Bone matrix quality and plasma homocysteine levels.

It has recently been reported in the clinical literature that blood homocysteine levels correlate well with fracture risk, although a couple of reports exist to the opposite. Bone strength depends on both bone quantity and quality. The purpose of the present study was to investigate possible correlations between plasma homocysteine levels and bone material properties (Bone Mineral Density Distribution; BMDD, and collagen cross-link ratio). In the present study, femoral heads from subjects (N=19, females, age range 70-95 years old) with known homocysteine plasma levels were investigated. The bone material was collected during hemiarthroplasty surgery. We have determined collagen cross-link ratio and bone mineralization density distribution (BMDD) in bone tissue from patients with acute femoral neck fractures, by Fourier Transform Infrared Imaging (FTIRI) and quantitative Backscattered Electron Imaging (qBEI), respectively. The collagen cross-link ratio that was spectroscopically determined was pyridinoline/divalent cross-links (pyr/divalent). The BMDD variables quantified were: CaMean: the weighted mean calcium concentration; CaPeak: the most frequent Ca concentration; CaWidth: the width of the distribution, a measure of the mineralization homogeneity; CaLow: the percentage of bone area that is mineralized below the 5th percentile in the reference range; CaHigh: the percentage of bone area that is mineralized above the 95th percentile in the reference range. There was a significant correlation between plasma homocysteine levels and collagen cross-link ratio in areas of primary mineralized bone (p<0.0001), unlike the case of trabecular bone surfaces undergoing resorption (p>0.05). On the other hand there was no correlation in any of the BMDD parameters and plasma homocysteine levels (p>0.05). The results are consistent with the known effect of homocysteine on collagen post-translational modifications. These changes were independent of bone mineral characteristics. The results of the present study offer a mechanism by which homocysteine affects bone quality, but caution should be exercised since all patients examined had sustained fracture.

Gamma-hydroxybutyric acid in the treatment of alcohol withdrawal syndrome in patients admitted to hospital.

Gamma-hydroxybutyric acid is a gamma-aminobutyric acid analogue which can be found in the human brain and is believed to be a neurotransmitter in the central nervous system. In animal experiments as well as in humans gamma-hydroxybutyric acid has been shown to alleviate the symptoms of the alcohol withdrawal syndrome. 299 patients, who were admitted to hospital for reasons primarily unrelated to their alcohol dependence, were treated with gamma-hydroxybutyric acid when symptoms of the alcohol withdrawal syndrome occurred. Gamma-hydroxybutyric acid was usually given at a daily dose of 50 mg/kg in 3 divided doses, the clinical course of the patients was followed for 7 days or until discharge from hospital. Patients were 214 men and 82 women aged 18-87 years. The reasons for admission to hospital were frequently internal diseases, neurological/psychiatric problems, trauma or surgery. At the start of gamma-hydroxybutyric acid treatment, tremor was present in 81% of patients, sweating in 76% and unrest in 92%. Symptoms occurred 1-72 hours after admission. The efficacy of gamma-hydroxybutyric acid to ameliorate or suppress the symptoms of the alcohol withdrawal syndrome was judged to be excellent in 57%, good in 34%, fair in 18%, insufficient in 3% of patients. Drug tolerance was judged to be excellent in 79%, good in 17%, fair in 2% and poor only in 1% of patients. Adverse events were rare and mild. It is concluded that gamma-hydroxybutyric acid is an attractive alternative to tranquilizers in the management of the alcohol withdrawal syndrome in hospital.

Thromboprophylaxis with 60 mg enoxaparin is safe in hip trauma surgery.

BACKGROUND: Little information is available concerning dosage and optimal initiation of thromboprophylactic therapy with low-molecular-weight heparin (enoxaparin) in nonelective hip surgery. The aim of our prospective study was to evaluate the incidence of clinically apparent deep vein thrombosis (DVT), pulmonary embolism (PE), and major hemorrhage in patients receiving thromboprophylaxis with enoxaparin undergoing hip surgery after hip fracture. METHOD: From 946 consecutive patients admitted with hip fractures, 897 were operated on and received enoxaparin according to the following regimen: Preoperative heparinization from time of admission onwards. Administration of 60 mg enoxaparin, in two doses (20 and 40 mg subcutaneously), during the first 5 days postoperatively. Prophylaxis for a minimum of 5 weeks (40 mg daily). RESULTS: Clinical signs of DVT were present in 37 patients (4.2%), who all underwent venography. In five patients, DVT was confirmed (0.6%). None of these patients suffered from PE. Another four patients (0.4%) developed clinical signs of PE, and suspected diagnosis was confirmed by computed tomographic scan in two (0.2%). No deaths because of PE were observed. Major hemorrhage occurred in 42 patients (4.7%), there was one death from hemorrhage caused by an intracerebral event. No case of heparin-induced thrombocytopenia type II was observed. CONCLUSION: Thromboprophylaxis with 60 mg enoxaparin daily, in split doses, starting before surgery, is safe and appropriate in patients with hip fractures. Clinically apparent DVT and PE are rarely observed, and bleeding complications are comparable to those occurring with a conventional thromboprophylactic regimen.

Predicting the risk of restenosis after angioplasty in patients with peripheral arterial disease.

Restenosis is a serious therapeutic problem after percutaneous transluminal angioplasty (PTA). Strategies for the prevention of late restenosis include the use of antiaggregatory and anticoagulant drugs, aggressive lipid-lowering, intravascular radiation and others. As some of these therapeutic options are not without side effects it is important to identify patients with an increased risk to develop restenosis. Major clinically recognizable risk factors for restenosis are advanced disease stage and female gender. Elevated plasma levels of fibrinogen, Lp(a), CRP, and migration-inducing activity appear to indicate an unfavorable clinical outcome, and so does post-interventional increase of vWF and PAI-1 antigen. For peripheral arterial disease, only one study has addressed the influence of homocysteine levels upon the restenosis rate after PTA. Although homocysteine levels were elevated in >50% of patients at entry, they were not associated with a higher restenosis rate. Currently the available data allow a rough approximation of a patient's individual risk.

Smooth muscle cell migration promoting activity of plasma predicts restenosis in patients with peripheral arterial occlusive disease undergoing angioplasty.

BACKGROUND: Efficacy of percutaneous transluminal angioplasty (PTA) is limited by restenosis occurring in a large proportion of patients. Smooth muscle cell (SMC) migration is a major pathomechanism of restenosis. We studied SMC migration inducing activity of plasma from patients with peripheral arterial occlusive disease (PAOD) undergoing PTA. METHODS AND RESULTS: SMC migration was determined in a two-dimensional assay system after addition of 1/25 plasma dilutions. Mean increase in migration area was 65.5 +/- 33.8% in normal controls and 67.7 +/- 53.2% in patients with PAOD. 6 hours after PTA, plasmatic migration inducing activity was largely unchanged. In 19/30 patients with restenosis (6 months after PTA) migration promoting activity (82.7 +/- 60.0) was significantly higher than in 11/30 patients with patent vessels (41.8 +/- 21.0; p = 0.03). No correlation of clinical risk factors with outcome was observed. A weak correlation was found between plasmatic migration promoting activity and levels of epidermal growth factor and transforming growth factor-beta. CONCLUSION: The capacity of human plasma to stimulate SMC migration in tissue culture can be used to assess the risk for restenosis after PTA in patients with PAOD.

Hepatic synthesis and clearance of components of the fibrinolytic system in healthy volunteers and in patients with different stages of liver cirrhosis.

We determined plasma levels of tissue-type plasminogen activator (t-PA) antigen, urokinase-type plasminogen activator (u-PA) antigen, and activity of the fast acting inhibitor of plasminogen activator (PAI-1) in patients with different stages of liver cirrhosis (Child A, B, and C) and in age and sex-matched healthy controls to investigate the contribution of the liver to the metabolism of these main components of the fibrinolytic system. For control purposes routine clotting parameters were also determined. In patients with the most severe form of liver cirrhosis (Child C) t-PA antigen levels were significantly elevated as compared to patients with Child A or Child B (p less than 0.05) or to controls (p less than 0.01). Furthermore, Child C patients exhibited significantly decreased PAI-1 plasma levels (p less than 0.05) as compared to controls. We were not able to demonstrate, however, any significant correlation between liver function and u-PA plasma levels. Furthermore, t-PA antigen and albumin plasma levels were negatively correlated (r = 0.48; p = 0.0015) and t-PA antigen and bilirubin were positively correlated (r = 0.46; p = 0.0022) thus indicating that the liver is mainly involved in the clearance of t-PA antigen. PAI-1 activity, however, seems to depend partially on synthesis by the liver as demonstrated by a positive correlation between PAI-1 and albumin (r = 0.33; p = 0.037). These physiologic liver functions are both progressively attenuated in severe liver damage and an increase of t-PA plasma levels and a decrease of PAI-1 might contribute to the higher fibrinolytic tendency observed in those patients.

Disseminated intravascular coagulation and decrease in fibrinogen levels induced by vincristine/prednisolone therapy of lymphoid blast crisis of chronic myeloid leukemia.

Therapy with vincristine (2 mg i.v. weekly) and prednisolone (100 mg p.o. daily) caused a decrease in fibrinogen levels in nine patients treated for lymphoid blast crisis LBC) of chronic myeloid leukemia (CML). During the first days of treatment disseminated intravascular coagulation (DIC), evidence by a positive ethanol gelation test, markedly increased thrombin-antithrombin III complex and fibrin-split product D-dimer levels, and a rapid fall in fibrinogen levels was observed in two patients. The induction of DIC in these two patients caused profuse bleeding in one and necessitated substitution therapy with fibrinogen and platelet concentrates. The remaining seven patients revealed no signs of DIC; nevertheless, four of them showed a moderate increase in D-dimer levels after initiation of therapy. In these patients a well-known side effect of long-term steroid therapy, namely a decrease of fibrinogen levels, was observed within the first week of treatment. Fibrinogen levels did not fall below 150 mg/dl and increased after dose reduction from 100 mg/day to 50 mg/day. We conclude from our results that two types of disturbances in fibrinogen metabolism can be observed during vincristine/prednisolone therapy of LBC of CML: (a) a decrease of fibrinogen levels due to a steroid-mediated impairment of liver synthesis, and (b) a rapid fall in fibrinogen levels in the course of DIC, most likely induced by the release of procoagulants from deteriorating blast cells, leading to severe bleeding in selected cases.

Activation of coagulation and fibrinolysis in patients with arteriosclerosis: relation to localization of vessel disease and risk factors.

Activation markers of blood coagulation and fibrinolysis and several fibrinolytic parameters were determined in arteriosclerotic patients to investigate the relation between extension and main localization of vessel disease, risk factors and disturbances within the blood coagulation and the fibrinolytic system. Indications of an increased intravascular fibrin formation and subsequent fibrinolysis were found in peripheral artery disease (PAD) patients but not in coronary artery disease (CAD) patients. Compared with healthy controls PAD patients had elevated TAT (median: 3.2 ng/ml, 1.5-70 vs. 2.1, 1.2-4.7, p less than 0.005) and D-Dimer (median: 365 ng/ml, range 85-2000 vs. 185, 79-360; p less than 0.0001) plasma levels, whereas TAT (2.4, 1.2-13) and D-Dimer (190, 58-1000) levels of CAD patients were in the normal range. No associations were detected between risk factors of arteriosclerosis (hyperlipidemia, diabetes mellitus, cigarette smoking, hypertension) and the plasma levels of the activation markers TAT and D-Dimer. Independent from risk factors PAD and CAD patients had elevated plasma plasminogen activator inhibitor capacity (PAI cap). Our results provide evidence that 1) increased plasma levels of blood coagulation and fibrinolysis activation markers are not related to risk factors of arteriosclerosis but seem to be unspecifically caused by activation processes on arteriosclerotic vessel wall defects, 2) increased plasma PAI cap found in arteriosclerotic patients is a relatively unspecific phenomenon associated with arterial vessel disease.

[A fatality caused by heparin overdose]. / Todesfall infolge Heparinüberdosierung.

Because of suspected pulmonary embolism 550.000 I.U. of heparin were administered instead of 55.000 I.U. of heparin within 24 h to a 62 year old patient. The man died because of cerebral hemorrhage the following day. Autopsy findings are reported and difficulties in medical expertise are discussed.

Evidence for an increased generation of prostacyclin in the microvasculature and an impairment of the platelet alpha-granule release in chronic renal failure.

The formation of prostacyclin (PGI2) and thromboxane A2 and the release of beta-thromboglobulin (beta-TG) at the site of platelet-vessel wall interaction, i.e. in blood emerging from a standardized injury of the microvasculature made to determine bleeding time, was studied in patients with end-stage chronic renal failure undergoing regular haemodialysis and in normal subjects. In the uraemic patients, levels of 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) were 1.3-fold to 6.3-fold higher than the corresponding values in the control subjects indicating an increased PGI2 formation in chronic uraemia. Formation of thromboxane B2 (TxB2) at the site of plug formation in vivo and during whole blood clotting in vitro was similar in the uraemic subjects and in the normals excluding a major defect in platelet prostaglandin metabolism in chronic renal failure. Significantly smaller amounts of beta-TG were found in blood obtained from the site of vascular injury as well as after in vitro blood clotting in patients with chronic renal failure indicating an impairment of the alpha-granule release in chronic uraemia. We therefore conclude that the haemorrhagic diathesis commonly seen in patients with chronic renal failure is--at least partially--due to an acquired defect of the platelet alpha-granule release and an increased generation of PGI2 in the microvasculature.

[High dosage and intermediate dosage cytosine arabinoside in the treatment of secondary leukemias]. / Hochdosiertes und mittelhochdosiertes Cytosinarabinosid zur Behandlung von sekundären Leukämien.

Patients with secondary acute myeloid leukaemia (AML) following treatment with alkylating agents and/or radiation show a poor response to standard induction therapy. Between 1983-1987 8 consecutive patients were treated with high-dose cytosine arabinoside (HD-ARA C; 3 g/sqm twice daily for 6 days) or intermediate-dose cytosine arabinoside (ID-ARA C; 0.5 g/sqm twice daily for 6 days). Complete remission was achieved in 3 patients (HD-ARA C: 2/3l; ID-ARA C: 1/5) and partial remission in 3 patients (ID-ARA C: 3/5). One patient (HD-ARA C) died during prolonged aplasia, one patient (ID-ARA C) proved refractory to treatment. The respective duration of remission in the 3 responsive patients was 3, 7 and 8 months. The probability of survival of the whole group was 50% after 12 months and 25% after 24 months. Our results confirm the efficacy of monotherapy with ARA C in the treatment of secondary AML. Consolidation therapy with ID-ARA C for 4 days seems to prolong remission.

Levels of plasminogen activator inhibitor in patients with angina pectoris.

Levels of plasminogen activator inhibitor type 1 (PAI) were measured in 180 patients with angina pectoris (148 males and 32 females, age range 29 to 70 years). An age-matched normal population served as a control. PAI was determined by a functional titration assay, its activity was expressed as arbitrary units (AU). PAI levels were significantly (P less than 0.005) higher in patients with angina (24.3 +/- 10.3 AU/ml) than in normals (20.4 +/- 4.6 AU/ml). PAI levels were unrelated to sex or age in both the patient and the control groups. Plasma triglyceride levels were correlated to PAI in patients and in normals. Patients with a history of previous myocardial infarction (n = 114) had similar PAI levels as patients without infarction (24.2 +/- 11.1 AU/ml as compared to 24.4 +/- AU/ml). It is concluded that PAI levels are elevated in patients with coronary heart disease, whether myocardial infarction has taken place or not.

[Home treatment in hemophilia]. / Die Heimtherapie der Hämophilie.

88 patients with severe haemophilia (66 with haemophilia A without inhibitor, 12 with haemophilia A and inhibitor, 10 with haemophilia B) currently receive comprehensive care at the Vienna haemophilia centre. Data available at the centre and a questionnaire answered by the hemophiliacs were used in order to evaluate the current situation of home care. At present, 62 (70%) out of 88 patients receive home treatment (51 with haemophilia A without inhibitor, 5 patients with haemophilia A and inhibitor and 6 with haemophilia B). For treatment of joint and muscle bleeding mean dosages of 15.3 units/kg body weight of factor VIII concentrate, 17.0 units/kg of factor IX concentrate and 30 units/kg of FEIBA were administered by the hemophiliacs. Children and young patients required higher doses (30 and 17.4 units/kg F VIII, respectively). Two thirds of the bleeding episodes were successfully treated by a single infusion. No severe side effects were observed during home treatment. Home treatment has been widely accepted by the patients. It is regarded as a practical and safe therapy and has improved the life quality of haemophiliac patients.

Enhanced fibrinolysis caused by tissue plasminogen activator release in hemodialysis.

The effect of hemodialysis on components of the fibrinolytic system was measured in 22 patients. Plasma levels of t-PA antigen, t-PA activity, u-PA antigen and plasminogen activator inhibitor were determined by means of immunological and functional assays. During hemodialysis, 11 patients exhibited an increase in t-PA antigen within the first hour to about three times the starting values (P less than 0.05), followed by a decrease to about double of the initial values until the end of the treatment. Eleven patients showed a continuous increase up to 200% of the starting values until the end of hemodialysis. u-PA levels did not change significantly during the time of investigation (P greater than 0.5).

Evaluation of fibrinolytic capacity by a combined assay system for tissue-type plasminogen activator antigen and function using monoclonal anti-tissue-type plasminogen activator antibodies.

An assay system has been developed that allows consecutive quantification of tissue-type plasminogen activator (t-PA) activity and t-PA antigen in the same plasma sample. In the first step t-PA is bound to an immobilized IgM monoclonal anti-t-PA antibody and functional activity of bound t-PA is quantified by its plasminogen-activating activity. In the second step the amount of bound t-PA antigen is determined by using a different peroxidase-labeled monoclonal anti-t-PA antibody. In this combined assay system t-PA functional activity was found to depend not only on the amount of t-PA antigen but also on the amount of plasminogen activator inhibitor (PAI), whereas in the t-PA antigen assay PAI did not affect the results. In plasma samples obtained from normal controls t-PA activity was detected only in post-venous occlusion plasma (3.7 +/- 2.5 IU/ml), whereas 2.7 +/- 0.5 ng/ml t-PA antigen was found before and 12.6 +/- 4.4 ng/ml after venous occlusion. Using this combined assay system to study plasma samples from patients who did not respond to venous occlusion with shortening of the euglobulin clot lysis time (ECLT), it was possible not only to confirm that in none of these patients could t-PA activity be detected in the postocclusion plasma samples but also to subdivide that group of patients into a group of about 39% not reacting with normal t-PA antigen release to venous occlusion and into a second group of about 61% that reacted with normal t-PA antigen release.(ABSTRACT TRUNCATED AT 250 WORDS)

[Oral anticoagulant therapy--renaissance of an old therapy?]. / Orale Antikoagulantientherapie--Renaissance einer alten Therapie?

Although the antithrombotic potential of oral anticoagulants is undisputed, bleeding complications constitute a serious problem. One of the main causes for these complications has been a lack of standardization of the prothrombin time. The introduction of the International Normalized Ratio (INR) has led to a better standardization of prothrombin time. Thus, the same level of anticoagulation can be reached using different reagents and therefore over- and undercoagulation can be avoided. Furthermore, the benefit/risk ratio can be improved by adapting the intensity of anticoagulation to the indication. The following clinical conditions are established indications for treatment with oral anticoagulants: Prevention of cardiac emboli in acute anterior myocardial infarction with atrial thrombus, in patients with atrial fibrillation with or without mitral valve disease, in patients with prosthetic heart valves and in patients with dilated cardiomyopathy. Furthermore, oral anticoagulants should be given to patients after femoropopliteal bypass. A relatively mild oral anticoagulant treatment (INR 2-3) is sufficient to prevent recurrences of venous thrombosis and pulmonary emboli. The duration of treatment in patients with venous thromboembolism depends on some clinical features and the results of clotting tests which indicate an increased tendency to thrombosis.

[Right heart failure as a clinical sign of pulmonary artery sarcoma]. / Rechtsherzinsuffizienz als klinisches Zeichen eines Pulmonalarteriensarkoms.

A 43 year-old female patient was admitted on account of severe dyspnoea of several months' duration and thrombocytopenia. The clinical symptomatology was compatible with pulmonary embolism, but no source of embolization was found and heparin therapy did not lead to clinical improvement. Angiography of the pulmonary artery revealed multiple filling defects. Symptoms improved after treatment with cortisone and so a malignant process was assumed. The patient died from right ventricular failure before the diagnosis could be established. At autopsy a sarcoma of the pulmonary artery, obviously originating from the pulmonary trunk was found. Thrombocytopenia most probably resulted from consumption of platelets by a mechanism corresponding to the Kasabach-Merritt syndrome. The difficulties in the diagnosis of pulmonary artery sarcomas are discussed and the 69 previously published cases are reviewed.