Showing papers in "Seminars in Thrombosis and Hemostasis in 1990"

A critical reappraisal of the bleeding time.

Abstract: Since its initial invention by the French worker Milian in 1901, the bleeding time has been put forward as a clinically useful test in three contexts: diagnosis (particularly of platelet disorders), prediction of clinically important bleeding, and assessment of the adequacy of various forms of therapy. Attempting a complete review of the published experience with this test, we assessed 862 articles. Original bleeding time data appeared in 664 of these articles, from which we tabulated 1083 distinct studies in humans. ROC analysis, which characterizes the sensitivity and specificity of the test, was applied in every instance in which published data were adequate (34 studies). ROCs from 27 studies of the bleeding time in association with aspirin ingestion reveal high variability in the ability of the bleeding time to detect aspirin intake, and provide evidence against claims that recently devised bleeding time methods have improved discriminatory ability based on improved reproducibility. Two ROCs from surgical studies, in which the bleeding time was used to try to predict abnormal bleeding, were statistically indistinguishable from that of a completely noninformative test. In ROCs from five studies of abnormal bleeding in uremia, the test performed approximately the same as the platelet count or hematocrit (taken singly); in one of these studies, prothrombin consumption was determined and was a better predictor of bleeding than bleeding time, hematocrit, or platelet count. In the settings of renal biopsy (one study) and massive transfusion (one study), data allowed estimation of predictive value: in no instance was there evidence that the bleeding time significantly altered a priori estimates (based on prevalence) of the risk of bleeding. Linear regression analysis was applied to data from 23 studies relating platelet count to bleeding time, to assess published claims that the bleeding time and platelet count follow a predictively useful linear relationship. In 22 of 23 instances, the inverse relationship between bleeding time and platelet count was associated with broad statistical scatter, making it impossible to predict precisely one variable given the other. The pathophysiology of an abnormal bleeding time remains poorly understood. The bleeding time is affected by a large number of diseases, drugs, physiologic factors, test conditions, and therapeutic actions, not all of them platelet-related. The test is likely to remain widely used for the diagnosis of inherited disorders of platelet function, such as von Willebrand's syndrome, despite the lack of clear criteria for its use in this context.(ABSTRACT TRUNCATED AT 400 WORDS)

Neonatal purpura fulminans due to homozygous protein C or protein S deficiencies

Abstract: Homozygous protein C deficiency or homozygous protein S deficiency are rare genetic diseases with catastrophic and fatal purpura fulminans-like or thrombotic complications occurring during the neonatal period. These diseases can now be successfully treated. Purpura fulminans is at least in part a cutaneous manifestation of the syndrome of systemic DIC. It is characterized by microvascular thrombosis in the dermis followed by perivascular hemorrhage, necrosis, and minimal inflammation. Laboratory findings are consistent with DIC. Although the pathogenesis is not fully understood, the DIC in purpura fulminans appears to involve the skin selectively. The development of purpura fulminans from homozygous protein C or protein S deficiencies can be separated into the two distinct phases. The first phase is the time period when the initial reversible lesions develop and grow. This reversible progression can be halted and reversed with the administration of protein C or protein S. The second phase is the irreversible stage in which the lesion continues to develop into a necrotic lesion, whether or not treated with protein C. This irreversible lesion will ultimately develop into a large full-thickness necrotic injury of the skin. It is very similar to the lesions seen in idiopathic purpura fulminans, warfarin-induced skin necrosis, and acute infectious purpura fulminans. Unfortunately, our current understanding of the mechanism or mechanisms of the induction and propagation of the purpura fulminans-like lesions in homozygous protein C or protein S deficiencies is minimal, since it has never been studied. We can only speculate on the mechanism based on laboratory data and comparison with the little that is known about the other similar types of lesions.

The fibrinolytic enzyme system and its role in the etiology of thromboembolic disease.

Abstract: In this communication the current knowledge of the regulation of fibrinolysis and its role in the pathophysiology of thrombosis (venous or arterial) is reviewed. In addition, possible connections between fibrinolysis and established clinical and metabolic risk factors for coronary heart disease (CHD) are discussed

A double-blind and randomized placebo-controlled trial of low molecular weight heparin once daily to prevent deep-vein thrombosis in acute ischemic stroke.

Abstract: The effect of LMW heparin (Kabi 2165, Fragmin) was compared with placebo for the prevention of DVT in 103 patients with acute ischemic stroke using a prospective, double-blind, randomized trial design Treatment was started within 72 hours, and LMW heparin was administered subcutaneously once daily according to body weight classes, which corresponded to about 55 to 65 Factor-Xa inhibitory U/kg, for 14 days, or until discharge from the hospital, if earlier All patients underwent thrombosis surveillance with unilateral venography of the paretic limb Evaluation of venography could be performed in 42 of 52 patients randomized to LMW heparin and in 50 of 51 patients randomized to placebo The frequency of DVT was 15 of 42 patients or 36% (95% confidence interval 22 to 52%) in the LMW heparin group and 17 of 50 patients or 34% (21 to 49%) in the placebo group The frequency of proximal thrombi was 5 of 42 (12%) and 8 of 50 (16%), respectively There was one fatal pulmonary embolism in the placebo group The mortality rate (28 days follow-up) was 5 of 52 in the LMW heparin group and 1 of 51 in the placebo group (p = 024) None of the deaths was related to treatment No major hemorrhagic complications were observed The mean Factor Xa inhibitory activity levels at peak concentration were 034 U/ml on day 2 and 042 U/ml on day 12 (p = 002) We conclude that LMW heparin in the dose range studied did not provide efficient prophylaxis against DVT in patients with acute ischemic stroke

Pharmacology of low molecular weight heparins.

Abstract: The investigations on LMW heparins that are reviewed in this article demonstrate that there is no relationship between the specific anti-Factor Xa activity and the release of HTGL activity after intravenous or subcutaneous administration to man. The measurement of anti-Factor Xa-like activity in patients treated with unfractionated or with LMW heparin was validated in whole blood samples obtained from the fingertip using Heptest reagents. Administration of high doses of LMW heparin twice daily resulted in a small but significant accumulation in healthy persons. The half-life of anti-Factor Xa-like activity increased after repeated administration, indicating that glycosaminoglycans or other compounds are released by LMW heparin into the bloodstream. The studies indicated that the improved pharmacologic properties may induce fewer side effects than unfractionated heparin and that patients with contraindications to unfractionated heparin or oral anticoagulants may be given long-term treatment with LMW heparin.

Dermatopathology of skin necrosis associated with purpura fulminans.

Abstract: Dermal vascular skin necrosis is associated with a complex group of clinical disorders. Many of these disorders are associated with an underlying abnormality of the PC anticoagulant system or DIC, or both. The clinical appearance and histopathologic features of dermal vascular skin necrosis are similar regardless of the etiology. Acute infectious purpura fulminans is distinct in that an acute vasculitis may be present in addition to microvascular thrombosis. Skin biopsy is a valuable diagnostic tool in the early recognition of these clinical disorders, since skin involvement is frequently an early manifestation of the disease process. Prompt recognition and institution of appropriate therapy at the reversible stages of dermal vascular thrombosis will, it is hoped, reduce the morbidity and mortality currently associated with skin necrosis and purpura fulminans.

Acquired purpura fulminans.

Abstract: It is the purpose of this review to discuss the pathogenesis, clinical features, and treatment of acquired purpura fulminans, within the context of recent advances in our understanding of the regulation of coagulation, the physiology of vascular endothelial cells, and the host response to immunologic challenge

Proposed classification and pathologic mechanisms of purpura fulminans and skin necrosis.

Abstract: The syndromes of purpuric lesions associated with a thrombotic mechanism are very rare in the general population. Dermal vascular thrombosis, however, can be devastating and associated with significant morbidity and mortality. These syndromes share common features in their clinical course, pathogenesis, and histology. Although these syndromes can be initiated by either the hemostatic or inflammatory pathways, both pathways center around perturbations of the endothelial cell, which promote thrombosis. If animal models or better testing can be developed, enhanced appreciation of mechanisms underlying purpura fulminans may be deduced. Characterization of the pathophysiology may then allow directed treatment modalities that could limit the course of these syndromes and reduce morbidity and mortality.

Fibrinolysis and cancer.

Abstract: Although Trousseau 1 was the earliest observer who noted the association between cancer and thrombosis, it was Billroth 2 who first described the presence of tumor cells within a thrombus 2 . He believed that this was a means by which tumors metastasize

Warfarin-induced skin necrosis.

Abstract: Warfarin-induced skin necrosis is a rare but serious complication of oral anticoagulant therapy. This review will discuss the clinical presentation, natural history, incidence, and possible etiologies of this condition as well as the limited therapeutic options available to the clinician

Thromboprophylactic effect of low molecular weight heparin started in the evening before elective general abdominal surgery: a comparison with low-dose heparin.

Abstract: A prospective randomized double-blind trial was performed comparing conventional low-dose heparin with a LMWH fragment (Kabi 2165, Fragmin) for thromboprophylaxis in elective general abdominal surgical patients. The first dose of the fragment was given in the evening before surgery, and thereafter every evening. There were 1002 analyzable patients, 826 having received correct prophylaxis. Sixty three percent of the patients were operated on for malignant diseases. The frequency of DVT was significantly reduced among patients with correct prophylaxis with the heparin fragment (9.2 to 5.0%, p = 0.02). In patients with malignancies the reduction was from 11.2 to 6.4% (p = 0.06). The frequency of bleeding was 6.7% among the heparin fragment patients and 2.7% among the patients given conventional heparin (p = 0.01). The corresponding frequencies for patients with malignancies were 3.2 and 2.8%, respectively (p = 0.28). All bleedings were minor and of no clinical significance. Local pain at the injection site was reported significantly less often among patients with the fragment. Twenty patients died, 13 with malignant disease, mortality being the same in the two groups. It is concluded that heparin fragment administered in the evening before surgery and then every evening is a practically acceptable alternative to prevent postoperative DVT in patients undergoing elective abdominal surgery, also when the histology shows malignancy. Thus, the advantages of using LMWH compared with conventional low-dose heparin are simplified administration routines, better thromboprophylactic effect, and less local pain at injection sites. A disadvantage is the slight increase in hemorrhagic side effects, all of minor clinical importance and not seen in patients undergoing surgery for malignancy.

Laboratory diagnosis of antithrombin and heparin cofactor II deficiency.

Abstract: Antithrombin activity should probably be determined in persons with early onset of recurrent thrombosis, especially if a family history is present The initial screening test should be a heparin cofactor assay optimized to reduce the contribution of heparin cofactor II If the heparin cofactor assay is low, an antigenic determination should be performed to rule out the possibility of an antithrombin variant At the present time, there is insufficient evidence to recommend the routine determination of heparin cofactor II levels in patients with thrombosis

Evolutionary assembly of blood coagulation proteins.

Abstract: The appearance of multicellular organisms was a revolutionary event that called for a multitude of novel proteins to ensure the communication among different cells, organs, and tissues. Of the proteins unique to multicellular organisms, the proteins of the blood coagulation, fibrinolytic, and complement cascades provided the first clear examples of this evolutionary stragegy. Analysis of the evolutionary history of these proteins has shown that the assembly process was facilitated by some unique features of the genes encoding the modules. The present review summarizes the most recent results of the analysis of the evolutionary history of the proteins of the blood coagulation, fibrinolytic, and complement systems

Laboratory diagnosis of protein C deficiency.

Abstract: No assays presently available test all aspects of protein C function. Overall, the potential for misdiagnosis is high

Laboratory diagnosis of lupus anticoagulants.

Abstract: Laboratories are now receiving requests to evaluate patients for the presence of LA. This review will focus on the characterization, clinical associations, and laboratory diagnosis of LA

Changes in the fibrinolytic system during pregnancy

Abstract: The physiologic changes in the fibrinolytic system during pregnancy establish a vulnerable state for disordered fibrin deposition both in the uteroplacental circulation and outside the uterus. Abnormal fibrin deposition is seen in pregnancies complicated by fetal growth retardation with and without preeclampsia

Pathologic fibrinolysis as a cause of clinical bleeding.

Abstract: Pathologic fibrinolysis as a cause of bleeding is much better understood as a result of the application of new and improved assays for components of the fibrinolytic system. In somes instances, improved therapy has resulted, but treatment of the underlying predisposing process often remains the primary objective

Hypercoagulability : introduction and perspective

Abstract: Although it may be impossible to distinguish reliably between normo- and hypercoagulable individuals on the basis of results from single assays of so-called baseline or resting levels of proteins or activities in blood, it might be feasible to do so by measuring the increases in the levels or activities in response to some kind of vascular stress, such as stasis or adequately reproducible vascular injury

Lipolytic effects of heparin and low molecular weight heparin and their importance in hemodialysis.

Abstract: The incidence and the degree of uremic hypertriglyceridemia in a hemodialysis population are exacerbated by the use of UF heparin as anticoagulant therapy. This hypertriglyceridemia is associated with an increase in the levels of triglyceride-rich remnant particles that are thought to be particularly atherogenic. Since arteriosclerosis and its related diseases are the major causes of morbidity and mortality in this dialysis population, the LMW heparins with their reduced stimulation of plasma lipolytic activity may provide a clinically superior alternative to UF heparin for anticoagulation therapy in long-term hemodialysis. One may also speculate that it may be more advantageous to use LMW heparin for all long-term treatments with heparin.

Clinical application of Fragmin (FR-860) in hemodialysis: multicenter cooperative study in Japan.

Abstract: A multicenter cooperative study was designed to evaluate the efficacy and safety of Fragmin (FR-860) as an anticoagulant in hemodialysis. Sixty-one stable maintenance hemodialysis patients were enrolled from 14 institutions in Japan. The study period was fixed at 2 weeks. Dosage requirements were 15.0 to 20.0 anti-Xa U/kg as bolus and 7.5 to 10.0 anti-Xa U/kg/hr as continuous infusion. The total dosage of Fragmin was 2505 +/- 127 anti-Xa U compared with 6124 +/- 190 U of conventional heparin. No differences were observed in residual blood in extracorporeal circuits between the groups. The hemostasis times at puncture sites after completion of dialysis were significantly shortened in the Fragmin group (7.9 +/- 0.7 minutes) when compared with the conventional heparin group (11.4 +/- 1.1 minutes; p less than 0.01). Plasma anti-Xa levels were 0.24 +/- 0.03 and 0.36 +/- 0.04 U/ml 1 hour after the initiation and at the completion of dialysis, respectively. ACTs, measured by the Hemochron method, were not prolonged during dialysis. APTTs varied from 34.3 +/- 1.2 before dialysis to 41.0 +/- 1.9 (p less than 0.01) 1 hour after the start of dialysis and 39.9 +/- 1.6 seconds (p less than 0.01) at the end of dialysis. Plasma AT III activity increased from 96.8 +/- 2.5% before dialysis to 113.0 +/- 3.2% (p less than 0.01) at the end of dialysis. No significant changes were observed in both ADP- and collagen-induced platelet aggregation during dialysis. Dialysis efficiency was the same for both groups. Slight itching developed in one of 61 cases. No abnormal laboratory data were observed during the study. The efficacy, safety, and utility rates were 98.4, 98.5, and 98.4%, respectively. Fragmin proved to have a higher utility rate and was a good and convenient alternative to conventional heparin as an anticoagulant in hemodialysis treatment.

Treatment of disseminated intravascular coagulation with low molecular weight heparin. Research Group of FR-860 on DIC in Japan.

Abstract: A multicenter cooperative study was carried out involving 47 nationwide institutions in Japan to assess the efficacy and safety of LMWH (FR-860) in DIC. Fifty-six cases were challenged by FR-860 injection principally for 5 days at doses of 75 U/kg/day in group I (n = 27) and 150 U/kg/day in group II, (n = 29). Scoring points were defined based on the severity of bleeding symptoms, organ failures, and abnormal coagulation-fibrinolytic tests. Therapeutic effects of FR-860 were evaluated objectively according to degrees of improvement of these scores. Six patients (10.7%) died of their underlying diseases or complications other than DIC. Hemorrhagic side effects occurred in 1 and 3 cases of groups I and II, respectively. Bleeding symptoms improved excellently or moderately in 45.5 and 31.6% of the cases in groups I and II, respectively. Concerning organ failures and coagulation-fibrinolytic tests, remarkable improvement was observed in 31.6 and 66.7% of the cases of the group I, whereas they remained 14.3% and 51.7% in group II. The overall usefulness of FR-860 was 66.7% in group I and 58.6% in group II. These results demonstrate that FR-860 is effective in DIC at a dose of 75 U/kg/day.

Clinical effects and basic studies of thrombolytic therapy on cerebral thrombosis.

Abstract: In this study, we will first report results from a clinical trial of a double-blind study using urokinase (UK, ZP-201) and then compare the results with the effect of a plasminogen activator (t-PA, AK-124) in fresh cerebral infarction. 7.14.15

Enhancing effect by heparin on shear-induced platelet aggregation.

Abstract: We have recently developed a new device for continuously measuring SIPA. Using the device, we have investigated the effects of heparin on SIPA. Heparin itself enhanced SIPA in the absence of agonists in a dose-dependent manner, whereas heparinoids had minimal effects on SIPA. LMW heparin had less enhancing effect on SIPA than unfractionated heparin. Effects of heparin were also investigated using PRP from patients with congenital bleeding disorders, including Bernard-Soulier syndrome, type III von Willebrand's disease, afibrinogenemia and Glanzmann's thrombasthenia. Heparin's effects were observed only when PRP from patients with Bernard-Soulier syndrome and type III von Willebrand's disease was exposed to low shear stress and when PRP from a patient with afibrinogenemia was exposed to high shear stress. These results gave us insights into heparin's effects on platelet aggregation.

Classification of abnormal plasminogens: dysplasminogenemias.

Abstract: An attempt will be made in this article to classify known abnormal Plgs based only on studies of the isolated highly purified proteins

Mechanism of acute gastrointestinal mucosal damage in endotoxic shock and the effect of Fragmin.

Abstract: 1. PAF and LTs may be mediators of the acute gastrointestinal mucosal damage due to endotoxic shock. 2. LTs may be mediators of the acute gastrointestinal mucosal damage due to PAF administration. 3. LMW heparin and unfractionated heparin prevented the increase of LTs due to endotoxin and PAF administration.

Effect of low molecular weight heparin preparations on the inhibition of thrombin by heparin cofactor II.

Abstract: 1. Heparin molecules approximately 24 to 30 residues in length are required to catalyze the thrombin-HC II reaction. The requirement for heparin molecules of this length is consistent with a model for catalysis in which heparin binds HC II and thrombin simultaneously to form a ternary complex in a manner similar to that proposed for the thrombin-AT III reaction. Smaller molecules (18 or more monosaccharide units in length) are required to catalyze the thrombin-AT III reaction. 2. The specific AT III-binding pentasaccharide containing 3-O-sulfated glucosamine is not required for activity with HC II. 3. Some low molecular weight heparin preparations have significant activity with HC II (approximately 10 to 20% that of standard heparin). This is probably related to the presence of species with molecular weights greater than 6000 to 7500 (24 to 30 monosaccharide units) in these preparations.

Laboratory diagnosis of impairment of fibrinolysis in patients with thromboembolic disease.

Abstract: In the following the principle and potential usefulness of the principal fibrinolytic tests is described (reviewed by Davidson and Walker)

Comparative studies of heparin cofactor activity toward antithrombin III and heparin cofactor II, and antithrombin III affinity between low molecular weight heparin and unfractionated heparin.

Abstract: The accelerating effects of an UF heparin (Novo) and two LMW heparins (Fragmin and PK 10169) on AT III and HC II were investigated in a purified system. The effects of these heparins on APTTs were examined using human plasma. Fractionation of these heparins by affinity column chromatography yielded the following results: UF heparin was separated into two distinct fractions, LA and HA for AT III. Both LMW heparins were separated into three fractions: NA, LA, and HA for AT III. The accelerating effects of these fractions on both antithrombin and anti-Factor Xa activity of AT III were dependent on the strength of their affinity to AT III. The accelerating effects of these fractions on the antithrombin activity of HC II was independent of the strength of their affinity for AT III. LA had a much stronger anticoagulant activity of HC II toward thrombin than did HA. It is concluded that LA for AT III is necessary to show HC II activity.