Influence of bleeding on haemorheology and haemostasis in surgery.

Changes in haemorheology and haemostasis may contribute to bleeding or thrombosis, which is of concern particularly in surgery. Blood loss itself has a major influence on both parameters being closely involved in the clinical outcome. In order to analyze the underlying interrelations, a prospective study with 122 patients (64 females, 58 males) aged between 18 and 83 years (mean: 51.8 years) was conducted. All patients were electively submitted to orthopaedic surgery. Haemorheological parameters included measurements of plasma viscosity, red body cell (RBC) and platelet aggregation index preoperatively, as well as by day 1 and day 7 after surgery. Additionally hematological and haemostaseological parameters including leukocyte and platelet counts, haematocrit and fibrinogen were investigated. Bleeding was defined as high (>500 ml) or low blood loss (≤500 ml) according to the drainage volume. High but not low blood loss was associated with an increase of RBC aggregation by day 1 and 7 after surgery. Plasma viscosity decreased significantly by day 1, returning to normal 7 days after surgery. Platelet count decreased significantly, concurrent with the haematocrit, by day 1 postoperatively, whereas by day 7 a significant increase was observed, being more distinct in high blood loss. Platelet aggregation index did not change under the influence of blood loss. Plasma fibrinogen, clearly corresponding to the extend of blood loss, showed a continuous postoperative increase, which was significantly higher at day 7. Leukocytes increased moderately but significantly in particular in high blood loss. In conclusion, the postoperative decrease of plasma viscosity and of platelet counts, concurrent with the haematocrit, provides evidence of being clearly dependent on blood loss which is regarded as a dilution effect corresponding with the haemorrhagic risk. The increase of RBC aggregation at the early postoperative stage is solely observed in high blood loss and is esteemed as a result of volume therapy. The marked increase of platelet counts and plasma fibrinogen at the late postoperative stage, being more pronounced in high blood loss, might contribute to an elevated prothrombotic risk and is ascribed to an inflammatory response to surgery. In summary, it is concluded, that bleeding tendency corresponding with haemorheologic parameters is enhanced in the early, whereas the prothrombotic risk, well correlating with haemostaseologic parameters, is elevated in the later stage after surgery.

Trimix instead of air, decreases the effect of short-term hyperbaric exposures on platelet and fibrinolysis activation.

PURPOSE: Short-term and saturated simulated dives followed by decompression with air, cause a decrease in platelet count and increased activation of fibrinolysis. The aim of this study was to determine whether short-term dives with trimix as a breathing mixture induce the activation of platelets, and/or fibrinolysis. MATERIAL AND METHODS: 30 male divers were subjected to short-term hyperbaric exposures to 0.7 MPa. Thirty divers used air and then the same divers used trimix as a breathing mixture. RESULTS: The mean platelet count dropped significantly after decompression only in the group breathing air. The number of CD62P positive platelets and the amount of platelet-derived micro particles were statistically significant higher after decompression in both exposures. The number of CD61 positive platelets increased significantly only in the group breathing air. We observed a significant decrease of factor XII and fibrinogen concentrations after decompression only in the group breathing air. A significant increase in the concentration of plasminantiplasmin complex in both groups was detected. CONCLUSIONS: Short-term hyperbaric exposure and decompression performed according to current safety standards activates platelets and the fibrinolytic system. Trimix protects divers from a reduction in the amount of platelets, fibrinogen and factor XII in the course of these exposures.

[Orthopedic patients with or without thrombophilia. Diagnostic, therapy and peri-operative strategies]. / Orthopädische Patienten mit bzw. ohne Thrombophilie. Diagnostik, Therapie und perioperative Einstellung.

Venous thrombosis and pulmonary embolisms are currently associated with high mortality rates in Europe as well as in the United States (mortality rate >300,000-500,000/year). The highest risk is attributed to orthopedic surgery. Besides the use of antithrombotic agents, surgical and anesthesiological procedures as well as a multitude of trigger mechanisms, many thrombophilic risk conditions have to be considered. The incidence of thrombotic complications could be continuously reduced by the improvement of different antithrombotic strategies and use of drugs. According to national and international guidelines low molecular weight heparins and fondaparinux (besides aPTT adjusted strategies by using unfractionated heparin) are mainly indicated in high risk patients undergoing hip and knee surgery.The use of newly developed anti-IIa and anti-Xa inhibitors (e.g. dabigatran etexilate, rivaroxaban) is not yet established in guidelines. The discovery of pentasaccharide has further improved the antithrombotic efficiency, but it is still unknown how to manage patients with thrombophilia. Otherwise the knowledge of thrombophilia is not mandatory to know how to manage high risk patients. In contrast information on a history of thrombotic complications as well as indications gained from the family history are of great importance. Whether and to what extent, which patients with or without thrombophilic disposition, under which conditions from which medication within an anti-coagulation prophylaxis profit most over which time period, will be of future interest. Fundamentally, the age of the patient as well as liver and kidney function values and possible interactions between medications must be taken into consideration for selection of individual anti-thrombotic drugs. Even prolongation of medical immobilization prophylaxis can lead to accumulative risks, such as heparin-induced thrombocytopenia, the risk of which grows with increased exposition to the triggering agent.

The use of antithrombotic agents in microvascular surgery.

Despite increasing advances in microvascular free tissue transfer, flap failures, most commonly resulting from thrombosis at the anastomotic vascular site, remain a significant concern. Although several experimental and clinical studies have been carried out, no consensus has been reached so far on the efficacy, dosage and timing of anticoagulant agents available for the prevention and treatment of thrombosis in microvascular surgery. Inhibition of fibrin formation and platelet function or the use of thrombolytic agents is a common approach in the antithrombotic management. However, some agents exhibit serious side effects and all of them carry the risk of bleedings. The current literature on the use of antithrombotic agents, targeting at clinical trials in microvascular surgery, is therefore reviewed, to provide an informative basis for recommendations for an appropriate pharmacological approach.

Comparison of the plasminogen activator inhibitor-1 4G/5G gene polymorphism in females with venous thromboembolism during pregnancy or spontaneous abortion.

Genetic polymorphisms in plasminogen activator inhibitor-1 gene-675 4G/5G (PAI-1 4G/5G) are claimed to contribute to an increased risk of venous thromboembolism. Inherited thrombophilia, on the other hand, is associated with the occurrence of spontaneous abortions. The objective of this study was, to explore the significance of genetic polymorphisms of PAI-1 4G/5G with particular emphasis on 4G alleles in pregnant women suffering from venous thromboembolism or early spontaneous abortion, respectively. Therefore genetic PAI-1 4G/5G polymorphisms were studied in 108 pregnant females suffering from venous thromboembolism (n=69) or from spontaneous abortion (<20 week, n=39), respectively. Healthy volunteers (n=238) were taken as controls. The frequencies of 4G alleles (4G/4G or 4G/5G genotypes) of PAI-1 were significantly higher in venous thromboembolism (OR: 3.40, p=0.0088) and slightly higher, but not significantly, in abortions (RR: 2.33; p=0.1162) compared to controls. The incidence of 4G-carriers in females with abortion was 0.68 (-32%) compared to women suffering from venous thromboembolism alone. We conclude from these data, that the occurrence of PAI-1 4G/4G or 4G/5G genotypes, respectively, is clinically significant for the pathogenesis of venous thromboembolism in pregnancy but not for early abortion.

T2* and FSE MRI distinguishes four subtypes of neurodegeneration with brain iron accumulation.

BACKGROUND: Neurodegeneration with brain iron accumulation (NBIA) defines a group of genetic disorders characterized by brain iron deposition and associated with neuronal death. The known causes of NBIA include pantothenate kinase-associated neurodegeneration (PKAN), neuroferritinopathy, infantile neuroaxonal dystrophy (INAD), and aceruloplasminemia. OBJECTIVE: To define the radiologic features of each NBIA subtype. METHODS: Brain MRIs from patients with molecularly confirmed PKAN (26 cases), neuroferritinopathy (21 cases), INAD (four cases), and aceruloplasminemia (10 cases) were analyzed blindly to delineate patterns of iron deposition and neurodegeneration. RESULTS: In most cases of PKAN, abnormalities were restricted to globus pallidus and substantia nigra, with 100% having an eye of the tiger sign. In a minority of PKAN cases there was hypointensity of the dentate nuclei (1/5 on T2* sequences, 2/26 on fast spin echo [FSE]). In INAD, globus pallidus and substantia nigra were involved on T2* and FSE scans, with dentate involvement only seen on T2*. By contrast, neuroferritinopathy had consistent involvement of the dentate nuclei, globus pallidus, and putamen, with confluent areas of hyperintensity due to probable cavitation, involving the pallida and putamen in 52%, and a subset having lesions in caudate nuclei and thalami. More uniform involvement of all basal ganglia and the thalami was typical in aceruloplasminemia, but without cavitation. CONCLUSIONS: In the majority of cases, different subtypes of neurodegeneration associated with brain iron accumulation can be reliably distinguished with T2* and T2 fast spin echo brain MRI, leading to accurate clinical and subsequent molecular diagnosis.

Antiplatelet and anticoagulant effects of "HN-11 500," a selective thromboxane receptor antagonist.

The antiplatelet and anticoagulant effect of a thromboxane receptor (TX receptor) antagonist developed by Nycomed (Linz) has been studied in a placebo-controlled double-blind phase I study. Sixteen healthy male volunteers received different single oral doses of "HN-11 500" (C(14)H(15)NO(5)S(2); 1, 10, 100, 200, and 400 mg). Eight volunteers received placebo. The washout period between each dosage applied was at least 12 days. Platelet aggregation induced by the thromboxane mimetic "U 46 619" (C(21)H(34)0(4)) and platelet adhesion to siliconized glass were significantly and dose-dependently inhibited. The effect lasted between 3 and 4 h (10 mg) and 8 h (400 mg), respectively, and correlated well with the pharmacokinetic data. Platelet aggregation seems to be more sensitive to monitor the effects of HN-11 500 on platelet function than platelet adhesion. Plasma levels of 300 ng/ml HN-11 500 probably leads to >90% inhibition of platelet aggregation. The template bleeding time slightly increased but did not exceed the normal range. Furthermore, there was a wide variation of results. There were no significant changes in platelet counts, platelet-induced thrombin generation time (PITT), and blood coagulation parameters. All doses of HN-11 500 were well tolerated. HN-11 500 is a potent TX receptor antagonist (TXRA), which inhibits either platelet aggregation or platelet adhesion, which has not yet been described. In clinical routine, TXRAs have to demonstrate the effectiveness in large clinical trials for different clinical indications and to compete with single or combined administrations of cyclooxygenase (COX) inhibitors, thienovridines, thromboxane synthase inhibitors, and GIIb/IIIa inhibitors.

Heparin-induced thrombocytopenia: a critical risk/benefit analysis of patients in intensive care treated with R-hirudin.

Patients in intensive care may be at high risk of in vivo platelet activation because comorbid conditions, such as infections, septicemia, shock, disseminated intravascular coagulation, and cancer represent procoagulant states. Hyperreactivity of platelets with or without a decline of cell count may result in thromboembolic complications potentially associated with the phenomenon of heparin-induced thrombocytopenia. We analyzed the data of 10 patients highly suspected of having heparin-induced thrombocytopenia during their intensive care treatment of 29 plus or minus 22 days. In seven patients, thrombocytopenia coincided with thromboembolic complications. Six patients had additionally undergone fibrinolytic therapy before starting activated partial thromboplastin time-adapted alternative anticoagulation with r-hirudin. In three patients, the platelet count decreased without a clinical manifestation, of heparin-induced thrombocytopenia. R-Hirudin treatment monitored by activated partial thromboplastin time and prothrombin time (PT) was effective and safe. The target value for activated partial thromboplastin time was a twofold prolongation. In four of five patients with deep venous thrombosis, a partial recanalization of the lower extremity could be achieved. Three patients with pulmonary embolism associated with deep venous thrombosis in two cases and in one additional case with an acute myocardial infarction did clinically profit from fibrinolysis with recombinant tissue plasminogen activator (rtPA) and r-hirudin treatment. Two lethal events probably caused by the underlying multimorbidity could not be prevented. No recurrence of thrombosis occurred, and there were no severe bleeding complications attributed to r-hirudin treatment. Platelet counts were significantly reduced on day 9.4 plus or minus 6.4 of heparin administration in all cases (>50% decrease related to the initial values) from 224,000 plus or minus 126,000/microL to 96,000 plus or minus 61,000/microL, and increased during rhirudin treatment to mean values of 224,000 plus or minus 126,000/microL. The heparin-induced platelet activation assay (HIPAA) assay was positive in 8/10 cases, whereas the PF4 enzyme-linked immunosorbent assay showed a positive result in four of eight analyzed cases. In four cases, the assays were concordantly positive. The PF4 enzyme-linked immunosorbent assay was not performed in two cases.

Fechtner's syndrome: considerations of anesthetic management.

IMPLICATIONS: Fechtner's syndrome is a rare form of macrothrombocytopenia (potentially associated with other hemostatic deficiencies, e.g., von Willebrand's disease and protein Z deficiency), which can exacerbate the risk of uncontrollable bleeding during surgery. We describe the management of a patient with Fechtner's syndrome involving desmopressin, prednisone, and platelets, which produced safe and effective results during cochlear implant surgery.

Platelet activation and its role in thrombin generation in platelet-induced thrombin generation time.

Platelet-induced thrombin generation time (PITT) is a newly developed global coagulation assay in which a small amount of partially anticoagulated platelet-rich plasma (PRP) is rotated in a disc-shaped cuvette within the light beam of a photometer. The time intervals from onset of rotation until aggregation and coagulation of the sample are registered. The aim of our study was to compare platelet activation with generation of thrombin during rotation of PRP in PITT system. Aliquots of PRP were taken before, 1, 3, and 8 min after the onset of rotation as well as at the beginning of aggregation and shortly before coagulation. Thrombin activity was measured with chromogenic substrate S-2238. We have also measured the level of generated prothrombin activation fragment 1+2 (F1+2), which reflects the concentration of liberated thrombin. Platelet activation was assayed by means of platelet factor 4 (PF4) and beta-thromboglobulin (beta-TG) concentration and registration of the aggregation. The concentrations of the F1+2, PF4, beta-TG increased very slowly from the beginning of the test until aggregation occurred. From the start of aggregation, the levels of F1+2 rose rapidly. In contrast to the F1+2 measurements, thrombin activity has not been detected from onset of rotation until the end of the test. Only trace thrombin activity was detectable just after the plasma sample had been clotted in the cuvette. Our results demonstrate that there exists a close relationship between platelet activation and thrombin generation. Viable platelets, which adhered to the cuvette walls, form an active template on which thrombin can be generated from prothrombin.

Improved therapeutic safety of oral anticoagulant therapy in Germany: the Saarland model.

In contrast to other European countries, in Germany more than 90% of oral anticoagulated patients are controlled by general practitioners. The International Normalized Ratio (INR) system in laboratory control is not in widespread use, often leading to misinterpretations of prothrombin time (PT) measurements. To improve the management of anticoagulated patients, a model was developed, consisting of different questionnaires and on the base of the INR system. Since 1993, 60 patients in our Department's outpatient anticoagulant clinic and since 1996 16 patients in the office of a general practitioner were followed for 146.32 patient years. There were no thromboembolic events and no major bleedings during follow-up. A total of 126 minor bleedings occurred in 30 patients. There were no significant differences in INR values and stable phases between the two centers; however, significantly shorter stable phases in patients with bleeding episodes were noted. Thus, this model seems to be useful also in general practitioners' hands.

The "Phoenix" ADR database of the Drug Commission of the German Medical Profession--a clinically useful approach to optimize evidence-based medicine in Germany.

The innovative "Phoenix" database system of the Drug Commission of the German Medical Profession (AkdA) permits rapid access to data on adverse drug reactions. It enables the user to conduct searches covering a wide variety of questions within a short period of time. No one needs to be an "expert" to extract scientific knowledge from a database that currently already contains some 106,000 reports on adverse drug reactions. While our traditional apprenticeship model of physician training has served us well, an adaptation will be required for the new millennium. New tools are needed to allocate the available resources. Clinical proposals of experts or opinion leaders, guidelines, and highly graded clinical studies, like the use of clinical databases may help to improve safety and efficacy of drug administration. Evidence-based critical care medicine is therefore a potential tool for improving the effectiveness of drug therapy and for the patient's outcome. Over and above, the Phoenix database might be interpreted as an initiative instrument, which is easy to use and contributes to highlight the determinants of clinical decisions.

Analysis and occurrence of adverse events with oral anticoagulant therapy.

The antithrombotic potential of oral anticoagulants is undisputed as the frequency of recurrent thrombosis is high unless anticoagulant therapy is continued after hospital discharge. However, the relationship between potency and/or changes in anticoagulant therapy and frequency of complications remains unclear. Optimizing the clinical management of oral anticoagulation information obtained by databases may be advantageous in addition to meeting safety criteria, as described in the "Saarland Model." The Phoenix-database implicates an association between bleeding complications and the hypertensive elderly. From 1968 to 1993 most reports about cerebral/intraspinal bleedings occurred at prothrombin (PT)-values below 20% in the elder patients (>60 years of age) (12%; 367 reports). In the Saarland Model, 60 patients were followed from our department during a 3-year period. Our findings suggest neither a correlation of the range of PT values and the bleeding events nor an association with age or hypertension. It became obvious that "stable phases" of International Normalized Ratio (INR) [+/-15% change of 4 serial controls using nearly constant weekly oral anticoagulant dosages (+/-15%)] might be considered as a valid criterion of safety. At least the individual risk profile determines the patient's fate.

Liver damage induced by coumarin anticoagulants.

Except for bleeding complications, relevant adverse effects of coumarin anticoagulants are comparatively rare considering the widespread use of these substances. Here we present the case of a 56-year-old woman who developed recurrent episodes of severe hepatitis following repeated exposure to phenprocoumon (Marcumar; Roche, Grenzach-Wyhlen, Germany) and warfarin (Coumadin; DuPont Pharma, Bad Homburg, Germany) after replacement of the mitral valve with a mechanical prosthesis. The diagnosis of "coumarin-induced hepatitis" is compatible with the time relationship between start of the drug and the onset of hepatopathy (first episode 8 months, second episode 4 weeks, and third episode 7 days), the rapid improvement following discontinuation of the drug, recurrence of liver dysfunction after re-exposure to the drug, and liver histology. After anticoagulant therapy was changed to heparin and acenocoumarol (Sintrom; Ciba-Geigy, Basel, Switzerland), the patient's general state was markedly improved and her liver values became almost normal. This case will be discussed and compared with other reports of coumarin-induced hepatic lesions. Although liver damage induced by coumarin derivates is rare, it is important to be aware of the hepatotoxic potential of these drugs, which, in most cases, mimics the clinical presentation of viral hepatitis.

The overdosed patient and bleedings with oral anticoagulation.

Overdose or bleeding with oral anticoagulation requires gradual antagonization of the drugs. Minor bleedings are most commonly managed by temporarily discontinuing treatment and by giving vitamin K to antagonize the coumarin derivative effects. Major bleedings, in contrast, especially intracranial hemorrhages, require immediate antagonization of anticoagulation. This is also necessary in required major surgery of anticoagulated patients. Instant normalization of hemostasis in such cases is achieved by the administration of clotting factors, in particular prothrombin complex concentrates. The use of fresh frozen plasma, instead, is less useful. The treatment with prothrombin complex concentrates requires a strict risk-benefit estimation and laboratory monitoring is recommended to optimize dosage adjustment. A 2-year follow-up of 45 out-patients receiving phenprocoumon at our center revealed a total of 11 bleeding complications (11.6/100 treatment-years, 10 minor and 1 major bleeding). Discontinuing or reducing oral anticoagulation together with vitamin K were the methods most frequently used to efficiently manage hemorrhages, whereas prothrombin complex concentrates were only used in one case with major bleeding. Oral anticoagulation appeared to be an enhancing factor for an otherwise existing bleeding diathesis rather than a genuine cause for hemorrhages.

Training of patients for self-management of oral anticoagulant therapy: standards, patient suitability, and clinical aspects.

Self-control and self-management of oral anticoagulant therapy have become more and more attractive for patients undergoing long-term treatment. In our training center, we examined 50 patients who took part in a standardized training course for self-management. Patients (36 men, 14 women) were preselected according to the guidelines of the German Association for Self-management of Oral Anticoagulation (ASA e.V.) and were all trained by the same physician. The complete course took an average of eight sessions. Patients older than 59 years needed significantly more training time in theoretical advising than younger patients; they did not need more training time in practical matters. The values between International Normalized Ratio (INR) measured in venous blood samples and by self-assessment were comparable for both groups. There was a good overall correlation between self-controlled INRs and laboratory assays, however, the self-assayed INRs were significantly lower than those from the venous blood samples.

Effects of aprosulate, a novel synthetic glycosaminoglycan, on coagulation and platelet function parameters: a prospective, randomized phase I study.

In a phase I clinical trial the effect of the highly sulfated polyanion "Aprosulate" was studied in healthy volunteers using different coagulation and platelet function parameters. Eighteen healthy volunteers aged 21 to 30 years received two single subcutaneous doses of aprosulate (0.5 mg/kg body weight; 1.0 mg/kg body weight), or unfractionated heparin (Calciparin 7,500 IU). The washout period between the different drugs/doses was at least 7 days. Coagulation and platelet function parameters (activated partial thromboplastin time, Heptest, fibrinogen, von Willebrand factor, ristocetin cofactor, platelet adhesion to siliconized glass, and platelet-induced thrombin generation time [a new method for measuring thrombin generation in platelet-rich plasma in the presence of platelets]) were assessed during 24 hours after each injection. Aprosulate led to a significant and dose-dependent prolongation of activated partial thromboplastin time and Heptest. This effect lasted for 4 hours (activated partial thromboplastin time) to 8 hours (Heptest). Activated partial thromboplastin time was not prolonged after the injection of unfractionated heparin (7,500 IU). Fibrinogen, von Willebrand factor, and ristocetin cofactor remained unchanged with both drugs. Platelet induced thrombin generation time was slightly prolonged and platelet adhesion was slightly diminished up to 2 hours using 0.5 mg/kg aprosulate, and up to 4 hours using 1.0 mg/kg aprosulate while the platelet induced thrombin generation time system was not influenced by the subcutaneous injection (7,500 IU) of unfractionated heparin. Both drugs and doses were well tolerated. Plasma transaminase concentrations alanin aminotransferase and aspartate aminotransferase serum values were slightly increased in some volunteers but returned to normal during or after the study (< 4 weeks). Further clinical trials will have to establish whether aprosulate is an effective drug for the prophylaxis of deep venous thrombosis.

No coagulation disorders under high-dose volume therapy with low-molecular-weight hydroxyethyl starch.

Hydroxyethyl starch (HES) is often used for volume therapy. Since bleeding complications have been reported repeatedly, a strict dose limitation of a maximum of 1,500 ml 6% solution per day is recommended. However, many indications require higher dosages. Bleeding complications are known to be caused by an acquired von Willebrand syndrome. It has been shown that the accumulation of large molecules and their impairment in the coagulation system can be avoided by using HES preparations with a low in vivo molecular weight. However, the effects of a high-dose therapy have not been studied yet. We have investigated, how a 4-day high-dose therapy, using 3,000 ml 6% HES 70/0.5 on the 1st day and 1,500 ml on days 2-4, affects the coagulation system and hemorheological parameters of acute stroke patients. Thromboplastin time, activated partial thromboplastin time and thrombin time showed no significant changes, except for a slight, clinically irrelevant change due to dilution. The subunits of von Willebrand factor VIII showed no significant change. Hematocrit decreased from 42.3 +/- 4.6 to 37.4 +/- 3.9% (p < 0.05) after day 1, reaching 35.3 +/- 4.2% (p < 0.01) at the end of the therapy, demonstrating a substantial volume effect. Plasma viscosity and erythrocyte aggregation decreased slightly, however not significantly. Our study shows that even a high-dose therapy with 6% HES 70/0.5 has no influence on the coagulation system.