[Activated protein C resistance in patients with venous leg ulcer]. / Aktiveret protein C-resistens hos patienter med venøst ulcus cruris.

Patients with venous leg ulcers often show evidence of previous deep venous thrombosis. Resistance to activated protein C (APC-resistance) is an autosomal dominant inherited defect in the anticoagulant system which is a significant risk factor for development of venous thrombosis. APC-resistance was determined in plasma samples obtained from 46 unselected, consecutively admitted patients with venous leg ulcers, included during a six-month period. Twelve of the 46 patients (26%) (95% confidence limits: 14%-41%) had APC-resistance. APC-resistance is thus a common anticoagulant deficiency among venous leg ulcer patients and should be considered a risk factor for development of venous leg ulcer disease.

[Copper-induced green hair. Treatment with a penicillamine containing shampoo]. / Kobberinduceret grønt hår. Behandling med en penicillaminshampoo.

A male patient with green hair is described. The cause was exogenous deposition of copper from domestic tap water which contained an increased copper concentration. The discolouration disappeared promptly following the use of a penicillamine containing shampoo.

Resistance to activated protein C: a common anticoagulant deficiency in patients with venous leg ulceration.

Patients with leg ulcers caused by venous insufficiency often show evidence of previous deep venous thrombosis. Resistance to activated protein C (APC resistance) is a newly identified, autosomal dominant inherited defect in the anticoagulant system which significantly predisposes affected individuals to develop venous thrombosis. To elucidate the significance of APC resistance in venous leg ulcer patients, APC resistance was determined in plasma samples obtained from 46 unselected, consecutive patients with venous leg ulcers, admitted to hospital during a 6-month period. Twelve of the 46 patients (26%: 95% confidence limits, 14-41%) had APC resistance. APC resistance is thus a common anticoagulant deficiency among patients with venous leg ulceration and should be considered a risk factor for the development of venous leg ulcer disease.

[Asymptomatic sexually transmitted infections among HIV-tested persons]. / Asymptomatiske seksuelt overførte infektioner hos HIV-testede.

We have prospectively determined the frequency of asymptomatic sexually transmitted diseases (STD) among patients seeking an HIV-test. In 246 patients, we observed 32 cases (13%) of asymptomatic STD, predominantly infections caused by Chlamydia trachomatis or human Papillomavirus. STD screening is of significance among patients seeking an HIV-test.

Low anti-streptokinase IgG concentrations following streptokinase-streptodornase treatment of leg ulcer patients.

We have evaluated whether neutralising anti-streptokinase IgG antibodies are produced following streptokinase-streptodornase therapy of leg ulcer patients. Serum anti-streptokinase IgG concentrations in 10 leg ulcer patients were determined before, and 1 week, 2 weeks, and 3 weeks following the treatment. We observed only a negligible increase in neutralizing anti-streptokinase IgG concentrations during the observation period, which was probably of no therapeutical significance.

Vein surgery with or without skin grafting versus conservative treatment for leg ulcers. A randomized prospective study.

In order for us to evaluate the efficiency of perforator vein surgery and skin grafting in leg ulcer patients, 47 patients were randomized into 3 treatment groups (group A: surgery for incompetent perforators, group B: surgery for incompetent perforators and ulcer excision followed by grafting, group C: control group). All the patients were treated with a compression bandage. When cellulitis was observed, a systemic antibiotic was given; eczema was treated with a steroid ointment. Fourty patients were evaluated regularly during one year after entry. There were no differences between the 3 treatment groups considering base-line characteristics, median ulcer size at entry and after one year. According to a review of the initial phlebograms, the occurrence of post-thrombotic changes in the deep veins were recorded in the majority of the legs. Our results suggest that ligation of incompetent perforators and skin grafting, as used in the present study, may not offer an additional advantage for venous ulcer patients with insufficiency of the deep veins when compared to conservative treatment. However, the removal of insufficient superficial veins was not studied.

[Plasmin-mediated activation of the coagulation system. A study of patients with acute ischemic heart disease treated with recombinant tissue-plasminogen activator]. / Plasminmedieret aktivering af koagulationssystemet. En undersøgelse af patienter med akut iskoemisk hjertesygdom behandlet med rekombinant voevsplasminogenaktivator.

We have studied the response of haemostatic reaction products in peripheral blood of patients with acute ischaemic heart disease receiving combined recombinant tissue type plasminogen activator/heparin therapy. We have found evidence that formation of excessive amounts of plasmin in vivo in relation to such therapy significantly enhances the degradation of fibrin, and of fibrinogen as well as the formation of thrombin. We conclude that excessive plasmin formation by thrombolytic therapy causes systemic effects including activation of coagulation.

Fibrinolysis in patients with acute ischaemic heart disease. With particular reference to systemic effects of tissue-type plasminogen activator treatment on fibrinolysis, coagulation and complement pathways.

The plasminogen activator systems in the blood, the coagulation system, and the complement pathways are reviewed. The review describes the role of the vascular intima in activation of coagulation and fibrinolysis and the interrelations between the complement system and haemostatic mechanisms. Physiological activation of fibrinolysis may be triggered by and limited to fibrin because of a special affinity of plasminogen and plasminogen activators. The binding of plasminogen to fibrin is regulated by histidine-rich glycoprotein, and the primary physiological inhibitor of generated plasmin is alpha 2-antiplasmin and especially the plasminogen-binding form of this immediate plasmin inhibitor. Plasminogen activator inhibitors in the blood, that is, notably plasminogen activator inhibitor type 1 (PAI-1), bind circulating tissue-type plasminogen activator (t-PA). However, local fibrinolysis in vivo mediated by t-PA may be independent of complex formation between plasminogen activator inhibitors and t-PA in the fluid phase. Circulating plasminogen activator inhibitors might regulate fibrinolysis by increasing the clearance of t-PA from the blood. The urokinase-type and factor XII-dependent fibrinolytic proactivator system can be activated following t-PA-mediated generation of plasmin, and could thus serve as an amplification system of t-PA-induced fibrinolysis. It is claimed that the as yet uncharacterized proactivator is essential for optimal generation of plasminogen activator activity by the factor XII-dependent fibrinolytic system. The normal antithrombotic condition of the vascular intima probably results from lack of tissue factor activity and the presence of significant antithrombotic components comprising, among others, antithrombin III and the protein C-protein S system. A number of pathophysiologic stimuli, notably mediators of the acute phase response such as the cytokines interleukin-1 and tumour necrosis factor-alpha (cachectin), have the potential to induce the vascular endothelium to express procoagulant activity. Vascular endothelium promoting coagulant activity releases increased amounts of t-PA antigen and PAI-1 antigen into the circulation, and elevated levels in the blood of both may be regarded as a marker of a generalized procoagulant condition involving the vascular endothelium. In a prospective study in patients with unstable angina pectoris, patients in whom disease progresses and acute myocardial infarction develops, have increased amounts of t-PA antigen and PAI-1 antigen in the blood. This suggests that the procoagulant potential and atherosclerotic process of the vascular intima is more pronounced in the risk group.(ABSTRACT TRUNCATED AT 400 WORDS)

The fibrinolysis and coagulation systems in ischaemic heart disease. Risk markers and their relation to metabolic dysfunction of the arterial intima.

This report reviews the major haemostatic deviations associated with the evolution of ischaemic heart disease (IHD) and also such deviations, which might be of importance for the evolution of the acute ischaemic heart syndrome. It is demonstrated that deviation in the t-PA/PAI-1 system indicate endothelial cell dysfunction in patients with IHD. Different factors which have the capability to induce such an endothelial cell dysfunction are proposed, i.e. hyperinsulinemia, mediators of chronic disease phase response, and thrombin. Finally, the intimate interrelation between coagulation and fibrinolysis in patients with IHD is discussed. The experimental and clinical studies reviewed provide good evidence that the endothelial cell response of t-PA and PAI-1 is coupled and that there is an intimate interrelation between generation of thrombin and production/release of t-PA and PAI-1 in IHD patients.

Depression of factor XII-dependent fibrinolytic activity in survivors of acute myocardial infarction at risk of reinfarction.

Defective fibrinolysis may constitute a risk for the development of myocardial infarction in patients with ischaemic heart disease. We studied prospectively the factor XII-dependent plasminogen proactivator system in 49 survivors of an acute myocardial infarction. Blood samples were collected 8 weeks after hospital discharge. The factor XII-dependent fibrinolytic activity in the specimens was determined on fibrin plates after complete immuno-inhibition of the urokinase-like and the t-PA related fibrinolytic systems. During the subsequent follow-up period of 2.4 years, 10 patients developed recurrent myocardial infarction, whereas the remaining 39 patients did not. The reinfarction group of patients had a significantly lower median factor XII-dependent fibrinolytic activity (24.9 blood activating units (BAU).ml-1) than the patients without a relapse (41.9 BAU.ml-1, P < 0.02). Plasma concentrations of factor XII did not deviate significantly between the groups (P > 0.05), whereas the median plasma concentrations of prekallikrein was slightly lower in the reinfarction group (90%) than in the non-reinfarction group of patients (105%, P < 0.02). These observations point to an association between a depressed factor XII-dependent fibrinolytic activity and an enhanced risk of reinfarction in patients with a previous episode of acute myocardial infarction.

Reactive coagulation induced by plasmin in patients treated with recombinant tissue-type plasminogen activator.

BACKGROUND: We and others have demonstrated that administration of thrombolytic agents causes the generation of thrombosis-promoting agents. At present, we have studied whether formation in vivo of excessive amounts of plasmin is responsible for the activation of coagulation in patients treated with recombinant tissue-type plasminogen activator. METHODS: Modified crossed immunoelectrophoresis was used for determination of the plasminogen-binding form of alpha 2-antiplasmin. Enzyme-linked immunosorbent assay methods were used for determination of hemostatic reaction products. RESULTS: The association between the generation of hemostatic reaction products and the exhaustion of the plasminogen-binding form of alpha 2-antiplasmin (PB alpha 2AP) was studied in 21 patients with acute myocardial infarction and 11 patients with unstable angina pectoris who were given a 3-hour, 100-mg intravenous infusion of recombinant tissue-type plasminogen activator (rt-PA). We observed in all patients a fall in blood concentrations of PB alpha 2AP (P < 0.01) after 2.25 hours of treatment and, simultaneously, a significant increase in fibrin degradation products (P < 0.01), D-dimer (P < 0.01), fibrinogen degradation products (P < 0.01), prothrombin fragment 1 + 2 (P < 0.01), and thrombin-antithrombin III complexes (P < 0.01). When we evaluated individual data, we observed high concentrations of the reaction products when the PB alpha 2AP concentration after 2.25 hours of treatment was lower than 25% of the pretreatment values. Also, we observed highly significant associations between the increase in the plasma concentrations of fibrin degradation products and thrombin-antithrombin III complexes (rs = 0.72; P < 0.01), the increase in plasma concentrations of fibrin degradation products and prothrombin fragment 1 + 2 (rs = 0.63; P < 0.01), the increase in plasma concentrations of D-dimer and thrombin-antithrombin III complexes (rs = 0.78; P < 0.01), and the increase in plasma concentrations of D-dimer and prothrombin fragment 1 + 2 (rs = 0.79; P < 0.01). CONCLUSIONS: Generation of excessive amounts of plasmin is the main factor in producing the procoagulant response in patients who receive thrombolytic therapy with rt-PA, and intravenous heparin does not abolish this response. Plasmin inhibitors might be used in relation to thrombolytic therapy as indirect "antithrombotics."

Possible role of vascular intima for generation of coagulant activity in patients undergoing coronary thrombolysis with recombinant tissue-type plasminogen activator. A randomized, placebo-controlled study.

In our present placebo-controlled study on recombinant tissue-type plasminogen activator (rt-PA) and heparin treatment of patients with acute ischaemic heart disease (IHD), we studied the extent of fibrin resolution and generation of coagulant activity. In rt-PA treated patients the lysis of fibrin in vivo (median 60 nmol of fibrin--estimated as fibrinogen equivalents) was significantly higher (p less than 0.02) than can be accounted for solely by lysis of a coronary thrombus (approximately 2 nmol) and circulating soluble fibrin (median 15 nmol). We observed a 200% increase of plasma concentrations of both prothrombin fragment 1 + 2 (p less than 0.001) and thrombin-antithrombin III complexes (p less than 0.001) as a consequence of rt-PA treatment, indicating that the coagulant activity is primarily caused by a physiological activation of the coagulation system. We conclude that an important contribution to the activation of coagulation in patients undergoing coronary thrombolysis is lysis of fibrin deposited widespread on the vascular intima, and that this process causes an intimal-dependent activation of the coagulation system.

Interleukin-1 and tumor necrosis factor-alpha in plasma of patients with acute ischemic heart disease who undergo thrombolytic therapy: a randomized, placebo-controlled study.

In patients with acute ischemic heart disease who undergo thrombolytic therapy we have previously observed a marked endothelium-dependent activation of the coagulation system. Concomitantly the concentrations of the fast acting plasminogen activator inhibitor type 1 (PAI-1) in plasma increased. The results of recent in vitro studies would suggest that these in vivo phenomena could be associated with the procoagulant effects of the cytokines interleukin-1 (IL-1) and/or tumor necrosis factor-alpha (TNF). In the present placebo-controlled study on patients with acute ischemic heart disease treated with thrombolytic agents we observe low or undetectable concentrations, and insignificant deviations during the study periods, of IL-1 and TNF in plasma. We conclude that IL-1 and TNF play a minor role for generation of coagulant activity and systemic deviations of PAI-1 in patients who undergo coronary thrombolysis.

Depression of factor XII-dependent fibrinolytic activity characterizes patients with early myocardial reinfarction after recombinant tissue-type plasminogen activator therapy.

Twenty patients with acute myocardial infarction treated with recombinant tissue-type plasminogen activator (rt-PA) had endogenous factor XII-dependent fibrinolytic activity levels measured throughout the hospital period and those levels were prospectively correlated with the incidence of recurrent myocardial infarction until 8 weeks after hospital discharge. Within the follow-up period, recurrent myocardial infarction was observed in 8 patients, whereas the remaining 12 patients showed no clinical evidence of recurrence. The patients in the reinfarction group were characterized by a more pronounced depletion of and sustained lower levels of factor XII-dependent fibrinolytic activity than were the patients with no reinfarction (p less than 0.05). The decrease in fibrinolytic activity during rt-PA therapy was significantly associated with a depletion of functional alpha 2-antiplasmin, the primary plasmin inhibitor. These results indicate that, paradoxically, coronary thrombolysis with rt-PA involves depletion of endogenous factor XII-dependent fibrinolytic activity levels, which constitutes a risk for early myocardial reinfarction.

Early thrombolytic treatment reduces analgesic requirement in patients with myocardial infarction.

The duration and amount of analgesics required were investigated in 67 patients with myocardial infarction treated with intravenous recombinant tissue-type plasminogen activator (rtPA) or placebo in a randomized double-blind trial. Infusion of rtPA (100 mg)/placebo was started within 5 h after the onset of symptoms, and the requirement for analgesics during the following 48 h was recorded. Sixty-seven per cent of the 30 rtPA-treated patients required analgesic treatment for less than 6 h, compared to 38% of the 37 patients in the placebo group (P = 0.04). During the study period, patients in the rtPA group used the equivalent of 5.3 mg (median value) intravenous morphine, which was significantly less than the 11.2 mg used in the placebo group (P = 0.04). In conclusion, the present study suggests that early thrombolysis with intravenous rtPA reduces the amount and duration of analgesic treatment required by patients with myocardial infarction.