[Evaluation of a Vocationally Oriented Concept within Inpatient Oncological Rehabilitation]. / Evaluation eines berufsbezogenen Konzepts im Rahmen der stationären onkologischen Rehabilitation.

AIM OF THE STUDY: We evaluated an occupation-related rehabilitation program, which has been designed to enhance the return to work of cancer patients. As return to work plays an important role to get back to normalcy after suffering from cancer, there is a substantial need for support and evaluated programs. METHODS: The study had a quasi-experimental design with an intervention group (IG) and a comparison group (CG). We defined performance-related outcomes (e. g. return to work, self-assessed working capacity), asked patients if they needed further vocational advice and how helpful they estimated the rehabilitation treatment. 1 year after the end of rehabilitation 309 employed patients had completed the study (65%). We addressed our research questions using non-parametric tests, t-tests, analyses of variance and logistic regressions. RESULTS: Of the 309 patients 58% started rehabilitation not later than 14 days after the end of acute treatment while the other 42% had finished their treatments at least some weeks or even months ago. Patients of the IG evaluated the work-related rehabilitation offers significantly better and needed less additional vocational advice after the end of rehabilitation (n. s.). Regarding the patients, who started rehabilitation not later than 14 days after the end of acute treatment (beginning of rehabilitation n=269, 12 months after rehabilitation n=174), the IG achieved a slightly higher return-to-work-rate 12 months after the end of rehabilitation (81% IG, 76% CG, n. s.). Above that the IG estimated their subjective working capacity significantly more often as fully re-established (IG 46%; CG 29%, p=0,030). CONCLUSIONS: A high percentage of the patients return to work (78%). These results show the success of oncological rehabilitation in helping patients to return to work. In addition, the occupation-related rehabilitation program enhances subjective variables as the satisfaction of the patients regarding the information and the improvement of the patients' working-capacity.

Coagulation activation in patients undergoing directional coronary atherectomy.

Restenosis is a major problem of percutaneous transluminal coronary angioplasty (PTCA) and related procedures. To better understand the underlying pathophysiologic mechanisms, coagulation and fibrinolytic variables were analysed prospectively in 35 patients after directional coronary atherectomy (DCA) and in 20 control patients undergoing diagnostic heart catheterisation and coronary angiography. Blood samples were taken before and 1 h, 24 h and 48 h after the procedure. No subacute thrombosis or unstable angina were documented in any patient. In 8 out of these 35 patients late restenosis was diagnosed during follow-up angiography 3-6 months after DCA. In these 8 patients prothrombin fragments (F1 + 2) rose from 0.7 to 0.9 nmol/l (P < 0.01) and thrombin-antithrombin III complexes (TAT) from 2.9 to 6.0 micrograms/l (P < 0.01), but not significantly in 27 patients without restenosis and in the control patients. In patients with late restenosis plasminogen activator inhibitor (PAI-1) also increased from 2.4 to 4.9 U/ml (P < 0.05) 24 h after DCA while there were no significant changes in patients without restenosis and in control patients. D-Dimer/TAT ratio reflecting the balance between clotting activation and fibrinolysis was significantly lower after 24 h in restenosis patients. The findings suggest that coagulation activation and hypofibrinolysis during 48 h after DCA might be associated with the development of late restenosis.

Anticoagulant fucoidan fractions from Fucus vesiculosus induce platelet activation in vitro.

Anticoagulant fucoidan fractions of different molecular weight and sulfate content were prepared and investigated for their effects on platelet function in vitro. The fucoidan fractions were incubated with human platelet rich plasma (PRP) at concentrations of 5, 10 and 50 micrograms/ml. Platelet activation was subsequently studied by a standard aggregation assay and flow cytometric determination of the activation dependent platelet-surface markers CD62p (P-selectin, GMP-140) and CD63 (GP53). All fucoidan fractions induced irreversible platelet aggregation in a dose-dependent manner. Comparing fractions of identical molecular weight (100 kDa) the low sulfate content fucoidan FF5 (S = 7.6%) exerted a significantly greater effect than the highly sulfated fucoidan FF7 (S = 10.2%) over the whole concentration range (n = 5, P < 0.05). Among fractions of identical sulfate content fucoidan-induced platelet aggregation was also found to depend on the molecular weight of the fucoidan. At concentrations of 10 and 50 micrograms/ml the high molecular weight fraction FF7/1 (150 kDa) showed a significantly greater effect than the 50 kDa fraction FF7/3 (24.8 +/- 6.7 vs. 7.0 +/- 3.5 and 54.6 +/- 13.5 vs. 15.0 +/- 9.0%, respectively; mean +/- SD, n = 5, P < 0.05). The molecular weight dependence of the fucoidan effect was also reflected by the flow cytometric data. Coincubation of FF7/1 and FF7/3 (10 micrograms/ml) with PRP increased the number of CD62p and CD63 positive platelets by 9.0 +/- 3.3 vs. 2 +/- 1.9 and 7.1 +/- 2.4 vs. 3.2 +/- 2.6% over control values, respectively (n = 5, P < 0.05). In conclusion, our results show that the low molecular weight fucoidan FF7/3 combines potent anticoagulant and fibrinolytic properties with only minor platelet activating effects and is therefore a suitable substance for further pharmacological studies.

[The thrombophilic status of patients with inflammatory diseases]. / Thrombophiler Status bei Patienten mit entzündlichen Erkrankungen.

BASIC PROBLEM AND OBJECTIVE OF STUDY: Inflammatory reactions are taken to be nonspecific defensive measures of the organism and are associated with complex changes at cellular and humoral level. Activation of blood coagulation plays an important part in this, especially as it is accompanied by an increased risk of thromboembolism. It was the aim of this investigation to assess this risk by measuring sensitive markers of coagulation activation. PATIENTS AND METHODS: Biochemical markers of coagulation activation (prothrombin-fragment F1 + 2 and thrombin-antithrombin III complex [TAT]) and fibrin formation (D-dimer) were measured in 130 patients (61 men, 69 women; mean age 56.9 [20-89] years). 44 had pneumonia, 44 bronchitis and 42 urinary tract infections. A healthy control group for comparison consisted of 11 men and 15 women (mean age 48.7 [23-79] years). RESULTS: F1 + 2, TAT and D-dimer were significantly increased, compared with the controls, in all three patient groups (P < 0.01). The greatest rises occurred in the patients with pneumonia: F1 + 2: median 1.2 vs 0.6 nmol/I, TAT: 6.2 vs 2.1 micrograms/l and D-dimer 2476 vs 223 ng/ml. CONCLUSION: These findings underline the importance of consistent thrombosis prophylaxis in patients with inflammatory disease, especially those at an increased risk.

The use of prothrombin fragment F1+2 to monitor the effect of oral anticoagulation.

In comparison to a control group of 47 healthy, non-anticoagulated persons, 164 patients under stable oral anticoagulation therapy showed significant reduction in the plasma level of the prothrombin fragment F1+2 (p < 0.0005). Even with low intensity anticoagulation (INR < 2.0), F1+2 levels were reduced to within the normal range (0.32 - 1.2 nM/l) in all patients. The reduction in the plasma level of prothrombin fragment F1+2 is directly dependent on the intensity of oral anticoagulation therapy and provides a means of monitoring the anticoagulation effect achieved. Clinical studies are required to assess the practicality of using F1+2 for monitoring anticoagulation and in particular to assess the usefulness of low levels in predicting bleeding risk and high levels in predicting thrombotic risk during treatment.

[Measurement of prothrombin fragment F1+2 for monitoring the anticoagulant effect of phenprocoumon]. / Messung des Prothrombinfragments F1+2 zur Kontrolle der antikoagulatorischen Wirkung von Phenprocoumon.

It was the aim of this study to ascertain whether the plasma level of prothrombin fragment F1+2 is a suitable indicator of the anticoagulant effect of coumarin derivatives. The F1+2 levels were measured in 164 patients (100 women, 64 men; mean age 63.3 [34-83] years) in whom stable anticoagulation had been achieved with phenprocoumon, comparing the results with those obtained in healthy subjects (28 women, 19 men; mean age 54.6 [25-72] years) without anticoagulation. There was a significant reduction (P < 0.0005) in F1+2 plasma levels with oral anticoagulation (0.45 + 0.23 vs. 0.67 + 0.32 nmol/l). Even on a low degree of anticoagulation (international normalized ratio [INR] < 2.0) the F1+2 value was reduced to within the normal range (0.32-1.2 nmol/l). These results indicate that changes in the plasma level of prothrombin fragment F1+2 are directly dependent on the degree of oral anticoagulation and that this measure seems suitable for the monitoring of the anticoagulant effect. This is also true for oral anticoagulation of mild degree (INR < 2.0) in which the effect cannot be satisfactorily measured by the thromboplastin time (Quick test).

Influence of heparin treatment on biochemical markers of an activation of the coagulation system.

Monitoring of anticoagulant treatment is not yet satisfactory. Otherwise optimal treatment control in special situations as low dose heparin prophylaxis in hip surgery or high dose anticoagulant treatment in patients after coronary stent implantation may be desirable. Recently available thrombin markers were analyzed in 51 patients under low dose (group 1) and 30 patients under high dose therapy with unfractionated heparin (group 2a and b) as well as in controls (n = 26). Before therapy these parameters were significantly elevated in both patient groups. Elevated thrombin-antithrombin III-complexes (TAT) despite adequate prolongation of aPTT under high dose heparin in 38.2% of patients indicate that therapeutic concentrations of heparin in these cases are insufficient for depressing this parameter completely. During low dose therapy only prothrombin fragment (F1 + 2) significantly decreased. This may be explained by catalytic induction of TAT-complex formation by heparin. Decrease of D-Dimer under heparin therapy in both groups does not parallel with TAT and F1 + 2 but was more prolonged. This can be explained by dependence of the D-Dimer level on spontaneous fibrinolytic activity and by a longer plasma half-life as well as a chronic and continuous fibrinolytic process in an older thrombus. In conclusion, thrombin markers seem to be helpful in estimating anticoagulant treatment efficacy. As a consequence, anticoagulant treatment has to be intensified in high-risk patients for complete depression of these markers. Whether the benefit of higher heparin doses is worth the risk of drug-induced hemorrhage, however, remains to be clarified in clinical studies.

Increased levels of fibrinolysis reaction products (D-dimer) in patients with decompensated alcoholic liver cirrhosis.

We studied the activation of coagulation and fibrinolysis in the blood of patients with compensated (n = 25) and decompensated (n = 25) liver cirrhosis. We observed increased blood concentrations of thrombin-antithrombin III (TAT) complexes (p less than 0.001) and of D-dimer (p less than 0.001) in both groups of patients compared with healthy volunteers (n = 25). The blood levels of tissue-type plasminogen activator (t-PA) activity (p less than 0.001) and the concentrations of t-PA antigen (p less than 0.001) were also significantly raised in both groups of patients compared with controls, whereas plasminogen activator inhibitor did not deviate. There were no significant differences in the determined variables between the two groups of patients except that the concentrations of D-dimer were significantly higher (p less than 0.001) in patients with decompensated liver cirrhosis. The ratio between D-dimer and TAT did not deviate between patients with compensated liver cirrhosis and healthy volunteers but was significantly increased in patients with decompensated liver cirrhosis. These observations indicate that efflux from the extravascular space (for example, ascitic fluid) contributes to the high concentrations of fibrin degradation products (D-dimer) in patients with decompensated liver cirrhosis. In addition, we conclude that patients with liver cirrhosis have an enhanced activation of both coagulation and fibrinolysis but that the balance between these two systems is not significantly displaced compared with healthy volunteers.

Influence of cytostatic treatment on the coagulation system and fibrinolysis in patients with non-Hodgkin's lymphomas and acute leukemias.

Cytostatic therapy is known to aggravate tumor-induced coagulopathy. Therefore, we have studied the effect of different chemotherapeutic regimens on the activation of coagulation and fibrinolysis in patients with non-Hodgkin's lymphomas or acute leukemias. In non-Hodgkin's lymphoma patients treated with an aggressive protocol (COL-BLAM) and in leukemia patients (TAD-9) fibrinopeptide A, prothrombin fragment (F1 + 2) and thrombin antithrombin III complexes (TAT) increased (Tables 4 and 6), while D-dimer did not deviate significantly. The ratio D-dimer/TAT consequently showed a significant decrease, indicating increased formation of thrombin after release of procoagulant factors, which is not paralleled by an activation of fibrinolysis. Both these groups were also characterized by an increase in uric acid and in C-reactive protein and plasminogen-activator inhibitor, two acute-phase reactants. In contrast, patients with non-Hodgkin's lymphomas treated with a less aggressive protocol (COP) showed no significant changes in hemostatic variables, uric acid, or acute-phase reactants. The release of procoagulant factors relates to the cytostatic sensitivity of the tumor and to a high tumor-cell destruction. Our results further emphasize the need for large-scale studies on antithrombotic prophylaxis in patients undergoing cytostatic treatment.

Investigations of coagulation system and fibrinolysis in patients with disseminated adenocarcinomas and non-Hodgkin's lymphomas.

Indicating activation of coagulation fibrinopeptide A (FPA) was elevated in 80.1% (mean = 10.5 ng/ml; P less than 0.01) and thrombin-antithrombin III complexes in 58.3% (TAT; mean = 5.3 ng/ml; p less than 0.05) in patients with adenocarcinomas (n = 57). In patients with non-Hodgkin's lymphomas (n = 30), however, elevation was observed only in 66.6% (FPA) and in 42.8% (TAT). Incidence of thrombosis is high only in the first group Local fibrinolysis explains elevated D-dimer in adenocarcinomas (1,818 ng/ml; p less than 0.01) and in non-Hodgkin's lymphomas (576 ng/ml; p less than 0.05). Significantly increased t-PA antigen was not committed by adequately increased t-PA activity in adenocarcinomas, because of high levels of the acute-phase protein, plasminogen activator inhibitor (mean = 25.3; p less than 0.01), indicating systemic hypofibrinolysis. Hemostatic disorder in patients with malignancy can be attributed to a combination of acute-phase reaction and an activation of coagulation.

[Probenecid affects liver metabolism]. / Probenecid beeinflusst den Lebermetabolismus.

The effect of probenecid on the pharmacokinetics of phenprocoumon (PPC) given as a single oral or intravenous dose, on the vitamin-K-dependent protein-C-antigen, and on the pharmacokinetics of antipyrine and 6 beta-hydroxycortisol was determined in 14 healthy volunteers. Probenecid caused a 75% decrease in urinary excretion of PPC and PPC-glucuronide and shortened the plasma half-life of PPC significantly (by about 35%). The results after oral and intravenous administration of PPC did not differ significantly. Plasma protein-C-antigen concentrations following intravenous PPC were significantly increased by probenecid. The plasma half-life of antipyrine after 7 days of probenecid therapy was significantly diminished. Accordingly, urinary excretion of 6 beta-hydroxycortisol was significantly increased. These data appear for the first time to reveal enzyme-inducing properties of probenecid, which may be responsible for the shortening of PPC plasma half-life when probenecid is given simultaneously. In addition, the influence of probenecid on plasma protein-C-antigen concentrations may indicate further effects of probenecid on liver metabolism.

[The effect of liver cirrhosis on activation of the coagulation and fibrinolysis system and on coagulation inhibitors]. / Der Einfluss der Leberzirrhose auf die Aktivierung des Gerinnungs- und Fibrinolysesystems und auf die Gerinnungsinhibitoren.

The activation of coagulation and fibrinolysis as well as coagulation inhibitors in the blood of patients with compensated (n = 25) and decompensated (n = 25) liver cirrhosis were studied. Protein C (PC) was decreased in a more pronounced manner than antithrombin III (AT III) in liver cirrhosis. Thereby, PC proved to be a highly sensible indicator of liver cell dysfunction. Decreased levels of PC activity (PC ratio activity/antigen 0.82) in decompensated liver cirrhosis suggest production of dysfunctional, undercarboxylated PC. We observed increased blood concentrations of fibrinopeptide A (FPA) (p less than 0.05) in both groups of patients compared to healthy volunteers (n = 25), while D-Dimer was increased only in patients with decompensated liver cirrhosis (p less than 0.01). Comparing both groups of patients. D-Dimer was significantly different with higher levels in decompensated liver cirrhosis (p less than 0.01). The ratio D-Dimer/FPA was significantly increased in decompensated liver cirrhosis compared to both other groups. These observations indicate that efflux from the extravascular space, e.g. ascitic fluid, contributes to the high contents of fibrin degradation products (D-Dimer) in patients with decompensated liver cirrhosis. In summary we conclude that patients with liver cirrhosis have enhanced activation of both coagulation and fibrinolysis but that the balance is not significantly displaced.

Immunological and functional determination of the protease inhibitors, protein C and antithrombin III, in liver cirrhosis and in neoplasia.

Using a new rapid coagulant method, protein C activity (PC act) was determined in liver cirrhosis and malignancies and compared with PC antigen and AT III values. PC was decreased in a more pronounced manner than AT III in liver cirrhosis, mainly due to impaired synthesis. This is of special clinical interest because PC proved to be a high sensible indicator of liver cell dysfunction. Decreased levels of PC act (PC ratio act/ag less than 1) in decompensated liver cirrhosis may be caused by the synthesis of dysfunctional PC and/or vitamin K deficiency with production of undercarboxylated PC most sensitively registered by this coagulant assay. An increased clearance of in vivo activated PC induced by DIC may play an insignificant role. In patients with liver metastases, PC act (but not AT III and immunological parameters) was significantly reduced, supporting the conclusion that in these patients liver dysfunction concomitant with synthesis of dysfunctional PC must be discussed as the main cause of this alteration.

[Immunologic and functional protein C determination in various internal diseases]. / Die immunologische und funktionelle Protein C-Bestimmung bei verschiedenen internistischen Erkrankungen.

A new practicable and precise functional protein C evaluation test is based on the activation of protein C by a snake venom activator and determination of PC activity by its property to prolong the aPTT in a clotting assay (VK = 1.9% and 4% for intra- and interassay variance respectively). In 40 healthy controls there was a good correlation (r = 0.74) between the functional and immunological (ELISA) evaluation. In 123 patients with both evaluation methods but more pronounced with the measurement of the protein C activity a significant protein C deficiency was found in the patient groups with disseminated solid tumors, inflammatory diseases and myocardial infarction. Besides detection of hereditary PC deficiency Type II (generation of functionally abnormal PC) the functional assay profits by recording PC inhibitor complexes and otherwise dysfunctional PC in DIC. Thus, in patients with hematological neoplasias, only protein C activity was significantly decreases. Decrease of PC activity was more pronounced compared to PC Ag in liver disease indicating synthesis of functionally deficient PC, and in oral anticoagulant treatment due to detection of PIVKA-PC.