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Hemostatic complications in young patients with essential thrombocythemia.

PURPOSE: The purpose of this study was to determine the incidence of hemostastic complications in young patients with essential thrombocythemia (ET). PATIENTS AND METHODS: The clinical course of 44 patients under the age of 45 with the diagnosis of ET was reviewed in a retrospective manner. Patients were collected from three medical centers in the United States and Italy: the Brigham and Women's Hospital and the Harvard Community Health Plan, Boston, Massachusetts, and the Ospedali Riuniti di Bergamo, Bergamo, Italy. RESULTS: The overall incidence of hemorrhage or thrombosis, or both, in this group of patients was 39% (17 of 44), with serious complications occurring in 23% (10 of 44). Two patients died of thrombotic events. Neither the presence of symptoms at diagnosis nor any single laboratory parameter proved predictive of clinical sequelae. Treatment with antiplatelet drugs or platelet-lowering agents was not protective. CONCLUSION: We conclude that ET in young patients may result in serious and life-threatening hemostatic problems and consequently that young age is not a favorable prognostic factor in this disease.

Adolescent↗

Mediastinal fibrin glue: hemostatic effect and tissue response in calves.

There is continued controversy regarding the effectiveness and potential adverse effects of fibrin glue. Thus, we chose to evaluate it in a model of experimental calf aortic valve replacement that has been previously well established. Concentrated fibrinogen and topical thrombin were sprayed to form a thin layer of fibrin glue over the mediastinal tissues of 20 consecutive calves undergoing aortic valve replacement. Chest tube outputs of these animals were compared with those of the preceding 20 consecutive calves undergoing aortic valve replacement without fibrin glue. All procedures were performed by the same surgeon, and no other technical changes were made between the two series. Total postoperative chest tube output (mean +/- standard error) was 553 +/- 50 mL for the calves treated with fibrin glue and 1,155 +/- 103 mL for the control calves (p less than 0.001). On histological examination of mediastinal tissues from 5 treated calves killed 6 weeks after operation, there was no evidence of inflammation, fibrosis, or residual fibrin. To our knowledge, this is the first controlled laboratory study to show that fibrin glue spray is an effective hemostatic agent and that it produces no long-term tissue reaction.

Animals↗

Preoperative hemostatic activity and excessive bleeding after cardiopulmonary bypass.

The rationale for predicting the risk of excessive postoperative bleeding by assessing the hemostatic status of a patient before cardiopulmonary bypass was investigated. A novel, rapid, overall test (hemostatometry) consisting of a physiologically relevant test of platelet function (shear-induced hemostasis) and coagulation was performed using nonanticoagulated blood and compared with the routine coagulation screen. Two hundred five patients undergoing elective coronary revascularization were studied 3 to 4 days before operation. Forty-nine bled excessively for nonsurgical reasons; none were predicted by the routine coagulation tests. Using a stepwise discriminant analysis, hemostatometry correctly predicted 31 of 49 (63%). Thirty of 156 predicted as bleeders by hemostatometry did not bleed. Thus, preoperative hemostatometry predicted 77% of the true outcome. The false predictions suggest, however, that certain bleeding abnormalities probably acquired during cardiopulmonary bypass cannot be predicted. These findings do not justify the routine use of preoperative tests in assessing the bleeding risk in patients undergoing cardiopulmonary bypass.

Blood Coagulation↗

Heparin-coated cardiopulmonary bypass circuits: hemostatic alterations and postoperative blood loss.

This prospective, randomized study involving patients undergoing isolated coronary artery bypass grafting investigated whether the use of heparin-coated bypass circuits with an uncoated cardiotomy reservoir (n = 10) compared with standard uncoated bypass circuits (n = 10) resulted in differences in patient outcome and hemostatic alterations. There were no differences in postoperative blood loss, transfusion requirements, and routine coagulation test results between groups. Immunoassays for platelet alpha-granule constituents platelet factor 4 and beta-thromboglobulin, thrombin generation by-product F1.2, fibrinopeptide A, thrombin-antithrombin complex, and fibrinolysis by-product D-dimer also demonstrated no significant differences between groups, although trends for lower platelet secretion with heparin coating were noted. Increases were found in beta-thromboglobulin and platelet factor 4 concentrations at 10 (p < 0.03) and 30 minutes (p < 0.001) of CPB, respectively, and continuing throughout CPB (p < 0.001) for both groups versus values measured before incision. No significant differences were seen between levels 5 minutes prior to aortic cross-clamp release and those obtained 8 and 45 minutes after cross-clamp release. Conversely, no significant increases in F1.2, thrombin-antithrombin complex, and D-dimer were seen prior to release of the aortic cross-clamp, but afterward increases occurred that were highly significant (p < 0.001). The temporal data suggest that platelet activation occurs primarily as a result of contact with the cardiopulmonary bypass circuitry, whereas thrombin generation and fibrinolytic activity are not significant until reperfusion of the heart and lungs.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

Effect of clofibrate on plasma proteins including components of the hemostatic mechanism.

The effect of clofibrate (1.5 g/day) on different plasma proteins and on components of the hemostatic system was studied in eight men with either mild diabetes mellitus or cardiosclerosis. Before treatment, the subjects were investigated weekly on five occasions. The means of these determinations were compared with the values observed after 2, 6 and 14 weeks of treatment. During the treatment albumin and transferrin increased significantly while orosomucoid, ceruloplasmin, beta1 E-globulin, IgA, IgM and fibrinogen decreased significantly. The decreases of the last proteins in per cent were found to be associated with each other in single subjects, i.e. a subject who reacted with a certain degree of change in one protein tended to react in a similar way with regard to the other proteins. A correlation was observed between the concentration before the treatment and the decrease in concentration during the treatment for ceruloplasmin, IgG, IgA, IgM and fibrinogen. The fibrinolytic activity increased significantly. Plasminogen decreased after 6 weeks and increased after 14 weeks of treatment. Platelet adhesiveness was not influenced.

Adult↗

The effect of a menhaden oil-containing diet on hemostatic and lipid parameters of nonhuman primates with atherosclerosis.

Three species of nonhuman primates were fed an atherogenic diet for 6 months (baseline period) and a menhaden oil (EPA)-containing diet for 8 weeks (test period) during which various hemostatic and lipid parameters were compared. The EPA-rich diet prolonged bleeding times, inhibited platelet aggregation response to ADP and collagen, and increased mean platelet lifespan. This diet elicited an increase in the polyunsaturated fatty acids C20:5 (EPA) and C22:6 (docosahexaenoic acid) at the expense of C18:2 (linoleic acid) and C20:4 (arachidonic acid) in pooled samples of platelet membranes, creating an increase in the ratio of n-3/n-6 polyunsaturated fatty acids. The serum lipid response to a menhaden oil diet comprised a nonsignificant decrease in total serum cholesterol and a significant decrease in HDL cholesterol.

Animals↗

Lipid-related hemostatic abnormalities in the elderly: imbalance between coagulation and fibrinolysis.

To clarify age-related and lipid-related hemostatic abnormalities in the elderly, we measured the plasma levels of active PAI-1 antigen (aPAI-1), tPA-PAI-1 complex (TPC), plasminogen, alpha 2-plasmin inhibitor (alpha 2-PI), plasmin-alpha 2-PI complex (PIC), and D-dimer, together with the plasma levels of fibrinogen, factor VII (F VII), and thrombin-antithrombin III complex (TAT) and the serum lipid levels in 68 hyperlipidemic and 82 normolipidemic elderly subjects. The aPAI-1 ratio was calculated as aPAI-1/(aPAI-1 + TPC). In the normolipidemic elderly subjects, plasma PIC and D-dimer levels were much higher when compared with healthy young controls, and there was also a decrease in plasma plasminogen and alpha 2-PI levels, an increase in plasma TPC levels, and high plasma F VII and fibrinogen levels. In elderly subjects with type IIb hyperlipidemia, both the plasma aPAI-1 level and the aPAI-1 ratio were significantly increased, while the plasma PIC and D-dimer levels were reduced despite higher plasma F VII, fibrinogen and TAT levels. Both serum total cholesterol and triglyceride levels were correlated positively with plasma F VII and TAT levels and with the TAT/PIC ratio, while only serum triglyceride levels showed a positive correlation with plasma TPC and aPAI-1 levels and with the aPAI-1 ratio. Thus, an increase of fibrinolytic activity appears to occur as part of normal aging to balance the increase of procoagulant activity. However, an imbalance between thrombin activity (increased procoagulant activity) and plasmin activity (hypofibrinolysis) appears to occur in elderly individuals with hyperlipidemia, perhaps resulting in a predisposition to thromboembolic disease.

Aged↗

Recent observations on the role of hemostatic determinants in the development of the atherothrombotic plaque.

Recent evidence suggests that hemostatic determinants play a major role in the evolution of the atherothrombotic plaque. Platelets can serve as cholesterol donors for macrophages, thereby facilitating foam cell formation. Lipoprotein(a) inhibits fibrinolysis and may also contribute to atherogenesis by serving as a ligand for the scavenger receptor. By complexing with fibrin(ogen) in atheromatous lesions, lipoprotein(a) attenuates clearance of this protein, promoting atherogenesis and vascular dysfunction. These observations suggest that thrombotic determinants are critical for the development of the atheromatous plaque, and may guide the appropriate selection of potential therapeutic options in the future.

Arteriosclerosis↗

The relationship of arterial compliance with endothelial-derived proteins of the hemostatic system.

Cardiovascular risk factors associated with hypertension include alterations in arterial compliance and an increased tendency to thrombosis. In this study we examined the relationship between arterial compliance and endothelial derived components of the hemostatic system: von Willebrand factor (vWF) and tissue plasminogen activator (t-PA). Ten males (4 normal and 6 untreated hypertensives, 41 +/- 12 years) were studied. Compliance of proximal (large vessel) and distal (small vessel) arteries was measured by intraarterial pulse wave analysis; left ventricular wall thickness by echocardiography; and vWF and t-PA by immunoassay of plasma obtained before and immediately after maximum treadmill exercise. Baseline t-PA and vWF correlated inversely with distal compliance (r = -0.74, p = 0.01; r = -0.56, p = 0.09). Exercise strengthened the relationship between vWF and both distal compliance (r = -0.56 to r = -0.86) and proximal compliance (r = -0.44 to r = -0.70). Moreover, post-exercise levels of vWF and t-PA were each significantly related to left ventricular posterior wall and septal thickness. Of note, these protein concentrations correlated more strongly with arterial compliance and left ventricular wall thickness than with blood pressure. Thus, arterial compliance and left ventricular wall thickness appear to be more powerful than blood pressure as predictors of the endothelial release of vWF and t-PA in response to exercise. These findings indicate that some of the key cardiac and arterial characteristics of hypertension might be linked to increased endothelial reactivity to hemodynamic stress.

Adult↗

Application of INSTAT hemostat in the control of gingival hemorrhage in the patient with thrombocytopenia. A case report.

Gingival bleeding in the patient with thrombocytopenia can be a difficult management problem. Primary therapy with platelet transfusions may not be sufficient to control the hemorrhage and adjunctive local therapy may be required. Currently, few local management techniques can effectively control this problem. INSTAT collagen absorbable hemostat can be used as a local adjunct with platelet transfusions and has certain application advantages over topical thrombin and microfibrillar collagen. Two successful techniques of INSTAT application to control gingival hemorrhage in a patient with severe thrombocytopenia in leukemic relapse are described.

Aged↗

Hemostatic effects of salsalate in normal subjects and patients with hemophilia A.

Salsalate in a non-acetylated salicylate with activity as an antirheumatic agent. The hemostatic effects of this agent were studied in twelve healthy subjects and nine patients with hemophilia A. Healthy subjects showed no change in bleeding time, platelet aggregation response to adenosine diphosphate (ADP) or collagen, or adenosine triphosphate (ATP) release in response to arachidonic acid as measured in an impedance whole blood lumi-aggregometer. The patients with hemophilia A showed no bleeding time prolongation nor an effect on ADP or collagen induced platelet aggregation in platelet rich plasma. It is concluded that this agent may be useful in the treatment of arthritis in patients with hereditary coagulation disorders.

Arthritis↗

Hemostatic effects of ephedrine.

The effects of ephedrine on coagulation and on fibrinolysis were studied in six healthy volunteers. Six volunteers, matched by age and sex, served as untreated controls. Ephedrine was found to significantly prolong mean bleeding time by 2 minutes. Ephedrine has been proposed to activate fibrinolysis, but we found no increased tPA activity. The platelet count, APTT, factor VIII and von Willebrand factor remained constant. In an in vitro study ephedrine was found to inhibit platelet aggregation induced by adrenaline and, to some extent, also by ADP. The inhibition was competitive and not mediated via beta 2 adrenoceptor stimulation. It is concluded that there are hemostatic effects of ephedrine and that these may be of clinical relevance, the drug being very commonly used in connection with procedures where blood loss as well as venous thromboembolism are considerable problems.

Adult↗

Recombinant soluble human thrombomodulin: a randomized, blinded assessment of prevention of venous thrombosis and effects on hemostatic parameters in a rat model.

UNLABELLED: Thrombomodulin is an endothelial surface receptor that binds thrombin and accelerates the activation of protein C. We compared the effects of a recombinant thrombomodulin analog (TME), recombinant hirudin (r-HIR), heparin sodium (HEP), and normal saline (Control) on thrombus formation, activated partial thromboplastin time (APTT), thrombin time (TT), platelet aggregation and tail transection bleeding time (BT) in a rat model of vena cava thrombosis. RESULTS: TME, r-HIR and HEP prevented venous thrombosis in this model in a dose-dependent manner. At the dose required to reduce vena cava thrombosis by 50% (ED50), TME did not prolong the APTT or TT as did HEP and r-HIR. Platelet aggregation in response to thrombin was not effected by TME but was inhibited by both r-HIR and HEP. BT did not differentiate the agents tested. CONCLUSION: TME inhibited venous thrombosis in a rat vena cava model with less effect on hemostatic variables than HEP or r-HIR.

Animals↗

Hemostatic studies in patients with carbohydrate-deficient glycoprotein syndrome.

The carbohydrate deficient glycoprotein (CDG) syndrome is a newly described disorder characterized by impaired glycosylated molecules. It has been reported that transient stroke-like episodes appear in half of the patients. We performed hemostatic studies on three CDG syndrome patients belonging to two unrelated families. The most characteristic findings were decreases in antithrombin III (AT III), protein C and alpha 2 plasmin inhibitor to nearly half normal levels. Protein S was reduced in two (siblings) patients. Isoelectric focusing of AT III in native plasma revealed decreased intensity of the major band and increased intensity of a minor cathodal band. These minor AT III molecules were considered to lack an oligosaccharide sidechain. A 12-year-old girl defective not only for AT III but also protein C and protein S developed disseminated intravascular coagulation accompanied by arterial thrombosis in her left hand following dyspnea associated with bronchial asthma. These findings suggest that thrombotic predisposition in patients with CDG syndrome is due to decreased levels of major coagulation inhibitors, particularly as a result of impaired glycosylation of AT III.

Adolescent↗

Do smoking and diabetes change the hemostatic parameters?--a study in the Chinese people.

Plasma plasminogen activator inhibitor-1 (PAI) antigen, fibrinogen, antithrombin III (ATIII), protein C, beta-thromboglobulin (BTG), platelet count, fibrinogen degradation product (FDP) D-dimer, factors VII and XII, as well as cholesterol, triglyceride (TG) and glucose were determined in 163 subjects. First we compared the difference of these parameters between 50 diabetics (Group D, mean age 64.9 years) and 50 age-matched healthy controls (Group C, mean age 63.1 years). Nineteen of the diabetics and 19 of the healthy controls were smokers. Plasma glucose, cholesterol, TG and protein C were significantly higher in Group D than in Group C (p = 0.0010, 0.0308, 0.0083 and 0.0068, respectively), whereas ATIII and factor XII were significantly lower in Group D (p = 0.0213 and 0.0061). Secondly, we divided 113 healthy controls (Group C, including Group C plus 63 subjects at various ages) into smokers (mean age 56.7 years) and non-smokers (mean age 40.0 years) and compared the difference between them. Fibrinogen and glucose were higher in the smokers than in the non-smokers (p = 0.0139 and 0.0402, respectively). Other parameters were not different. In conclusion, our study did not find any important hypercoagulation state in the diabetics. Smoking can only increase fibrinogen and glucose without the change of other hemostatic parameters.

Adult↗

The hemostatic profile of equine ovarian follicular fluid.

The coagulation factors VII and X and fibrinogen were detected in equine ovarian follicular fluid. The amounts of fibrinogen and factor X were approximately 40 percent of that found in normal equine plasma while the level of factor VII was lower, at approximately 14 percent. The addition of human recombinant tissue factor caused fibrin formation in the follicular fluid. The thrombin generating activity appears to be confined to the tissue factor pathway since no activity associated with factors VIII:C, IX or IX was detected. Fibrinolytic activity, at higher levels than that found in plasma, was detected in all follicular fluid samples. It is proposed that the hemostatic mechanism may be modulated in follicular fluid in a manner analogous to that in plasma since inhibitory proteins including AT-III and antiplasmin were present in the follicular fluid samples at relatively constant levels that approached those found in normal equine plasma.

Animals↗

A study of platelet functions, some hemostatic and fibrinolytic parameters in relation to serotonin in hemodialyzed patients under erythropoietin therapy.

Erythropoietin corrects anemia and improves hemostasis, but on the other hand bears a risk of thrombotic complications. Therefore in the present study an attempt has been made to evaluate bleeding time, platelet functions and some hemostatic and fibrinolytic parameters in relation to blood and platelet serotonin before and after 1, 2, 4, 8 and 12 weeks of treatment. 22 chronically hemodialyzed patients were administered with human recombinant erythropoietin (rHuEPO) in a dose of 2000 IU s.c. 3 times a week. Bleeding time was shortened significantly as early as after 1 week of the therapy, whereas hematocrit and hemoglobin increased after 2 weeks. These changes lasted throughout the study. Only a transient rise in platelet count, collagen-induced platelet aggregation, beta-thromboglobulin and VIII:C activity were observed during therapy relative to baseline values. ADP- and arachidonic acid-induced platelet aggregation seemed to be unaffected by rHuEPO treatment, whereas a gradual and progressive enhancement in platelet aggregation in response to ristocetin was found, starting from the 2nd week of the therapy. It lasted throughout the study and correlated inversely with the bleeding time and positively with a rise in both blood and platelet serotonin. rHuEPO did not alter plasminogen, fibrinogen, platelet factor 4, alpha 2 macroglobulin levels, protein C activity and euglobulin clot lysis time. A decline in protein C and S concentrations and antithrombin III activity observed during the therapy were counterbalanced by a fall in the activity of alpha 2 antiplasmin, C1 esterase inhibitor and plasminogen activator inhibitor. It is concluded that rHuEPO may improve platelet/vessel wall interactions possibly by means of serotonergic mechanisms. A lowered activity of inhibitors of fibrinolysis may be regarded as a protection against a general tendency to thrombosis during rHuEPO therapy.

Adenosine Diphosphate↗

Hemostatic abnormalities in inflammatory bowel disease.

Patients affected by inflammatory bowel disease (IBD) frequently suffer from thromboembolic events. Aims of this study were to investigate hemostatic system and the presence of antiphospholipid antibodies (aPL) in IBD patients. Forty-one patients affected by Crohn's disease (CD) and 19 by ulcerative colitis (UC) were studied, compared to 40 healthy control subjects. Platelet count (PLT), PT, aPTT, fibrinogen (Fib), prothrombin fragment F1+2, antithrombin (AT), protein C (PC), protein S (PS), factor XIII (FXIII), plasminogen (PLG), plasminogen activator inhibitor (PA1), spontaneous platelet aggregation in platelet-rich plasma (PRP-SPA) and in whole blood (WB-SPA), and antiphospholipid antibodies (aPL) were evaluated. PLT, Fib, F1+2 and WB-SPA were significantly increased in IBD patients (p at least <0.05) both in active and inactive phases; aPL positivity was more frequent (p<0.05) and FXIII was significantly decreased (p<0.05) in comparison to control subjects. The thrombophilic state of IBD patients is not related to the degree of activity of the disease or to previous thrombotic events; aPL express the immunological alterations connected with IBD and are not the main cause of thrombotic events.

Adolescent↗