and after open-heart surgery.

Bradykinin↗
PubMed1992

Studies of surface activated coagulation: antisera binding onto methyl gradients on silicon incubated in human plasma in vitro.

Human plasma proteins factor XII, high molecular weight kininogen, prekallikrein, factor XI and fibrinogen, participate in surface-initiated coagulation. Antisera binding to methyl gradients made on hydrophilic silicon was studied after immersion in normal and deficient human blood plasma. Scanning ellipsometry was used to quantify the adsorbed organic material. The hydrophilic part of the gradient deposited anti-factor XII and anti-high molecular weight kininogen, but low amounts of anti-fibrinogen. Increased amounts of anti-fibrinogen bound onto the hydrophobic part, and the intermediate gradient region with mixed polar-nonpolar surface characteristics bound low amounts of anti-factor XII, anti-high molecular weight kininogen and anti-fibrinogen. Tentatively, in this gradient region, simultaneous polar and non-polar surface characteristics result in a low-level of surface-activated coagulation. Surfaces immersed in heparinized-and EDTA-plasma indicate different antisera depositions.

Adsorption↗
PubMed2004

Factor XII-dependent increases in thrombin activity induce carboxypeptidase-mediated attenuation of pharmacological fibrinolysis.

Activation of the contact system in patients treated with fibrinolytic agents may be an important source of thrombin that activates thrombin-activated fibrinolysis inhibitor (TAFI) and attenuates fibrinolysis. Factor (F)XIIa in plasma increased 2-fold over 60 min in patients given either tissue plasminogen activator (t-PA) or streptokinase (SK). To determine whether FXIIa-mediated generation of thrombin and activated TAFI (TAFIa) attenuates fibrinolysis in vitro, plasma clots were incubated with SK (250 U mL-1) or t-PA (2.5 g mL-1) and the rate of lysis was measured. Plasma FXIIa impaired lysis judging from marked acceleration when 2.5 micro m corn trypsin inhibitor were added (lysis increased by 172 +/- 144% for SK and 40 +/- 31% for t-PA vs. no inhibitor, n = 16, P < 0.01). Moreover, inhibition of thrombin with hirudin and TAFIa with carboxypeptidase inhibitor accelerated lysis. We conclude that activation of FXII increases thrombin generation, which promotes TAFIa-mediated attenuation of fibrinolysis.

Carboxypeptidase B2↗
PubMed1991

Depression of factor XII-dependent fibrinolytic activity characterizes patients with early myocardial reinfarction after recombinant tissue-type plasminogen activator therapy.

Twenty patients with acute myocardial infarction treated with recombinant tissue-type plasminogen activator (rt-PA) had endogenous factor XII-dependent fibrinolytic activity levels measured throughout the hospital period and those levels were prospectively correlated with the incidence of recurrent myocardial infarction until 8 weeks after hospital discharge. Within the follow-up period, recurrent myocardial infarction was observed in 8 patients, whereas the remaining 12 patients showed no clinical evidence of recurrence. The patients in the reinfarction group were characterized by a more pronounced depletion of and sustained lower levels of factor XII-dependent fibrinolytic activity than were the patients with no reinfarction (p less than 0.05). The decrease in fibrinolytic activity during rt-PA therapy was significantly associated with a depletion of functional alpha 2-antiplasmin, the primary plasmin inhibitor. These results indicate that, paradoxically, coronary thrombolysis with rt-PA involves depletion of endogenous factor XII-dependent fibrinolytic activity levels, which constitutes a risk for early myocardial reinfarction.

Aged↗
PubMed2002

Changes in high molecular weight kininogen levels during and after cardiopulmonary bypass surgery measured using a chromogenic peptide substrate assay.

High molecular weight kininogen (HK) is a co-factor in the blood-contact activation system. A chromogenic peptide substrate assay for HK (HKcs) has been developed in which test plasmas are mixed with diluted HK-deficient plasma and incubated with a soluble contact system activator that activates prekallikrein and factor XII. Calcium chloride, a synthetic thrombin inhibitor and a chromogenic peptide substrate for activated factor X (FXa) are then added. The FXa generated cleaves the FXa substrate releasing p-nitroanaline, which is measured photometrically. Test plasma HK values were calculated from a standard curve generated using a pooled normal plasma. Acceptable intra-assay and inter-assay precision values were obtained and levels of HK up to 200% were measurable. The assay measured HK in plasmas deficient in factor XII, prekallikrein and factor XI, was not affected by antiphospholipid antibodies and gave an acceptable correlation (r = 0.95) when normal plasmas and mixtures of HK-deficient and normal pooled plasma, calculated to give HK levels of 25 and 50%, were compared using HKcs and a HK one-stage clotting assay. The HKcs was used to measure HK levels in seven patients undergoing cardiopulmonary bypass (CPB). HK levels fell significantly during CPB (P = 0.0014) and were significantly higher (P = 0.016) 6 days after CPB, suggesting that HK may be a positive acute-phase reacting protein.

Acute-Phase Proteins↗
PubMed1994

Advances and dilemmas in factor XI.

Factor XI is a key component of the intrinsic pathway of blood coagulation in vitro. The poor correlation between the clinical bleeding diathesis in factor XI deficiency and abnormalities in clotting assays that measure intrinsic coagulation brings into question the role of this serine protease in in vivo hemostasis. The characterizations of the point mutations responsible for the majority of cases of severe factor XI deficiency in Ashkenazi Jews and subsequent epidemiologic studies have provided insight into the perplexing hemostatic abnormalities in this disorder. It appears that excessive bleeding in factor XI deficiency depends on the severity of the deficiency in certain situations and on the location of the hemostatic challenge in others. Additional coexisting abnormalities of hemostasis, such as von Willebrand's disease, may also be responsible for variation in clinical presentation, particularly in those individuals with mild factor XI deficiency. The absence of abnormal bleeding in congenital deficiency of factor XII, the protease that activates factor XI in the intrinsic cascade, has stimulated a search for other mechanisms for factor XI activation. Recent studies have pointed to the serine protease thrombin and autoactivation by activated factor XI as possible alternatives to factor XII as activators of factor XI. These findings suggest that factor XI, rather than operating in a pathway for the initiation of hemostasis, may function in the consolidation of clot formation after the initiation of the hemostatic process by other mechanisms.

Amino Acid Sequence↗
PubMed1992

Hageman factor deficiency presentation and implications for management.

One of the more fascinating aspects of patient management arises when dealing with coagulation disorders. Factor XII deficiency, first described by Ratnoff in 1968, is one such coagulation disorder which provides some interesting challenges in management. Factor XII deficiency has been shown to be an inherited autosomal recessive disorder. The presence of Hageman factor abnormality trait can be clinically suspected in a patient with a prolonged activated partial thromboplastin time (APTT), normal prothrombin time (PT), normal bleeding time, and no clinical history of bleeding. Once suspected, the deficiency can be confirmed by normalization of partial thromboplastin time (PTT) with normal aged plasma and by factor assay. The importance of understanding the mechanism of factor XII deficiency has clinical significance when attempts are made to heparinize individuals who have this deficiency. Three methods can be used to monitor therapy: the chromogenic heparin assay, the citrated thrombin time, and the recalcified thrombin time. Two cases are presented.

Aged↗
PubMed1989

Peritoneal lavage efficiently eliminates protease-alpha-2-macroglobulin complexes and components of the contact system from the peritoneal cavity in patients with severe acute pancreatitis.

Trypsin (Try), plasma kallikrein (KK) and plasmin activities together with coagulation factor XII (F XII, Hageman factor), high-molecular-weight kininogen (HMWK), plasma prekallikrein (PKK), alpha 2-macroglobulin (alpha 2-M), C1 inhibitor (C1Inh), and functional plasma kallikrein inhibition (KKI) values were studied in peritoneal fluid and lavage taps of 9 patients with severe acute pancreatitis treated with peritoneal lavage. Both immunochemical methods and functional techniques based on chromogenic peptide substrate assays were used. In the exudate obtained before peritoneal lavage was performed, F XII was 52%, HMWK was 30%, PKK was 40%, alpha 2-M was 29% and C1Inh was 57% of standard plasma pool values, determined by immunochemical technique. Functional plasma KKI values were zero, whereas Try activities determined by chromogenic peptide substrate technique were markedly elevated in the exudate. Using a prepacked HR 10/30 Superose Tm 12 column (Pharmacia, Uppsala, Sweden) and chromogenic peptide substrate assays, Try and KK activities were detected in the alpha 2-M containing fractions of the peritoneal exudate demonstrating KK-alpha 2-M and Try-alpha 2-M complex formation. The peritoneal lavage procedure efficiently eliminated components of the contact system and protease activities. In the first lavage tap, Try activities were markedly reduced compared to values found in the exudate and concentrations of F XII, HMWK, PKK, alpha 2-M and C1Inh were all zero. In consecutive lavage taps Try values were also zero. The study shows that the lavage procedures efficiently clears the peritoneal cavity for protease-alpha 2-M complexes generated during acute pancreatitis. Also, components of the contact system found in peritoneal exudate, and which might serve as substrates for the protease-alpha 2-M complexes, are rapidly eliminated by the procedure.

Acute Disease↗
PubMed1993

Activation of the kallikrein-kinin system after endotoxin administration to normal human volunteers.

The objective of this study was to determine the role of the kallikrein-kinin system in healthy humans after intravenous administration of either Escherichia coli endotoxin or saline. We studied a total of 18 healthy nonsmoking volunteers, 23 to 38 years old, in an open-label study at the Critical Care Medicine Department, Clinical Center, National Institutes of Health (Bethesda, MD) in which some of the patients served as their own controls. After baseline data collection, the subjects received intravenously either E coli endotoxin (n = 15, 4 ng/kg of body weight) or saline (n = 8, controls). Signs, symptoms, systemic blood pressure, factor XII, plasma prekallikrein (PK), factor XI (FXI), antithrombin III (AT-III), high molecular weight kininogen (HK), and alpha 2-macroglobulin-kallikrein complexes were measured at baseline and 1, 2, 3, 5, and 24 hours after injection of either saline or endotoxin. After infusion of endotoxin, we found the functional plasma levels of FXI decreased at 2 hours (P < .05) and at 5 hours (P < .05). Functional PK was significantly depressed by 2 hours (P < .05), at 5 hours (P < .05), and at 24 hours (P < .01), whereas the PK antigen was only low at 5 hours (P < .05). These changes were accompanied by a significant increase in circulating alpha 2-macroglobulin-kallikrein complexes at 3 hours (P < .05) and 5 hours (P < .01). No significant changes occurred in the plasma levels of factor XII or HK. We concluded that clinical response to intravenous endotoxin in healthy human volunteers is associated with activation of the kallikrein-kinin systems. Further investigation is needed with specific inhibitors of the kallikrein-kinin system to define its primary or secondary role in the endotoxin-mediated reactions.

Adult↗
PubMed1989

Adenotonsillectomy. A safe outpatient procedure.

Traditionally, adenotonsillectomy in children and tonsillectomy in adults have been performed as inpatient procedures. Our experience with this procedure as outpatient started in 1975 at the University of Miami-Jackson Memorial Medical Center. From 1975 to 1987, 1428 cases performed in Florida and Cleveland were reviewed to evaluate the safety and efficacy of the technique used. Bismuth subgallate and epinephrine mixture for hemostasis is used without relying on electrocautery, ties, or suture technique to control bleeding. The incidence of immediate and delayed postoperative bleeding in a series of patients was extremely low (four [0.28%] of 1428 cases). Our technique has good hemostatic properties allowing vessels to contract and retract into the muscle of the tonsillar fossae and adenoid bed. Bismuth subgallate activates factor XII (Hageman factor) and, therefore, markedly accelerates the cascade of blood clotting. Outpatient adenotonsillectomy is safe, cost-effective, and minimizes psychologic implications, which may be an important factor, especially in children. Ambulatory adenotonsillectomy has not been well emphasized in the literature.

Adenoidectomy↗
PubMed2006

Coagulation disorders and hemostasis in liver disease: pathophysiology and critical assessment of current management.

Normal coagulation has classically been conceptualized as a Y-shaped pathway, with distinct "intrinsic" and "extrinsic" components initiated by factor XII or factor VIIa/tissue factor, respectively, and converging in a "common" pathway at the level of the FXa/FVa (prothrombinase) complex. Until recently, the lack of an established alternative concept of hemostasis has meant that most physicians view the "cascade" as a model of physiology. This view has been reinforced by the fact that screening coagulation tests (APTT, prothrombin time--INR) are often used as though they are generally predictive of clinical bleeding. The shortcomings of this older model of normal coagulation are nowhere more apparent than in its clinical application to the complex coagulation disorders of acute and chronic liver disease. In this condition, the clotting cascade is heavily influenced by numerous currents and counter-currents resulting in a mixture of pro- and anticoagulant forces that are themselves further subject to change with altered physiological stress such as super-imposed infection or renal failure. This report represents a summary of a recent multidisciplinary symposium held in Charlottesville, VA. We present an overview of the coagulation system in liver disease with emphasis on the limitations of the current clinical paradigm and the need for a critical re-evaluation of the current tenets governing clinical practice. With the realization that there is often limited or conflicting data, we have attempted to represent diverse opinion and experience from the perspectives of both hepatology and hematology beginning with a brief update on the physiology of normal coagulation.

Blood Coagulation Disorders↗
PubMed1990

Transfusion requirements in conservative nonoperative management of blunt splenic and hepatic injuries during childhood.

Nonoperative management of splenic and hepatic injuries in children is safe, and the majority of those with isolated injuries do not require blood transfusion. Thirty-seven children were treated for blunt splenic or hepatic trauma from November 1983 to September 1989. There was one death in a patient with a lethal head injury. No operations were performed on those with isolated splenic or hepatic injuries. Three of those with multiple injuries underwent delayed laparotomy. Two had perirenal and retroperitoneal hematomas without active bleeding, and one had a bowel obstruction secondary to an intramural jejunal hematoma. There were no late complications related to the splenic or hepatic injuries. Eight children (22%) required surgery for other injuries. Twelve children were not transfused, including the majority (8/11) of those with isolated splenic or hepatic injury. The hematocrit of four of these children fell to below 28% and this anemia was well-tolerated. Two children with bleeding disorders (factor VIII [antihemophilic factor] and factor XII [Hageman factor] deficiency) did not require packed red blood cells transfusion. Two clinically distinct groups of children received blood transfusions: (1) eight patients with multiple injuries were transfused during initial resuscitation when unstable or during early operation for other system trauma (mean, 62.0 mL blood/kg body weight); and (2) three hemodynamically stable patients with isolated injuries and 14 stable patients with multiple injuries were transfused empirically after initial resuscitation solely because of decreasing blood counts. They received an average of 16.5 and 21.1 mL blood/kg body weight, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Accidental Falls↗
PubMed1986

Activation of coagulation during therapeutic whole body hyperthermia.

Coagulation parameters were initially monitored in 8 patients receiving whole body hyperthermia (WBH). Patients were heated by the warm water blanket technique to 41.8 degrees C (Tmax), maintained at this temperature for 2 hours, then allowed to cool. A fall in platelets was apparent by the time Tmax was achieved and continued during the 18 hours after WBH. Levels of beta-thromboglobulin (BTG) and platelet factor 4 rose by 56% and 191% by the end of treatment but returned to baseline 18 hours later. Fibrinogen, plasminogen and alpha 2-antiplasmin levels declined and FDP and fibrinopeptide A (FPA) levels increased during WBH. Factor XII and Factor VIII:C fell moderately during WBH while Factors VIII R:Ag, VIII:RC and V did not change or showed a late rise. Factor VII levels fell in 7 of 8 patients, reaching levels of 30% of normal in four. To better define the sequence of these coagulations perturbations, earlier and more frequent timepoints were studied in an additional 3 patients. This revealed that decreases in fibrinogen and plasminogen and increases in FPA and BTG occur very early (by the time the patient reaches 39 degrees C). On the other hand, a decrease in Factor VII activity was not apparent until patients had reached Tmax. WBH is therefore associated with a consumption coagulopathy. Possible mechanisms are discussed and extrapolations to the situation seen in heat stroke are suggested.

Adult↗
PubMed2002

Elevated levels of plasma prekallikrein, high molecular weight kininogen and factor XI in coronary heart disease.

Increased levels of hemostatic factors may play a role in the pathogenesis of myocardial infarction by triggering thrombin formation. We measured factor XII (FXII), factor XI (FXI), plasma prekallikrein (PK) and high-molecular-weight kininogen (HK) in 200 patients having survived myocardial infarction for at least 2 months, and in 100 healthy controls. We found significantly elevated levels of FXI clotting activity (FXI:C), HK:C and of the amidolytic activity of PK (PK:Am) among the patients as compared to the controls. Plasma levels of FXI:C, HK:C and PK:Am in the highest quartile were associated with an odds ratio of 1.9 (95% CI: 1.0-3.8), 2.0 (95% CI: 1.0-4.0) and 5.4 (95% CI: 2.6-11.2), respectively, compared to the respective plasma levels in the lowest quartile. After correction for established clinical and laboratory risk factors, the association between PK:Am plasma levels and myocardial infarction remained significant (P=0.0007). Combination of high PK:Am plasma levels and smoking or arterial hypertension, respectively, resulted in a more than additive relative risk for myocardial infarction.

Adult↗