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[A clinical study on hemostatic fluctuation during and after cardiopulmonary bypass using hemostatic molecular markers].

Heparin is indispensable anticoagulant for cardiopulmonary bypass, but the dose of heparin is even now under discussion. In this study, hemostatic fluctuation was analyzed during and after the bypass using hemostatic molecular markers. The subjects were 16 adult cases of open heart surgery, 12 males, 4 females. The average age was 55.0 year. Operations were aortocoronary bypass in 12, valvular surgery in 3 and ASD patch closure in one with moderate hypothermic cardiopulmonary bypass. At the beginning of cardiopulmonary bypass, 3 mg/kg heparin was administered and the equivalent amount of protamine sulfate was used for neutralization at the end of the bypass. Platelet count, hematocrit, antithrombin III (ATIII), beta-thromboglobulin, platelet factor 4, fibrinopeptide A, thrombin antithrombin III complex, FDP, D dimer FDP, plasmin alpha 2 plasmin inhibitor complex, tissue plasminogen activator (t-PA), and thrombomodulin (TM) were measured through the operation up to two weeks after surgery. ATIII decreased to 50% of control value all through the bypass. Platelet markers increased immediately, and the activated state continued 3 hours after the bypass. Coagulation markers increased markedly after the aortic declamping, and reached at its peak by three times as control value, immediately after the protamine neutralization and continued for 3 hours. During the bypass, fibrinogenolysis caused by t-PA which was stimulated by non-physiological circulation and stimulating substances, was observed. Fibrinolysis occurred following the hypercoagulability after the neutralization. TM was within normal range before the aortic declamping. But increased gradually after the declamp, and reached twice as much as the base line. It could be concluded that hypercoagulability and high platelet activation might play a role of perioperative thrombosis. Hypercoagulability and increase of serum TM would be related to reperfusion of the lung. The increasing of TM would reflect broad injury of vessel walls after the bypass, because plasma TM increased following the generalized injury of endothelial cells.

Adult

Hemostatic studies in racing standardbred horses with exercise-induced pulmonary hemorrhage. Hemostatic parameters at rest and after moderate exercise.

The purpose of this study was to determine whether a defect in hemostasis might be a factor in the etiology of exercise-induced pulmonary hemorrhage (EIPH). Hemostatic parameters were evaluated in 22 EIPH-positive and ten EIPH-negative racing horses while in a rested state. Nineteen EIPH-positive and ten EIPH-negative horses were further evaluated just before and immediately after a 15 min exercise period on a 260 m oval track. When EIPH-positive and EIPH-negative horses were compared at rest, there was no significant difference in any of the coagulation and fibrinolytic parameters studied. There was however, a significant difference in platelet function as assessed by aggregometry. The platelets from affected horses were significantly less responsive than those from nonaffected horses when exposed in vitro to the platelet agonists adenosine diphosphate, collagen and platelet activating factor. Exercise tended to increase the packed cell volume and factor VIII/von Willebrand factor and to decrease platelet aggregation responses to low concentrations of adenosine diphosphate. These effects of exercise however were quantitatively similar in both EIPH-positive and EIPH-negative horses. Reduced platelet function may therefore be a contributing factor in the bleeding characteristic of horses with EIPH.

Adenosine Diphosphate

Preoperative hemostatic assessment of the adenotonsillectomy patient.

Intraoperative or postoperative hemorrhage in the patient who has undergone an adenotonsillectomy because of an unrecognized hemostatic defect may increase morbidity and can be potentially life-threatening to the patient in what should be a "routine" procedure. Preoperative identification of occult hemostatic abnormalities, coupled with perioperative management directed at correcting the effects of the defects, should serve to reduce the incidence of this distressful complication. Routine use of preoperative laboratory screening tests for this purpose has been discouraged recently as a result of concerns over cost-effectiveness and the low predictiveness of the tests for bleeding. Our experience with the routine use of a comprehensive hemostatic laboratory screening panel--which includes a bleeding time test--in the adenotonsillectomy patient population demonstrated that 11.5% of our patients had abnormal initial screening laboratory tests; these results were ultimately attributable to occult hemostatic defects. Clinical history, the universally recommended method of preoperative hemostatic assessment, failed to detect any previously unrecognized coagulation disorder. Laboratory screening improved preoperative detection of occult hemostatic defects and allowed for appropriate alterations in perioperative care. Our results with this approach are presented, along with illustrative case histories and a discussion of the current recommendations for preoperative laboratory screening of the hemostatic system, as found in a review of the literature.

Adenoidectomy

Maturation of the hemostatic system during childhood.

The hemostatic system is assumed to be similar in children and adults and reference ranges established for adults are commonly used to evaluate children suspected of having congenital or acquired hemostatic problems. However, we know that the hemostatic system is not fully mature by 6 months of age and comprehensive studies of healthy older children have not been published. Therefore, we conducted a prospective cohort study of the hemostatic system in healthy children having minor, elective day surgery. After obtaining informed consent, a 3-mL blood sample was obtained at the time routine preoperative blood work was drawn. The plasma was fractioned and stored at -70 degrees C for batch assaying. We measured the concentration of 33 components of the hemostatic system (functional and immunologic assays) and the bleeding time (automated pediatric device) in 246 children aged 1 to 16 inclusive (a minimum of four subjects at each age). Eleven components of hemostasis (fibrinogen, prekallikrein, high-molecular weight kininogen, factors VIII and XIII, antithrombin III [ATIII], heparin cofactor II [HCII], alpha 1-antitrypsin [alpha 1AT], protein S, plasminogen, alpha 2-antiplasmin [alpha 2AP]) had mean values and ranges of normal that were similar to adults. Mean values of seven coagulants (II, V, VII, IX, X, XI, XII) were significantly lower than adult values and varied with age. Values for three inhibitors, alpha 2-macroglobulin (alpha 2M), protein C, and protein C1-inhibitor (C1-Inh) also differed from adults. Alpha 2M and C1-Inh inhibitor levels were elevated throughout childhood, whereas protein C levels were low, with a lower limit of normal of 0.40 U/mL until the age of 11. Finally, the upper limit of normal for the bleeding time was longer in children during the first 10 years of life, but decreased to adult values in the teenage years. In summary, there are important physiologic differences in the hemostatic system in children compared with adults. The decreased levels of several critical coagulants and increased levels of alpha 2M may contribute in part to the lower risk of thrombotic events in childhood. Age-matched controls should be used for evaluation of the hemostatic system in children with suspected congenital or acquired defects.

Adolescent

Biocompatibility and bioabsorption of microfibrillar collagen hemostat in experimental animals.

The effects of Microfibrillar Collagen Hemostat (MCH) and Gelfoam after surgical implantation into incision sites of the liver, kidney, and brain were studied in beagle dogs, rabbits, and beagle dogs, respectively. The results of these experimental animal studies suggest that MCH is comparable to Gelfoam with respect to biocompatibility, rate of bioassimilation, and a lack for adverse systemic effects. The brain, liver, and kidney tissues responded comparably to MCH and Gelfoam with a mild to moderate infiltration of macrophages and mononuclear cells. Most of the hemostatic compound had disappeared from the incision sites by Day 28 and completely disappeared by Day 84. The tissue degree response was interpreted as a factor in the process of bioassimilation of the two hemostatic materials. Both hemostatic compounds contributed to adhesion formation in the experimental models. The incidence of adhesions was somewhat lower for MCH than for Gelfoam, but both produced more adhesions than were found at the control sites. The adhesions were only to the adjacent structures and always localized to the surgical site. When MCH or Gelfoam is used under conditions similar to those in the present experimental study, where tissue approximation is impaired, and where growth of granulation tissue is stimulated by the physical presence of the hemostatic compound, there is the possibility for increased incidence of adhesion formation. However, when an intraperitoneal absorbable hemostatic compound is desired, the present studies in experimental animals suggest that MCH will be safe by exhibiting minimal tissue reaction.

Absorption

Development of the hemostatic system in the neonate and young infant.

Our understanding of the coagulation and fibrinolytic systems (the hemostatic system) in the adult has progressed rapidly in recent years. However, a more complete understanding of the physiology of the hemostatic system in the neonate has lagged behind that of the adult for many reasons. First, the hemostatic system in the newborn exists in a dynamic state and is rapidly evolving toward the adult system. This situation necessitates the generation of not one, but several, reference ranges (or ranges of normal values) in the postnatal period for the various tests and components of the hemostatic system. Also, microtechniques must be used to perform the required assays, both because of the small size of blood samples available and because of the difficulty of obtaining blood from infants. Recently, many of these problems have been resolved, which resulted in a better appreciation of the development of the hemostatic system in the infant. This article reviews our current understanding of the protein components of the coagulation and fibrinolytic systems in the neonate. Reference ranges for normal values of the various tests and components of the hemostatic system have been provided for the premature and full-term infant at birth and during the first 6 months of life.

Aging

Immunofluorescent localization of factor VIII-related antigen, fibrinogen, and several other plasma proteins in hemostatic plugs in humans.

Factor VIII-related antigen and its low ionic strength subunits were demonstrated in endothelium and hemostatic plugs obtained from punch biopsies of bleeding time wounds according to Mielke. No IgG, IgA, IgM, C4-C3, albumin, or prothrombin was demonstrated in the cryostat sections of hemostatic plugs. Antifibrinogen stained the hemostatic plug and fibrin fibers along the edges of the skin wound. Antiplatelet actomyosin stained the hemostatic plug and the endothelium and pericytes of blood vessels. These results suggest that factor VIII is present in the hemostatic plug not by trapping of plasma but by close association with or presence within the blood platelets. The positive staining of a hemostatic plug in which most platelets have undergone the release reaction indicates that antifactor VIII may be useful for the detection of platelet thrombi in tissue of patients with suspected diffuse intravascular coagulation.

Albumins

Prognostic value of hemostatic parameters after liver transplantation.

The prognostic value of hemostatic parameters after orthotopic liver transplantation was evaluated in 37 consecutive patients. Six simple hemostatic parameters (prothrombin time, activated partial thromboplastin time, thrombin time, thrombin coagulase time, plasma fibrinogen and platelet count) were obtained for each patient pre-transplantation and daily post-transplantation for at least 8 days. Using the results of these tests, the degree of hemostatic impairment was arbitrarily scored from 0 to 6. Starting from the first day post-transplantation, hemostatic parameters improved progressively, reaching plateau values on day 7 post-transplantation. On day 8 there were significant differences in the activated partial thromboplastin time, prothrombin time, and in the overall hemostatic scores between patients who survived at least 6 months and those who died. Comparing these hemostasis parameters with such liver function tests as AST, ALT and serum bilirubin, univariate analysis showed that activated partial thromboplastin time, coagulation score and AST were significant predictors of 6-month survival, but by multivariate analysis (Cox proportional hazard rate model) only the activated partial thromboplastin time was an independent predictor. Hence, a simple coagulation test is useful for predicting the survival of patients undergoing liver transplantation.

Adolescent

Global and molecular hemostatic markers in acute myeloid leukemia.

Patients with acute myeloid leukemia have multiple hemostatic and thrombotic complications, which may or may not result from disseminated intravascular coagulation. Previous studies incorporating routine coagulation analyses failed to detect any clinically useful information in most of these patients. In this study, the first comprehensive evaluation of the various aspects of the hemostatic system in a population of patients with acute myeloid leukemia was performed. Eighteen patients (23-71 years of age) were studied at either diagnosis or relapse. Hemostatic studies were performed at onset and on days 3, 7, and 30 after initiation of therapy. The bone marrow blast counts ranged from 8% to 98%; prothrombin time and activated partial thromboplastin time showed only minor prolongations in a few of these patients. However, in all patients measurement of platelet-associated markers revealed elevated platelet factor 4 and thromboxane B2 and normal 6-keto-prostaglandin F1 alpha levels. Fibrinolytic markers showed an increase in D-dimer and tissue plasminogen activator and a decrease in alpha 2-antiplasmin levels. Plasminogen, plasminogen activator inhibitor, and fibrinogen levels were normal. Coagulation markers demonstrated a decrease in protein C and antithrombin III levels and an elevation of the thrombin-antithrombin complex. The pretreatment values for all hemostatic markers studied were similar to the values obtained on days 3, 7, and 30 during treatment. This investigation demonstrated a subclinical activation of the components of the hemostatic system possibly leading to a hypercoagulable state. Although only six patients (33%) experienced hemorrhagic complications, the risk of bleeding and/or thrombosis was strongly evident in all patients. The significance of finding abnormal levels of specific molecular markers of hemostasis will be established in the future application of such markers in clinical evaluations of leukemic patients known to be at risk for coagulation disorders.

Acute Disease

Intraocular hemorrhages: a hemostatic therapeutic approach.

Our knowledge of the local hemostatic factors capable of playing a role in certain intraocular hemorrhages is reviewed as a background to therapy with agents active in hemostasis. Common to hyphemas and subretinal hemorrhages are some conditions which are apt to disturb hemostasis and result in recurrent bleeding. They are: 1) Dilution of blood by aqueous humor or subretinal exudative fluid followed by the formation of hemostatic plugs which are prone to spontaneous lysis; 2) Contiguity of certain structures, such as the iris and the choroid, which are extremely rich in fibrinolytic activators favoring premature dissolution of the hemostatic plug and thereby recurrent bleeding; and 3) Presumptive high local concentration of fibrin degradation products (FDP), which have an anticoagulant action and would counteract hemostasis in the event of rebleeding. Based on these observations, the use of fibrinolytic inhibitors for the treatment of hyphema and subretinal hemorrhages seems warranted. Hemostatic mechanisms in intraocular hemorrhages and their treatment with various agents are discussed.

Antifibrinolytic Agents

Prospective evaluation of hemostatic techniques for liver injuries.

The methods of hemostasis used for liver injuries were evaluated prospectively in 637 patients treated at Detroit General Hospital during a 5-year period. Variables evaluated included severity of injury, presence or absence of bleeding, and methods of hemostasis, The liver injury was either not bleeding or was controlled by temporary pack compression during laparotomy in 325 patients: none of these patients, including the 284 in whom no hemostatic procedure was used, rebled postoperatively. Active bleeding at laparotomy was directly related to the severity of liver injury, and required some hemostatic procedure in 312 patients. The methods of hemostasis were liver sutures (244 patients), nonanatomic resection (30 patients), anatomic resection (21 patients), hepatic artery ligation (nine patients), hepatotomy with intraparenchymal vascular control (five patients), and temporary internal pack with later re-operation (three patients). Rebleeding occurred in eight of the 243 patients who survived (seven after liver sutures and one after nonanatomic resection) and four required re-operation for control of bleeding. Sixty-nine patients with active bleeding died. Death on the table in 38 patients was related primarily to uncontrolled bleeding from liver and major vessel injury. Postoperative rebleeding from the liver occurred in 14 of 31 patients who died after surgery: following initial control by liver sutures (seven patients); anatomic resection (four patients); and hepatic artery ligation (three patients). There was no apparent relationship between any hemostatic procedure and the subsequent appearance of the hepatic ischemia or parahepatic abscess. Based on this experience, the merits and detriments of individual hemostatic procedures are presented.

Hemorrhage

Hemostatic agents. Adjuncts to control bleeding.

1. Allergic reactions can occur with the use of topical hemostatic agents. 2. Some hemostatic agents may be used in combination to provide more effective hemostasis (eg, thrombin and Gelfoam). 3. Documentation should be made of any hemostatic agent left in situ at the time of closure. 4. Use of topical hemostatic agents is generally contraindicated in contaminated wounds.

Education, Nursing, Continuing

Postoperative venous thromboembolism and brain tumors: Part II. Hemostatic profile.

Preoperative hemostatic data were obtained on 42 brain tumor patients and correlated with the subsequent occurrence of venous thrombosis detected with 125I-labeled fibrinogen leg scans. The occurrence of thrombosis correlated significantly with an increased prothrombin time, plasminogen, and total fibrinolytic activity and a decreased fibrinogen level. This overall trend in the group of patients with postoperative thrombosis indicates that the hemostatic disorder noted in brain tumor patients is most closely related to a subclinical form of chronic disseminated intravascular coagulation syndrome. Differences in hemostatic parameters seen with the various types of brain tumors suggest that biological factors specific to each tumor are likely responsible for the described hemostatic disorder and support the need for further research directed at the tumor tissue level.

Blood Coagulation Tests

Predictive value of factors of the hemostatic system in screening procedures for coronary artery disease.

Thromboembolic events play a major pathogenetic role in the final occlusion of atherosclerotic vessels. May such a catastrophic event be predicted or an increased risk be indicated by analyzing the hemostatic system in plasma? A hugh literature exists about disturbances of the platelet, coagulation and fibrinolytic systems after atherosclerotic events such as myocardial infarction or stroke. This data, however, has no predictive significance. In contrast, the epidemiological studies in healthy persons have shown fibrinogen to be a potent risk predictor which is independent from other risk factors such as age, cholesterol or cigarette smoking. Results on factor VII:C are still controversial. Ongoing studies have included further factors of the hemostatic system. A second approach to elaborate the predictive power of hemostatic factors is to follow up patients with overt atherosclerotic disease and to correlate baseline hemostatic tests with event recurrences. The ECAT Angina Pectoris Study performed in 19 European clinical centers will present its prospective results by 1990. Some correlations of risk factors at baseline point to the many interrelationships among each other and to the need of careful statistical management of such data. It is reasonable to include fibrinogen in the recently developed coronary risk scores. So far, thrombin clotting time procedures, such as the Clauss method, appear to be appropriate for the purposes of risk prediction.

Blood Coagulation Factors

Disorders of the hemostatic system and the risk of the development of thrombotic and cardiovascular diseases: limitations of laboratory diagnosis.

The relationship between hemostatic abnormalities and thrombotic and cardiovascular diseases is summarized. All known congenital and acquired abnormalities in the biochemistry of hemostasis are related to thrombotic and cardiovascular diseases in the way that would be expected on the basis of theories about the role of balances between coagulation and fibrinolysis and between activating and inhibiting factors. Notwithstanding the consistency between theory and observed abnormalities, a causal relationship between biochemical abnormality and clinical symptoms has been proved only in a limited number of situations, and it is possible that certain abnormalities only (or also) mark pathologic events. The limitations of laboratory diagnosis of hemostatic disorders in relation to hemostasis as a local process are discussed. It is proposed that more attention be paid to methods of evaluating the local aspects, for example, methods that assess reaction products in the circulation and that can provide an averaged message of the local phenomena. In addition, such methods can provide information about the dynamic balances in the hemostatic system, whereas historically more attention has been paid to the static balances in the potential of hemostatic processes.

Blood Coagulation

Preoperative and postoperative hemostatic profiles of dogs undergoing ovariohysterectomy.

Hemostatic profiles were evaluated in 15 healthy dogs immediately before and 24 hours after celiotomy for routine ovariohysterectomy. Prothrombin time, activated partial thromboplastin time, fibrinogen, fibrin degradation products, antithrombin III activity, platelet count, and hemogram were measured. There were no significant changes in prothrombin time, activated partial thromboplastin time, fibrin degradation products, antithrombin III activity, or platelet count. Fibrinogen concentration was significantly higher following surgery. Postoperative leukocyte differential counts were typical of stress leukograms, and were characterized by leukocytosis, neutrophilia, lymphopenia and eosinopenia. Mild decreases in packed cell volume, red blood cell count and hemoglobin concentration were consistent with minor blood loss during surgery or fluid retention and hemodilution postoperatively. It was concluded that celiotomy and routine ovariohysterectomy in healthy dogs did not alter hemostatic profiles 24 hours after surgery. Abnormal postoperative hemostatic profiles should not be attributed to surgery alone; other causes of abnormal hemostatic profiles should be investigated.

Animals

Evaluation of hemostatic analytes after use of hypertonic saline solution combined with colloids for resuscitation of dogs with hypovolemia.

The effects of hypertonic saline solution (HTSS) combined with colloids on hemostatic analytes were studied in 15 dogs. The analytes evaluated included platelet counts, one-stage prothrombin time, activated partial thromboplastin time, von Willebrand's factor antigen (vWf:Ag), and buccal mucosa bleeding times. The dogs were anesthetized, and jugular phlebotomy was used to induced hypovolemia (mean arterial blood pressure = 50 mm of Hg). Treatment dogs (n = 12) were resuscitated by infusion (6 ml/kg of body weight) of 1 of 3 solutions: HTSS combined with 6% dextran 70, 6% hetastarch, or 10% pentastarch. The control dogs (n = 3) were autotransfused. Hemostatic analytes were evaluated prior to induction of hypovolemia (baseline) and then after resuscitation (after 30 minutes of sustained hypovolemia) at 0.25, 0.5, 1, 6 and 24 hours. All treatment dogs responded rapidly and dramatically to resuscitation with hypertonic solutions. Clinically apparent hemostatic defects (epistaxis, petechiae, hematoma) were not observed in any dog. All coagulation variables evaluated, with the exception of vWf:Ag, remained within reference ranges over the 24-hour period. The vWf:Ag values were not statistically different than values from control dogs, and actual values were only slightly lower than reference ranges. Significant (P < or = 0.04) differences were detected for one-stage prothrombin time, but did not exceed reference ranges. The results of this study suggested that small volume HTSS/colloid solutions do not cause significant alterations in hemostatic analytes and should be considered for initial treatment of hypovolemic or hemorrhagic shock.

Animals