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In patients with peripheral arterial occlusive disease (PAOD) a restricted circulation in cutaneous microvessels has been reported. In this study the velocity of erythrocytes (very) in finger nailfold capillaries - a vascular area without upstream macroangiopathy - and also in toe nailfold capillaries - a post-stenotic area –was investigated using capillary microscopy in apparently healthy subjects and patients with PAOD. Already in finger nailfold capillaries very of patients with PAOD under resting conditions was significantly lower than in capillaries of healthy subjects. This was also true for the circulation in toe capillaries. In addition, the erythrocyte velocities under resting conditions in the toe capillaries were significantly lower than in the finger capillaries. Similar results were found for the duration and the maximum velocity of postocclusive hyperemia. It is concluded that the resting blood flow in the skin microcirculation is impaired in PAOD patients, both under resting conditions and during postocclusive hyperemia in finger as well in toe nailfold capillaries.

BACKGROUND: The laser Doppler fluxmetry (LDF) is a non-invasive method to assess skin blood perfusion, measuring the flow of blood cells inside a tissue volume without harming the tissue. In the diagnosis of skin circulation disorders, the results of the LDF measurement are generally used in such a way that “normal” (or non-ill) or “pathological” values are achieved by comparison with a reference sample, for example of apparently healthy subjects. MATERIAL AND METHODS: In this study, the values of LDF for the diagnosis of microcirculatory disorders in patients with coronary artery disease (n = 20) or in patients with microcirculatory disorders, already diagnosed by capillary microscopy (n = 46), were examined. RESULTS: The mean values of LD amplitudes in the four frequency windows for patients with coronary artery disease were in the reference range. However, some of the patients showed reduced LD values: in eleven of the twenty patients, one or more mean LD amplitudes were below the reference range. Four of the eleven patients had pathologically decreased capillary erythrocyte velocities of v ery = 0.09–0.21 [mm/s], while the other seven patients had normal blood circulation at rest. For all patients with a proven cutaneous microcirculatory disorder, the mean LD amplitude in at least one of the frequency windows FF2 to FF4 was pathologically reduced. CONCLUSION: The Laser-Doppler fluxmetry method used in the study allows the reliable diagnosis of cutaneous microcirculatory disorders.

Thrombotic disorders remain the leading cause of mortality and morbidity, despite the fact that anti-platelet therapies and vascular implants are successfully used today. As life expectancy is increasing in western societies, the specific knowledge about processes leading to thrombosis in elderly is essential for an adequate therapeutic management of platelet dysfunction and for tailoring blood contacting implants. This study addresses the limited available data on platelet function in apparently healthy subjects in relation to age, particularly in view of subjects of old age (80-98 years). Apparently healthy subjects between 20 and 98 years were included in this study. Platelet function was assessed by light transmission aggregometry and comprised experiments on spontaneous as well as ristocetin-, ADP- and collagen-induced platelet aggregation. The data of this study revealed a non-linear increase in the maximum spontaneous platelet aggregation (from 3.3% +/- 3.3% to 10.9% +/- 5.9%). The maximum induced aggregation decreased with age for ristocetin (from 85.8% +/- 7.2% to 75.0% +/- 7.8%), ADP (from 88.5% +/- 4.6% to 64.8% +/- 7.3%) and collagen (from 89.5% +/- 3.0% to 64.0% +/- 4.0%) in a non-linear manner (linear regression analysis). These observations indicate that during aging, circulating platelets become increasingly activated but lose their full aggregatory potential, a phenomenon that was earlier termed "platelet exhaustion". In this study we extended the limited existing data for spontaneous and induced platelet aggregation of apparently healthy donors above the age of 75 years. The presented data indicate that the extrapolation of data from a middle age group does not necessarily predict platelet function in apparently healthy subjects of old age. It emphasizes the need for respective studies to improve our understanding of thrombotic processes in elderly humans.

The Laser Doppler technique (Laser-Doppler-Fluxmetry, LDF), a noninvasive method to estimate skin blood flow (LDF), is frequently used in research and clinical routine [1]. Here, the measurements were carried out with a new Laser Doppler system, the DOP-system, which allows to measure frequency spectra in four different frequency windows according to the velocities in venules (low velocity), capillaries (low to medium velocities), and in arteries (with high and very high velocities). However, the diagnostic reliability or the effectiveness of the LDF has not yet been evaluated sufficiently, which is indispensable, where medical diagnostics and therapy controls are concerned. For a valid interpretation of LDF values of individual patients, the knowledge of the reference range and the variability of the measured parameters is required.In four successive studies the reference range (62 apparently healthy subjects), the circadian variability (8 subjects), the variability from day-to-day (6 subjects) and over one year with monthly measurements (6 subjects) were evaluated.With the knowledge of the reference range, microcirculatory disorders can now be diagnosed using the DOP method. Following a standard measurement procedure there was no dependence of the measured data on the day or season of measurement.

Cerebrovascular diseases are considered in a different way concerning their etiology with regard to arterial and venous occlusion. The role of thrombophilia in this context remains undetermined. For this reason, a case-control study was conducted including a total of 202 patients (154 females, 48 males) aged from 18 to 76 years (mean: 39.8 years) suffering either from cerebral sinus venous thrombosis (n = 101) or from arterial ischemic stroke (n = 101). Study groups were evaluated on the basis of age- and gender-matched pairs. Gene mutations of factor V-1691 (factor V Leiden) and prothrombin-20210 being considered as the most common thrombophilia markers were analyzed in this study. Factor V Leiden-mutations were found in 16.8% of patients with cerebral sinus venous thrombosis (CVT) and in 17.8% of patients with arterial ischemic stroke (AIS), which was significantly more frequent than in controls at a rate of 4.95% (ORs: 3.89 and 4.16). Prothrombin-mutations were significantly more frequent in CVT at a rate of 14.9% versus 2.97% in controls (OR: 5.70). This does not apply for AIS showing a rate of 4.95% prothrombin-mutations. Rates of factor V Leiden-mutations are not different in CVT compared with AIS. In contrast, however, prothrombin-mutations were significantly more frequent in CVT than in AIS with a rate of 14.9% versus 4.95% (OR 3.35). Furthermore, 3 cases with combined heterozygosity of factor V Leiden- and prothrombin-mutation have been identified in CVT, but not in AIS or controls. All of the above mentioned mutations were exclusively heterozygous. We conclude from these data that thrombophilia in terms of factor V Leiden genotype is a risk factor for both CVT and AIS in equal measure. In contrast, prothrombin-20210-mutations were different playing a significant role in the pathogenesis of cerebral sinus vein thrombosis, but not in arterial ischemic stroke. Also, the combined occurrence of heterozygous prothrombin- and factor V Leiden-mutation clearly favors the emergence of cerebral sinus venous thrombosis. Therefore, in terms of thrombophilia such as investigated in this study, pathogenesis of arterial and venous occlusions in cerebrovascular disease has to be regarded as different.

Regardless of the mechanisms that initiate the increase in blood pressure, functional and structural changes in the systemic vasculature are the final result of long-standing hypertension. These changes can occur in the macro- but also in the microvasculature. The supply of the tissues with oxygen, nutrients, and metabolites occurs almost exclusively in the microcirculation (which comprises resistance arterioles, capillaries and venules), and an adequate perfusion via the microcirculatory network is essential for the integrity of tissue and organ function. This review focuses on results from clinical studies in hypertensive patients, which have been performed in close cooperation with different clinical groups over the last three decades. Intravital microscopy was used to study skin microcirculation, microcatheters for the analysis of skeletal muscle microcirculation, the slit lamp for conjunctival microcirculation and the laser scanning ophthalmoscope for the measurement of the retinal capillary network. The first changes of the normal microcirculation can be found in about 93% of patients with essential hypertension, long before organ dysfunctions become clinically manifest. The earliest disorders were found in skin capillaries and thereafter in the retina and the skeletal muscle. In general, the disorders in the different areas were clearly correlated. While capillary rarefaction occurred mainly in the retina and the conjunctiva bulbi, in skin capillaries morphological changes were rare. A significant decrease of capillary erythrocyte velocities under resting conditions together with a marked damping of the postischemic hyperemia was found, both correlating with the duration of hypertension or WHO stage or the fundus hypertonicus stage. Also the mean oxygen tension in the skeletal muscle was correlated with the state of the disease. These data show that the microcirculatory disorders in hypertension are systemic and are hallmarks of the long-term complications of hypertension. There is now a large body of evidence that microvascular changes occur very early and may be important in their pathogenesis and progression.

Background: Endothelial cells secrete different mediators depending on biochemical and/or biophysical conditions, which can lead to vasodilation or vasoconstriction, respectively. Impaired endothelial responsiveness to specific vasodilator stimuli has been used as a surrogate marker of cardiovascular risk. Multiple methods allow testing endothelial responses in both microvessels and conduit arteries, but it is still unclear whether there is a relationship in endothelial function between these two different vascular beds. Material and methods: In order to examine, whether such macrocirculatory data might correlate with data obtained in the supplied microvessels, a parallel investigation in the brachial artery (BA) and the supplied nailfold capillaries was performed. The duration and amplitude of the postischemic hyperemia (stasis in the vasculature of the left arm using a blood pressure cuff for 3 minutes) were measured (ultrasound technique) and simultaneously the amplitude and duration of the postischemic hyperemia in ipsilateral nailfold capillaries (intravital capillaroscopy). Results: There was absolutely no correlation between the duration (n = 153, r = 0.076, p = 0.3493) of the diameter increase in the BA and in ipsilateral nailfold capillaries. Conclusion: The regulation of the cutaneous microcirculation did not follow diameter changes of the conduit artery (BA) but seems to be dominated by the precapillary arterioles.

Septic and haemorhagic shock carry the risk of high mortality. Failure of microcirculation secondary to alterations of haemostasis and fibrinolysis play a major role in the pathogenesis of shock. The aim of this study was to evaluate the clinical relevance of procoagulatory and fibrinolytic activities referring to survival. Therefore, 39 patients (23 to 80 yrs, 16 females, 23 males) suffering from haemorrhagic (n = 21) and septic shock (n = 18) were screened prospectively for plasmatic coagulation and fibrinolysis parameters. Thirteen patients (33.3%) developed lethal outcome. Concerning fibrinolysis, plasminogen was significantly lower in non-survivors by day 1 and plasmin-antiplasmin complex significantly higher by day 4 compared to survivors. Consecutive increase of plasminogen over day 4 and 7 was significantly stronger in survivors. Concerning haemostasis activation, thrombin-antithrombin complex was higher and D-dimers or fibrinogen levels were lower, but not significantly different, in non-survivors compared to survivors. We conclude from these data, that procoagulant activities are increased, but not significantly predictive for the clinical outcome in septic and haemorrhagic shock. By contrast, fibrinolysis, as measured by enhanced capacity and responsiveness, is clearly predictive and plays a significant role for survival, possibly due to its clearing function in microcirculation.

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.

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.

Genetic polymorphisms in plasminogen activator inhibitor-1 gene-675 4G/5G (PAI-1 4G/5G) are claimed to con- tribute 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 spon- taneous 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 (

Introduction: To reduce intraoperative blood loss in liver resections surgical bleeding control is often performed by a complete inflow obstruction of the liver called Pringle manoeuvre leading to a portal venous stasis. Platelet aggregability may be affected by this circulatory stasis. Materials and methods: A study population of 11 patients (37-67 years old, 7 females and 4 males) with hepatic tumours underwent elective liver resection. Pringle manoeuvre of up to 50 min duration was used in 4 patients. The other 7 patients were operated using selective vascular clamping. Platelets were aggregated before and after liver resection with adenosine diphosphate, collagen and ristocetin (according to Born). Results: Mean maximal amplitudes of platelet aggregation were comparable before and after liver resection. Statistic analysis did not detect a significant difference between the values before and after liver resection as well as between Pringle manoeuvre and selective vascular clamping. Conclusion: Induced platelet aggregability is not affected by the method of surgical bleeding control used in liver resection. Platelet aggregability seems to be resistant even to portal venous stasis of up to 50 min during Pringle manoeuvre.

Activation of coagulation and inflammatory response including the complement system play a major role in the pathogenesis of critical illness. However, only limited data are available addressing the relationship of both pathways and its assessment of a predictive value for the clinical outcome in intense care medicine. Therefore, parameters of the coagulation and complement system were studied in patients with septicaemia and multiple trauma regarded as being exemplary for critical illness. 34 patients (mean age: 51.38 years (±16.57), 15 females, 19 males) were investigated at day 1 of admittance to the intensive care unit (ICU). Leukocytes, complement factors C3a and C5a were significantly (p < 0.0500) higher in sepsis than in trauma, whereas platelet count and plasma fibrinogen were significantly lower in multiple trauma. Activation markers of coagulation were elevated in both groups, however, thrombin-antithrombin-complex was significantly higher in multiple trauma. DIC scores of 5 were not exceeded in any of the two groups. Analysing the influences on mortality (11/34; 32.35% ), which was not different in both groups, non-survivors were significantly older, had significantly higher multiple organ failure (MOF) scores, lactate, abnormal prothrombin times and lower C1-inhibitor activities, even more pronounced in early deaths, than survivors. In septic non-survivors protein C was significantly lower than in trauma. We conclude from these data that activation of the complement system as part of the inflammatory response is a significant mechanism in septicaemia, whereas loss and consumption of blood components including parts of the coagulation and complement system is more characteristic for multiple trauma. Protein C in case of severe reduction might be of special concern for surviving in sepsis. Activation of haemostasis was occurring in both diseases, however, overt DIC was not confirmed in this study to be a leading mechanism in critically ill patients. MOF score, lactate, C1-inhibitor and prothrombin time have been the only statistically significant predictors for lethal outcome suggesting that organ function, microcirculation, haemostasis and inflammatory response are essential elements of the pathomechanism and clinical course of diseases among critically ill patients.

Objectives: To evaluate homocysteine and methylentetrahydrofolat reductase (MTHFR 677 C → T) mutations as risk factors in ocular arterial and venous occlusive disease. Materials and methods: Over a period of 3.5 years (1/1999–8/2002) 410 patients with ocular occlusive disease presented to our tertiary care center. Of these, 362 patients (195 male, 167 female) were screened for hyperhomocysteinemia and MTHFR 677 C → T mutation. Results: Among these 362 patients, venous occlusions (45%) were less frequent than arterial occlusions (55%). Age between these subgroups did not differ significantly (p = 0,109). The following subgroups were analyzed: central retinal vein occlusion (n: 93), retinal branch vein occlusion (n: 70), central retinal artery occlusion (n: 41), retinal arterial branch occlusion (n: 49), anterior ischemic optic neuropathy (n: 68), posterior ischemic optic neuropathy (PION, n: 11) and amaurosis fugax (n: 30). A moderate hyperhomocysteinemia (≥12 μ mol/l) and a higher percentage of heterocygo...

5 Assessment According to current knowledge, HIV-1 has been transmitted via blood and blood products in Germany since 1979. With the introduction of antibody testing of blood and plasma donations in 1985, transmission of infections via blood, blood components and plasma products has been dramatically reduced. The residual risk of transmission of HIV with red cell, granulocyte and platelet concentrates, which are not currently subject to virus inactivation/removal procedures, is already very low at approximately 1 per 1.5 million donations. In the case of fresh-frozen plasma, which is subject to quarantine rules, there have been no known cases of transmission of HIV. Plasma products that have correctly undergone virus inactivation/ removal procedures during manufacture currently pose no residual risk of HIV transmission. The introduction of NAT for HIV-1 genome will bring about a further reduction in the residual risks for cellular blood components. The window period for antibody formation of approximately 21–45 days will be reduced as a result to approximately 11 days, as even incipient HIV infection is detectable with NAT. The spread of HIV amongst the German population in around 1978 is an example of how rapidly an established level of safety can collapse even in the blood services sector. The measures introduced for donor selection, inactivation of plasma products and selective use of blood and blood components should prevent a repeat of transmission of an enveloped virus on such a scale in the future. ...

The aim of the present study was to evaluate the effects of ionic (ioxaglate) and non-ionic (iopromide) contrast media on haemostatic parameters ex vivo. In 40 patients undergoing coronary angiography, platelet function (platelet reactivity and serotonin concentration) and coagulation markers [thrombin-antithrombin III complexes, prothrombin fragments (F1+2) and the D-dimers] were measured. The use of an ionic X-ray contrast agent (XCA) (ioxaglate) in diagnostic cardiac catheterisation angiography is associated with lower thrombin generation and lower activation of the platelet system than when a non-ionic XCA is employed (iopromide). The results thus confirm the results of various in vitro studies and animal investigations.

BACKGROUND: The role of the microcirculation in the pathophysiology and symptoms of peripheral arterial obliterative disease (PAOD) has been progressively emphasized during the past decades. Under resting conditions, already, the tissue oxygen partial pressure in the m. tibialis anterior (pO2im) is reduced to about 50% compared to healthy subjects. METHODS: In the framework of this study the pO2im of patients with PAOD stage II according to Fontaine (n = 16) in the m. tibialis anterior was measured under resting conditions and during walking on a treadmill in comparison to healthy subjects (n = 10). RESULTS: Under resting conditions the pO2im only marginally differed between PAOD patients and healthy subjects. But during exercise the pO2im dropped significantly more severely in PAOD patients and a return to baseline values could only be reached when the treadmill was stopped and the patients stood still. The pO2im minima correlated clearly with the clinical symptom of calf pain. CONCLUSION: The data revealed that the pO2im values were lower in PAOD patients and dropped significantly faster during walking compared to the pO2im values in healthy subjects. The pO2im decrease correlated with the calf pain occurring when the pO2im values approached or fell below 10 mmHg.

Patients in intensive care may be at high risk of in vivo platelet activation because comorbid conditions, such as infections, septicemia, shock, disseminated intravascular co agulation, and cancer represent procoagulant states. Hyperre activity 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, throm bocytopenia 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 moni tored 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 recana lization of the lower extremity could be achieved. Three pa tients 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 fibrino lysis with recombinant tissue plasminogen activator (rtPA) and r-hirudin treatment. Two lethal events probably caused by the underlying multimorbidity could not be prevented. No recur rence of thrombosis occurred, and there were no severe bleed ing 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/μL to 96,000 plus or minus 61,000/μL, and increased during r- hirudin treatment to mean values of 224,000 plus or minus 126,000/μL. 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.

Bleeding events are a common adverse effect in oral anticoagulation that frequently depend on the duration and intensity of treatment. Major bleeding events, particularly intracerebral hemorrhages, are a serious complication in cases that require the rapid reversal of anticoagulation. Urgent correction of the coagulation defect is also indicated when major emergency surgery is necessary. In addition to vitamin K supplementation, the administration of prothrombin complex concentrates is the most effective measure for the rapid reversal of anticoagulation. Due to the time-consuming administration and increased risk of volume overload, the administration of fresh frozen plasma is less advisable in such instances. The application of prothrombin complex concentrates requires a precautious risk-benefit evaluation, including an estimation of contraindications and repeated laboratory monitoring for dose adjustment.

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.

SummaryInitially, hydroxyethyl starch (HES) was only characterized by its in vitro molecular weight (MW). This is not sufficient because HES is degraded in vivo. One relevant parameter that predicts the rate of enzymatic breakdown is the degree of substitution, a measure of the average number of hydroxyethyl groups per glucose unit. The higher this degree of substitution, the slower the break-down. In addition, because the glucose units can be substituted at carbon 2,3 and 6, different substitution patterns are possible. They are classified by their C2/C6 hydroxyethylation ratio. A higher C2/C6 ratio results in less metabolism of the starch in vivo and results in a larger in vivo MW. This in turn affects therapy, because the larger the in vivo MW, the longer is the duration of the volume effect of HES.Of particular importance is the fact that HES with a high in vivo MW affects factor VIII/von Willebrand factor which can lead to an acquired von Willebrand syndrome. During a 10-day volume therapy with a medium-MW HES 200, a form that is difficult to metabolize, we observed an 80% drop in factor VIII/von Willebrand factor. Therapy with a medium-MW HES 200, a form that is easily degraded, and therapy with a low-MW HES 70 did not result in a relevant decline of factor VIII/von Willebrand factor.This explains why hemorrhagic complications have been observed repeatedly in the United States after therapy with HES infusions, some of them lethal. In the United States high-MW HES 480 which is difficult to degrade is most frequently used and results in a larger in vivo MW and subsequent decrease in factor VIII/von Willebrand factor levels. In Europe, medium-MW HES 200 that is easily degraded and low-MW HES 70 are preferred. In the future, HES should be characterized by the in vivo, not the in vitro MW.

Delayed-type hypersensitivity reactions (DTHRs) after subcutaneous application of unfractionated heparins or low-molecular-weight heparins are not uncommon. Standard allergological testing usually includes intracutaneous skin tests and patch testing of different heparins, heparinoids, and thrombin inhibitors followed by subcutaneous and/or intravenous challenge with skin test-negative drugs. We present data from a single-center case series of 15 patients with DTHR after low-molecular-weight heparin administration. Intracutaneous testing that can be considered as gold standard identified the suspicious elicitor in 11 (73.4%) of 15 of the patients. Patch testing was positive in 5 (33.4%) of 15 of the patients and was only positive in patients who were also reacting in the intradermal testing. Intravenous challenge with heparin sodium was performed in 10 of 15 patients and was well tolerated in all cases, despite prior positive intracutaneous tests with the same substance. Intracutaneous documentation of DTHR was not an adequate predictor of intravenous challenge. Keywords: heparin, allergy, alternatives, pregnancy, cardiac surgery, thrombosis

Objective: Fibronectin (Fn) plays an important part in unspecific defense mechanisms because of its ability to mediate the binding of foreign-body particles, bacteria, collagen, and other macromolecules to phagocytising cells of the reticulo-endothe-lial system (RES). The aim of the present study was to examine the effect of a 10-day hemodilution therapy on Fn concentration in humans. Design: The patients were randomized and treated with either 10% hydroxyethyl starch (HES) 200/0,62 or 6% HES 200/0,62. Setting: Neurology department of an university clinic. Patients: We examined 12 patients with cerebrovascular perfusion disturbances. Interventions: The Fn concentration was determined using simple radial immunodif-fusion. Results: The Fn concentration dropped significantly in all 12 patients (p < 0.01) in a dose-dependent manner beyond the dilution effect. 10% HES 200/0,62 caused a Fn decrease from 26.6 ± 9.2 to 10.0 ± 2.2 mg/dl (-62.2%), 6% HES reduced Fn from 25.5 ± 9.9 to 15.0 ± 3.2 mg/dl (-41.1%). In one patient there was a continuous decrease of Fn from 41.0 down to only 6.4 mg/dl. Conclusion: According to the results of animal experiments, the decrease of Fn seems to indicate depression of the RES. Besides its defense function, Fn probably plays a role in embryogenesis, wound healing, and blood clotting. Therefore, we assume that the drug-induced reduction of Fn possibly has clinical relevance.

Objective: Since plateletpheresis is being used increasingly, it is important to regard quality control to check health risks for donors and to exclude these. Design: Controlled randomised prospective open comparative study. Setting: Department of Transfusion Medicine of a University Clinic. Participants: 112 platelet donors were examined. Interventions: Prior to and after plateletpheresis platelet reactivity was determined. The platelet concentrates in the two groups of 56 donors each were produced using either the cell separator ‘CS-3000’ and the collecting chamber PLT 30TM with the OmnixTM system (group I) or the cell separator ‘AS-104’ (group II). Results: In group I five donors showed a pathologically increased platelet reactivity (p = 0.1297) after plateletpheresis. In group II there were 10 donors with a pathologically increased platelet reactivity (p = 0.0046) after plateletpheresis. The mean concentration of platelets was reduced by separation using the CS-3000 Omnix from 238 ± 49 · 103/µl to 172 ± 32 · 103/µl (68 ± 27 · 103/µl) and from 243 ± 53 · 103/µl to 180+31 · 103/µl (63 ± 33 · 103/µl) using the AS-104. In the first case the platelet yield was 3.9 1011 platelets/concentrate, in the latter case it was 2.9 · 1011 platelets/concentrate. The ‘CS-3000 Omnix’ is significantly more effective in separating (58.4 ± 15.5%) than the ‘AS-104’ with 44.2 ± 7.2% (p < 0.0001). Conclusions: Since both donor groups were comparable regarding all factors recorded – especially the cardiovascular risk factors – the separation process could be responsible for the different traumatisation of platelets.

Ziel: Zur Verhütung einer Gefährdung der Gesundheit von Mensch und Tier bei Anwendung von Arzneimitteln fordert der Gesetzgeber im Arzneimittelgesetz die zentrale Erfassung und Auswertung von Arzneimittelrisiken, insbesondere von Nebenwirkungen und Wechselwirkungen mit anderen Mitteln. Bereits seit 1988 müssen die pharmazeutischen Unternehmen einen qualifizierten Stufenplanbeauftragten benennen, der für die Erfüllung der Anzeigepflichten von Arzneimittelrisiken verantwort-lich ist und gemäβ einem internen Maβnahmenplan («Stufenplan») geeignete Maβ-nahmen bei Auftreten von Beanstandungen ergreifen muβ. Quellen und Auswahlkriterien: Grundlagen dieser Übersicht sind die gesetzlichen Bestimmungen, insbesondere das Arzneimittelgesetz und ergänzende Vorschriften, die die Pflichten des Stufenplanbeauftragten präzisieren. Ergebnisse: Blutkomponenten unterliegen ohne Einschränkung den Vorschriften für Arzneimittel, so daβ die entsprechenden Richtlinien für transfusionsmedizinische Einrichtungen unverändert zur Anwendung kommen. In diesem Artikel werden die geltenden Vorschriften zusammengefaβt. Am Beispiel einer transfusionsmedizinischen Abteilung an einer Universitätsklinik wird die praktische Umsetzung dar-gestellt. Schluβfolgerungen: Im Zusammenhang mit der Übertragung viraler Infektions-krankheiten hat sich in den letzten Jahren mehrfach gezeigt, wie wichtig die Funk-tion des Stufenplanbeauftragten für die Ergreifung effektiver Maβnahmen beim Auftreten von schwerwiegenden Nebenwirkungen ist. Durch die in den transfusions-medizinischen Einrichtungen erfolgte Umsetzung der entsprechenden gesetzlichen Bestimmungen konnte die Arzneimittelsicherheit von Blutkomponenten entschei-dend verbessert werden.

SummaryThe plasma clearance of hydroxyethyl starch (HES) depends on the initial molecular weight and the degree of substitution. So far, little attention has been paid to the clinical relevance of the C2/C6 substitution ratio of hydroxyethyl starch.10 patients with cerebrovascular circulatory disturbance received hemodilution therapy for 10 days, consisting of 10% HES 200/0.5 (mean molecular weight 200 kD, degree of substitution 0.5) with a C2/C6 ratio of 13.4. A second group of 10 patients received a starch solution with identical initial molecular weight and degree of substitution but with a C2/C6 ratio of 5.7.After the administration of a single dose, no significant differences between the two groups were observed. After repeated administration, significant differences could be detected in hemorheology, coagulation and elimination (pThe higher C2/C6 ratio of HES 200/0.5/13.4 slows down enzymatic degradation. After repeated administration of this starch, large molecules accumulate which are inefficiently degraded. The same effect has been observed after therapy with highly-substituted HES. This accumulation of large molecules leads to a beneficial longer lasting volume effect. The disadvantages include an increase in plasma viscosity and coagulation disturbances, which cannot be explained with the respective dilution effect alone. For these reasons, the C2/C6 ratio is of clinical relevance and should be included in the product labeling in the future.

Ziel: Prüfung des Einflusses des C2/C6-Besetzungsverhältnisses und des Substitutionsgrades von zwei 6%igen Hydroxyäthylstärke-(HES-)Lösungen auf die Eliminationskinetik und die Fluidität des Blutes. Design: Einfach-blinde prospektive randomisierte Cross-over-Studie. Rahmen: Hämostaseologisch-angiologische Ambulanz der Universitätsklinik Homburg. Teilnehmer: 6 freiwillige, klinisch unauffällige Probanden. Interventionen: Es wurde jeweils eine Infusion von 500 ml zweier verschiedener HES-Lösungen (6% HES 200/0,5 bzw. 6% HES 200/0,62) intravenös innerhalb von einer Stunde verabreicht. Zwischen den beiden Infusionen wurde eine Auswasch-phase von 3 Monaten eingehalten. Gemessen wurden Konzentration und Moleku-largewichtsverteilung der intravasalen HES-Moleküle bis zu 24 h nach Infusion so-wie die Fluidität des Blutes vor und nach Infusion. Ergebnisse: Neben der molaren Substitution (MS), die für die beiden eingesetzten HES-Lösungen unterschiedlich ist, beeinflußt das Besetzungsverhältnis der C2- bzw. C6-Atome (C2/C6-Besetzungsverhältnis) am Glukosering den Abbau der HES-Moleküle. Die entstehenden Degradationsprodukte haben bei hohem C2/C6-Beset-zungsverhältnis und hoher MS ein im Mittel höheres Molekulargewicht. Dies beeinflußt die Fließfähigkeit des Blutes. Während die Hämatokritabnahme eine Stunde nach Infusionsende vergleichbar ist, bleibt die Hämatokriterniedrigung bei hohem C2/C6-Besetzungsverhältnis und hoher MS länger erhalten. Der Plasmaviskositäts-anstieg ist bei hohem C2/C6-Besetzungsverhältnis und hoher MS starker ausgeprägt. Schlußfolgerungen: Die Infusion von HES 200/0,62 führt zu einer wesentlich längeren Verweildauer im Vergleich zu HES 200/0,5, verbunden mit deutlich größeren Degradationsprodukten im Plasma, was einen stärkeren Verdünnungseffekt, aber auch einen stärkeren Anstieg der Plasmaviskosität bis zu 24 h nach Infusionsende bewirkt. Bei der Hämodilutionsbehandlung von Patienten mit arterieller Verschlußkrankheit wird der Einsatz von HES, die einen Plasmaviskositätsanstieg induziert, eher als unwillkommen diskutiert.

Ziel: Ziel der Studie ist die Erprobung und Qualitätssicherung einer speziellen Bocksprungtechnik als fremdblutsparende Maßnahme. Design: An 40 von 100 Patienten mit koronarer Herzkrankheit wurde vor einer aortokoronaren Bypassoperation in einer randomisierten doppelblinden placebokontrollierten Studie Eigenblut in «Bocksprung-Technik» gesammelt. Innerhalb von 8 Wochen wurde jeweils die Gewinnung von 3-4 Erythrozytenkonzentraten und 0,9-1,2 Liter Plasma vorgenommen. Das substituierte Volumen (Verum: HES 200/0,5 10%, Placebo: 0,9% NaCl) entsprach dem Volumen des entnommenen Blutes. Jeder Patient erhielt täglich 200 mg Fe2+ oral. Ergebnisse: Klinisch profitierten nur die mit HES behandelten Patienten in der Phase der Eigenblutgewinnung signifikant. Zwei Patienten zeigten unerwünschte Begleiterscheinungen. Der peri- und postoperative Verlauf war vergleichbar. Nur in der NaCl-Gruppe erhielt ein Patient homologe Erythrozytenkonzentrate. Kein Patient starb pr-ä, perioder postoperativ. Schlußfolgerungen: Von den kardiochirurgischen Patienten kamen nur 40% für eine Eigenblutspende in Frage; für diese scheint die isovolämische Hämodilution mit HES 200/0,5 10% eine geeignete und sichere Form der präoperativen Blutgewinnung zu sein. Eine körperliche Belastung sollte vor und nach jeder Eigenblutspende durchgeführt werden. Bei verschlechterter Belastbarkeit sollten keine weiteren Eigenblutspenden vorgenommen werden.

One thousand two hundred and fifty-six subjects (apparently healthy subjects and patients with cardiovascular diseases) were registered in a prospective study including demographical and clinical data, rheological parameters (hematocrit, plasma viscosity, erythrocyte aggregation, erythrocyte deformability) as well as the erythrocyte velocity in human nailfold capillaries under resting and postischemic conditions. A multivariate regression analysis showed that under resting conditions there was no correlation between rheological parameters and erythrocyte velocity in capillaries. The blood flow regulation seemed to be so effective, that pathological changes of the blood fluidity showed no effect on the velocity of an erythrocyte passing the capillaries. During vessel paralysis in the early phase of the postischemic hyperemia following a stasis of three minutes in the vasculature distal to a pressure cuff at the upper arm a very clear correlation between the plasma viscosity and the maximum postischemic erythrocyte velocity in ipsilateral cutaneous capillaries could be observed (p < 0.0001) while none of the other rheological parameters seemed to play a role. In a subgroup of diabetic patients the erythrocyte aggregation (measured during stasis) also correlated with the erythrocyte velocity (p = 0.0175) besides the plasma viscosity. This shows that a correlation of rheological parameters with the capillary perfusion could only be found during vessel paralysis. In of diabetic patients besides the plasma viscosity also the erythrocyte aggregation correlated with the mean capillary erythrocyte velocity. Theses results are in agreement with the hypothesis from Barras that plasma viscosity determines the perfusion of microvessels. Under certain conditions e.g. diabetic disorder, also the erythrocyte aggregation plays a role.

+: Pentapharm Ltd., 4002 Basel, Switzerland (Received 31.1.1992; accepted 21.7.1992) In this study adhesivity of leucocytes, neutrophil granulocytes and lymphocytes was compared using 3 different anticoagulants (Li-Heparin, Hirudin, EDTA) in a filtration test. Samples of 10 apparently healthy subjects were used. The filtration rate of leucocytes depends significantly on the anticoagulant (p=O.001). Neutrophil granulocytes, in particular, show a strong adhesivity after use of hirudin. After filtration none of the 10 samples contained neutrophils. After heparin neutrophils were found in 2 samples, and after EDTA in 6 samples. Lymphocytes could be demonstrated in 2 of the heparin samples, in 2 of the hirudin samples, and in 8 of the EDTA samples. The results show that the choice of an anticoagulant has an essential influence on leucocyte adhesivity. In future it has to be found out which anticoagulant ressembles the most the in-vivo conditions.

Background: Oral anticoagulants are routinely used for prevention of thromboembolism in cardiac, arterial or venous diseases. Hemorrhages are serious treatment complications, frequently occurring under long-term and/or high-dose regiments. From animal experiments it is known that coumarin-type anticoagulants may cause capillary dilatation and increased perme- ability, red blood cell extravasation and punctate bleeding. Controlled human trials are lacking. Methods: 31 patients under oral anticoagulation were examined by video capillary microscopy. 52 patients with comparable diseases and treatment but without oral anticoagulation served as controls. Nailfold capillaries of four fingers of each hand were examined and analyzed off-line according to the following criteria: (1) numbers of capillaries investigated, (2) numbers of capillary bleedings, and (3) bleeding incidence (bleedings per 100 capillaries). Results: In 23 out of 31 patients (74.2%) capillary bleedings were observed. The bleeding incidence ranged from 0.33 to 4.29 per 100 capillaries. In contrast, only 4 out of 52 controls were detected with capillary bleedings (2.1%, p< 0.001). The bleeding incidence was 0.34-2.41. In patients on anticoagulation there was no correlation between the number of capillary bleedings and the INR or Quick values. During a two year follow-up of patients on oral anticoagulation no significant difference was found in terms of clinically obvious bleedings in patients with or without capillary bleedings. Conclusion: This study shows that capillary bleedings can be demonstrated in patients on oral anticoagulation. Bleedings occur independent of the INR-value. Thus, other factors than the vitamin-k-dependent coagulation effect seem to be causal for the damage of microvessels. Further, the evidence of capillary bleedings is not a prognostic indicator for future hemorrhage.

Sodium pentosanpolysulfate (Fibrezym) and unfractionated heparin (Liquemin) had significant antithrombotic efficacy in rats. 1 mg/kg body weight (BW) FibrezymR had its maximal effect 2-4 hours after subcutaneous administration; 200 U/kg BW LiqueminR s.c. were most effective 4-6 hours after application. Both drugs caused frequent embolic break-offs of thrombi during the time periods of maximal antithrombotic efficiency.

The pharmacokinetics of urokinase (two-chain urokinase-type plasminogen activator, tcu-PA) and single-chain urokinase-type plasminogen activator (scu-PA) were studied in 20 patients with acute myocardial infarction (AMI). Ten consecutive patients received 2.5 million units tcu-PA by bolus injection within 5 min during the first 6 h after AMI (group I). Ten further consecutive patients received 250,000 U tcu-PA within 5 min, followed by 4.5 million U scu-PA by intravenous infusion over 40 min (group II). An enzyme immunoassay was developed for urokinase antigen determinations, and a fibrin plate assay for determinations of fibrinolytic activity was applied. Using a 3-compartment model, in group I 98% of urokinase antigen were cleared with a half-life of 60.8 min. After scu-PA, urokinase antigen was cleared with half-lives (area under the curve in parentheses) of 6.9 min (74.8%), 26.5 min (23.6%), and 329.7 min (2.2%). The half-disappearance times of fibrinolytic activity were 18 and 8 min in group I and II, respectively. A more pronounced decrease of plasminogen was observed after tcu-PA.

The influence of additional hirudin in low doses on platelet and coagulation parameters was studied in platelet concentrates (PC) prepared by cytapheresis using citrate-dextrose solution formula A. The in vitro release of platelet factor 4 and β-thromboglobulin was markedly lowered and morphological platelet alterations, as assessed by platelet size studies were considerably less accentuated in the presence of hirudin over a 5-day storage period; this suggests a possibly protecting effect on platelet function. No clear activation of the coagulation and fibrinolysis system was evident during PC storage with and without hirudin since thrombin-antithrombin III complexes and D-dimers did not markedly change.

The potency and tests for thrombogenicity were studied prospectively in 7 different (two lots of each brand, A - G) prothrombin complex concentrates (PCC). Human albumine (H) and a factor IX concentrate (I), served as controls. The potency of coagulation factors and inhibitors varied considerably. Two brands (E, F) contained no protein S, additionally one brand contained no protein C. Two preparations exhibited high amidolytic activities, especially towards the thrombin-sensitive chromogenic substrate S-2238, in vitro. These activities could be quenched in part by the addition of hirudin or antithrombin III. The heparin and antithrombin III content of the PCCs was significantly different, and, after addition of antithrombin III an increase of thrombin-antithrombin III complexes in 2 preparations (B, D) was observed in vitro. Additionally, three brands (B, D, F) caused more severe cardio-pulmonary reactions in rabbits, associated with an increase of fibrin split products for brands B and D. We conclude that the use of these preparations in patients, in whom an acquired protein C or S defect, or a hypercoagulable state, can be suspected, cannot be recommended.

Examination of the interaction between biomaterials and tissues from a clinical realistic as well as scientific viewpoint to complement the highly advanced experimental and biochemical basis research is an undertaking that has suffered a considerable amount of neglect in the past. Attempts to realize internationally a Central Registry for documenting clinically relevant side effects will be reported in detail. Implementation of the registry involves the review of present literature (prospective clinical studies, retrospective studies and case reports). An "incompatibility incident report/questionnaire" has been developed according to the guidelines of the "Report on Pharmacological Side Effects" of the Pharmaceutical Commission of the German Medical Association. The aims of registering and evaluating these reports will be demonstrated and discussed in detail.

Purpose: It was the aim of this study to evaluate antiphospholipid antibodies (APA), i.e. lupus anticoagulants (LA) and anticardiolipin (ACA) IgG and IgM, in ophthalmic occlusive disease. Methods: Over a 3.5-year period, APA were evaluated in 368 patients. Results: Eighty-six patients (23.4%), compared to 5% in the general population, tested positive for APA. APA did not differ significantly between patients with venous (20.6%) or arterial (25.5%) occlusive disease. This included 93 patients with central retinal vein occlusion (18% APA positive), 67 with retinal branch vein occlusion (24% APA positive), 41 with central retinal artery occlusion (22% APA positive), 53 with retinal branch artery occlusion (32% APA positive), 71 with anterior ischemic optic neuropathy (23% APA positive), 12 with posterior ischemic optic neuropathy (33% APA positive) and 31 patients with amaurosis fugax (23% APA positive). Excluding patients with accepted main risk factors, APA were positive in 15.3% of 85 patients. Conclusion: The high APA prevalence confirms its relevance in ocular occlusive disorders.

In future, the capillary microscopy may add to the spectrum of differential diagnosis finding in haemostaseological and angiogical centres as a screening test. Especially the fast and simple observation of the capillary morphology with changes such as capillary dilatations, capillary bleeding (the easiest case, extravasal cells, but also fresh bleeding at the summit of the capillary) and simultaneous findings of torqua-tion of the capillaries seem to be very sensitive for the diagnosis of the von Willebrand-Jürgens syndrome – according to the data collected until now.

Heparin-induced thrombocytopenia (HIT) is a rare but dangerous complication of heparin prophylaxis or treatment. The present laboratory tests to measure heparin-associated antibodies are not specific. The diagnosis of HIT mainly depends on the decrease in platelet count and on clinical symptoms. To evaluate clinical outcome, bleeding complications and platelet counts were evaluated in 45 patients with HIT type II (HIT II) treated prophylactically (subcutaneous injections) or therapeutically (intravenous infusion) with danaparoid. Group I included 24 patients with HIT II without thromboembolic complications who received danaparoid twice daily subcutaneously (10 IU/kg) for a mean of 16 days. Group II included 21 patients with thromboembolic complications. They were treated with intravenous danaparoid (2.6 IU/kg/h ± 1.1) for a mean of 17 days. During subcutaneous prophylaxis, mean anti-Xa levels of 0.2 U/mL and during intravenous treatment, mean anti-Xa levels of 0.4 U/mL were reached. No deaths, amputations, or serious bleeding complications occurred, and no new thromboses were observed in both patient groups.Treatment with danaparoid led to a fast normalization of the platelet counts. This normalization occurred earlier and the concentration of platelets was higher in patients treated with intravenous doses. Danaparoid with subsequent vitamin K-antagonist treatment effectively prevents thromboembolic complications in patients with HIT.

Real-time PCR methods for the detection of RHD and the C, c, and E allele of RHCE were applied for the prediction of fetal Rh phenotype using maternal plasma. In one of 36 samples investigated the DNA extraction failed. When we tested the remaining 35 samples for Rh antigens which were absent on the mother's red cells, the fetal D-status was correctly determined in 26 of 27 cases (1 false negative). Fetal C was tested correctly in 23 samples, c was true positive in the only c-negative woman and the fetal E-status was correctly determined in 35 cases. In conclusion real-time PCR of maternal plasma is a non-invasive method to determine fetal RH genotype. However, more studies are required for routine applications because the method is not 100% sensitive.

Fourteen patients with different types of von Willebrand disease (vWD) having acute bleeds or elective surgery were treated with Immunate(sound recording copyright sign), a double-virus inactivated factor VIII/von Willebrand factor (FVIII/vWF) concentrate. The concentrate was applied as a bolus or via continuous infusion. FVIII activity (FVIIIc), vWF antigen (vWF:Ag), ristocetin cofactor activity (vWF:RCo), collagen binding activity (vWF:CB), activated partial thromboplastin time (aPTT), and von Willebrand multimers (vW-multimers) were monitored for 48 hours. Pharmacokinetic analyses were performed. The clinical efficacy was rated excellent or good. Bleeding complications occurred in 3 patients due to an additional FXIII deficiency in one patient, to a surgically induced bleed in another patient, and a rather short substitution period in the third patient. There were no serious adverse experiences. One patient showed a phlebitic reaction at the site of venous access after more than 100 hours of continuous infusion, requiring a change to application via bolus.

Twenty-four patients with arterial hypertension (WHO class I) received either 4 capsules of an onion-olive oil maceration product, containing essential ingredients of the Mediterranean diet, or placebo daily over a period of one week. In order to investigate the acute effect on arterial blood pressure, measurements were performed before and 5 h after the administration of the first dose of 4 capsules verum or placebo, respectively. For the evaluation of the long term effect further blood pressure measurements were performed after one week's treatment with a daily dose of 4 capsules. After a wash-out phase of 2 weeks followed by a crossover, the second study phase, which was identical in design, was carried out. In addition patients were instructed to measure their blood pressure 4 times daily at home for the whole study period. Haemorheological parameters (platelet aggregation, erythrocyte aggregation, plasma viscosity and haematocrit) were also determined at the measuring points mentioned above. The onion-olive oil maceration product led to a significant decrease in systolic blood pressure. There was also a trend towards a decrease in diastolic blood pressure. The improved blood fluidity observed resulted from a decrease in haematocrit. All effects could be shown immediately and after one week's administration.

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.