Release of endothelium-associated proteins into blood by injection of heparin in normal subjects and in patients with Type 1 diabetes.

AIMS: Disturbances in heparan sulphate proteoglycans in patients with diabetic nephropathy might contribute to the pathogenesis of vascular disease in these patients. To investigate this possible link, we measured the heparin-induced, immediate release of eight proteins with heparan sulphate binding properties in patients with nephropathy. METHODS: We studied three groups, Type 1 diabetic patients with (n = 10) or without (n = 15) albuminuria and matched controls (n = 12). Blood samples were obtained before and 5 min after the injection of 40 anti-Xa IU low molecular weight heparin/kg body weight. RESULTS: Lipoprotein lipase increased more in diabetic patients without albuminuria than in controls and patients with albuminuria [261 (170-293) vs. 177 (103-438), P < 0.05 and 203 (159-280) mU/ml, P < 0.05]. Total tissue factor pathway inhibitor increased more in the diabetic patients [284 (198-449) and 275 (243-399)] than in the controls [221 (169-289) ng/ml, P < 0.005]. Vitronectin increased significantly only in the diabetic patients with albuminuria. The remaining proteins did not increase significantly (antithrombin, von Willebrand factor, fibronectin) or increased equally in the three investigated groups (extracellular superoxid dismutase and platelet factor 4). CONCLUSIONS: The different release of lipoprotein lipase and vitronectin in diabetic subjects with and without albuminuria may reflect novel aspects of vascular derangement in patients with albuminuria.

Lack of effect of fish oil supplementation on coagulation and transcapillary escape rate of albumin in insulin-dependent diabetic patients with diabetic nephropathy.

OBJECTIVE: We studied the effect of a diet supplementation with fish oil in insulin-dependent diabetic patients with nephropathy in order to evaluate whether abnormal transcapillary escape rate of albumin and procoagulant activity in these patients could be modified. METHODS: A double-blind, randomized, controlled study was carried out at a tertiary referral centre. The subjects were 29 insulin-dependent diabetic patients with nephropathy. One year of fish oil supplementation (4.6 g n-3 fatty acids/day) was compared with placebo (olive oil). The main outcome measures were N-3 fatty acid proportions of platelet lipids, transcapillary escape rate of albumin, prothrombin fragment 1 + 2, thrombin-antithrombin complexes, markers of fibrinolysis, fibrinogen, factor VII antigen and activity, thrombomodulin, von Willebrand factor, platelet factor 4 and beta-thromboglobulin. These were measured every 6 months. RESULTS: Neither transcapillary escape rate of albumin (7.4 (median) (5.0-9.8) (range) % vs. 7.0 (4.6-10.6) %) nor prothrombin fragment 1 + 2 (0.97 (0.72-2.40) nmol/L vs. 1.01 (0.59-3.11) nmol/L) changed after 12 months of fish oil supplementation. CONCLUSION: Increased transcapillary escape rate of albumin and activity could not be modified during diet supplementation with fish oil in insulin-dependent diabetic patients with nephropathy.

Treatment of enteritis in chronic granulomatous disease with granulocyte colony stimulating factor.

BACKGROUND: In several diseases there is a relation between deficiency of neutrophil granulocytes and granulomatous lesions. Recently, in glycogen storage disease type Ib, this relation has been supported by the beneficial effect of treatment of enteritis with granulocyte-macrophage colony stimulating factor. AIM: To investigate whether chronic granulomatous disease could be treated according to the same principle. PATIENTS AND METHODS: Inflammatory lesions were monitored in two brothers with chronic granulomatous disease demonstrated by very low superoxide production in neutrophil granulocytes. The two patients were treated with recombinant human granulocyte colony stimulating factor on three occasions when the disease was active. RESULTS: In one patient, remission of an inflamed stenosis of the colon sigmoideum was shown by granulocyte scintigraphy after one month of treatment with granulocyte colony stimulating factor. In the other patient, remission of colon disease of later of a non-malignant tumor in the right lung hilum was shown by colonoscopy and computed tomography scans respectively. CONCLUSION: Remission of inflammatory lesions in two brothers with chronic granulomatous disease was induced by granulocyte colony stimulating factor on three occasions. The mechanism for this effect is now known. The result is similar to the response found in patients with leucocyte deficiency due to glycogen storage disease type Ib.

No effect of unfractioned or low molecular weight heparin treatment on markers of vascular wall and hemostatic function in incipient diabetic nephropathy.

OBJECTIVE: The high risk for cardiovascular disease in IDDM patients with nephropathy may be mediated by abnormal function of the vascular wall. We investigated whether heparin was able to modulate markers of vascular wall and hemostatic function in patients with incipient nephropathy. RESEARCH DESIGN AND METHODS: Thirty-five IDDM patients with incipient nephropathy were randomized to treatment with placebo, unfractioned heparin, or low molecular weight heparin in a double-blind trial. The treatment was given as 1 h of conventional intravenous high-dose treatment and in a conventional subcutaneous low-dose regime for 3 months. Transcapillary escape rate of albumin and plasma levels of von Willebrand factor, fibrinogen, prothrombin fragment 1 + 2, thrombin-antithrombin III complexes, tissue type plasminogen activator, tissue plasminogen activator inhibitor type 1, total cholesterol, HDL cholesterol, and triglycerides were measured before and after treatment. Of the patients, 31 completed the study. RESULTS: We found no significant effect of heparin on markers of vascular wall and hemostatic function by any of the treatments. CONCLUSIONS: Treatment with high- or low-dose heparin induced no modulation of markers of vascular wall or hemostatic function in IDDM patients with incipient diabetic nephropathy.

Fish oil in diabetic nephropathy.

OBJECTIVE: Recent studies in nondiabetic kidney diseases suggest that dietary supplementation with n-3 polyunsaturated fatty acids (fish oil) may have beneficial effects on albuminuria, kidney function, arterial blood pressure, and dyslipidemia. Therefore, we evaluated the long-term effect of fish oil in diabetic nephropathy. RESEARCH DESIGN AND METHODS: A 1-year double-blind randomized controlled study comparing fish oil (4.6 g n-3 fatty acids/day) with placebo (olive oil) was performed in an outpatient clinic in a tertiary referral center. Thirty-six normotensive IDDM patients with diabetic nephropathy were included; 18 were treated with fish oil. Seven patients dropped out (four received fish oil), and results for the remaining 29 are presented. Albuminuria (enzyme immunoassay), glomerular filtration rate (51Cr-labeled EDTA plasma clearance), 24-h ambulatory blood pressure, and lipid profile were determined every 6 months. RESULTS: Albuminuria increased by 22% (1-46%) (mean [95% CI]) in the fish oil group vs. 15% (-11-49%) in the placebo group (NS). Glomerular filtration rate decreased from 116 +/- 7 to 105 +/- 7 ml.min-1.1.73 m-2 (mean +/- SE) vs. from 108 +/- 6 to 103 +/- 7, fish oil and placebo, respectively (NS). No significant changes occurred in 24-h ambulatory blood pressure: from 141 +/- 4/82 +/- 2 mmHg to 142 +/- 5/83 +/- 2 vs. from 140 +/- 4/78 +/- 2 to 144 +/- 4/80 +/- 3, fish oil and placebo, respectively (NS). In the fish oil group, serum triglycerides (median [range]) decreased from 0.97 (0.5-4.0) mmol/l to 0.8 (0.4-3.0) vs. from 1.01 (0.4-2.0) to 1.09 (0.4-2.0) in the placebo group (P < 0.05) and VLDL cholesterol decreased from 0.45 (0.23-1.88) to 0.37 (0.21-1.43) mmol/l vs. from 0.44 (0.21-0.94) to 0.41 (0.17-1.94) (P < 0.05), but total and LDL cholesterol rose in the fish oil compared with the placebo group. CONCLUSIONS: Our study does not suggest that fish oil has beneficial effects on albuminuria, kidney function, blood pressure, and dyslipidemia in normotensive IDDM patients suffering from diabetic nephropathy.

Raised serum sialic acid concentration precedes onset of microalbuminuria in IDDM. A 10-year follow-up study.

OBJECTIVE: Elevated concentrations of serum sialic acid, a potent cardiovascular risk factor in the general population, have been found in patients with IDDM and microalbuminuria. We investigated whether a coincidence exists between the increase of sialic acid concentrations and albuminuria in the transition from normoalbuminuria to microalbuminuria. Furthermore, the predictability of increased sialic acid as well as von Willebrand factor (vWF) and total and HDL cholesterol concentrations in development of persistent microalbuminuria in IDDM was investigated. RESEARCH DESIGN AND METHODS: This 10-year prospective study was carried out in a cohort of 209 IDDM patients with normoalbuminuria at baseline. RESULTS: Of the cohort, 198 patients completed the follow-up period and 27 developed persistent microalbuminuria (urinary albumin excretion rate [UAER] > or = 30 mg/24 h). A coincident increase of UAER and serum sialic acid concentration was seen before persistent microalbuminuria was diagnosed. Elevation of serum sialic acid concentrations in those who later developed microalbuminuria occurred 3 years before the diagnosis of persistent microalbuminuria. Baseline serum sialic acid concentrations were significantly higher in the group of patients who later developed microalbuminuria than in the group who remained normoalbuminuric (2.02 +/- 0.41 vs. 1.85 +/- 0.31 mmol/l [means +/- SD], P < 0.05). Baseline serum sialic acid concentration correlated significantly with HbA1c, UAER, blood pressure, total cholesterol, HDL cholesterol, and vWF and was significantly predictive for development of microalbuminuria (hazards ratio [95% CI], 3.1 [1.2-8.1]; P = 0.02) after adjustments for sex, duration of diabetes, smoking, blood pressure, vWF, total cholesterol, and HDL cholesterol. Adjustment for the effects of HbA1c and UAER, however, canceled out the predictive effect of serum sialic acid. CONCLUSIONS: UAER and serum sialic acid concentration increase coincidentally before the onset of persistent microalbuminuria. An increased serum sialic acid concentration is predictive for the onset of microalbuminuria independent of age, sex, diabetes duration, smoking, blood pressure, vWF, and total HDL cholesterol.

Increased tissue factor pathway inhibitor activity in IDDM patients with nephropathy.

OBJECTIVE: Tissue factor pathway inhibitor (TFPI) is bound to vascular endothelium (presumably to heparan sulfate) and circulates in complex with plasma lipoproteins. It directly binds and inhibits factor Xa. The purpose of the study is to investigate whether plasma TFPI activity is altered in IDDM and nephropathy and to evaluate the possible determinants of the alteration. RESEARCH DESIGN AND METHODS: We assessed plasma concentration of TFPI (total, truncated, and domain 3 TFPI) and plasma activity of factor Xa inhibition in nondiabetic control subjects (n = 22) and in IDDM patients with normoalbuminuria (urinary albumin excretion rate [UAE] < 30 mg/24h, n = 17), incipient nephropathy (UAE 30-300 mg/24 h, n = 17), clinical nephropathy (UAE > 300 mg/24h, n = 25). RESULTS: Total, truncated, and domain 3 TFPI concentrations were increased in IDDm patients compared with those in control subjects and were more pronounced in IDDM patients with nephropathy. Plasma activity of factor Xa inhibition measured by HEPTEST (Haemachem, St. Louis, MO) assay was increased in IDDM patients, especially in those with nephropathy. TFPI-dependent factor Xa inhibition, obtained as the difference in clotting time with and without adding activity-neutralizing anti-TFPI antibody to samples, was increased in IDDm patients with nephropathy. This was, however, not sufficient to inhibit the biological activity of factor Xa as demonstrated by increased levels of prothrombin fragment 1 + 2. LDL cholesterol and HbA1c were independently correlated to plasma TFPI. CONCLUSIONS: Inhibition of factor Xa activity is increased in IDDM patients with nephropathy, mainly because of increased plasma TFPI activity. The increased plasma TFPI activity in these patients may be associated with and regulated by LDL in plasma and metabolic control. The anticoagulant activity of TFPI may attenuate the hypercoagulable state in diabetes but does not seem to be able to normalize hemostasis.

Effects of heparin and aminoguanidine on glomerular basement membrane thickening in diabetic rats.

The effects of heparin and aminoguanidine on glomerular basement membrane thickening were studied in streptozotocin diabetic Sprague-Dawley rats. A placebo-treated group and a non-diabetic group served as controls. All diabetic rats remained severely hyperglycaemic (23 mmol/l) throughout the 8-month study period. At the end of this time relative kidney weight was significantly increased in diabetic control rats (4.9 +/- 0.5 g/kg b.w.) compared with non-diabetic rats (3.3 +/- 0.3 g/kg). This increase was not affected by the intervention treatments. Glomerular basement membrane thickness increased 32% in diabetic control rats (240 +/- 24 nm) compared with non-diabetic rats (182 +/- 20 nm). This increase was prevented by s.c. treatment with both unfractionated and low molecular weight heparins, while basement membrane thickness was the same in animals treated with oral heparins and aminoguanidine and untreated diabetic rats. Macroscopic malignant kidney tumours were seen in three aminoguanidine-treated rats. In conclusion, subcutaneously administered heparin prevents diabetes-induced glomerular basement membrane thickening.

Elevated fibrinogen and the relation to acute phase response in diabetic nephropathy.

Insulin-dependent diabetic patients with nephropathy have a high risk of cardiovascular disease. Chronic inflammation is a part of the pathogenesis of atherosclerosis, and presently we have studied the relation between the inflammatory state, measured as levels of interleukin-6 and C-reactive protein and fibrinogen in diabetic nephropathy. Thirty-three insulin-dependent diabetic patients with diabetic nephropathy (urinary albumin excretion rate (AER) > 300 mg/24-h) and 22 patients with incipient diabetic nephropathy (AER 30-300 mg/24-h) were compared with 14 non-diabetic controls and 17 diabetic patients with normal AER (<30 mg/24-h). Fibrinogen was significantly higher in diabetic nephropathy than in non-diabetic controls and diabetic patients with normal AER (median 8.1, range (5.4-15.6) mu mol/l vs. 6.6 (5.0-12.1) mu mol/l, p < 0.05, and 6.2 (5.0-9.0) mu mol/l, p < 0.005, respectively), while C-reactive protein did not deviate between groups. Interleukin-6 was significantly elevated in all insulin-dependent diabetic patients (diabetic nephropathy (3.2 (1.0-14.5) pg/ml, p < 0.005), incipient nephropathy (3.7 (1.0-22.9) pg/ml, p < 0.005) and diabetic patients with normal AER (2.7 (1.0-9.0) pg/ml, p < 0.05) compared with nondiabetic controls (1.2 (1.0-6.2) pg/ml)). When fibrinogen was adjusted for interleukin-6, C-reactive protein or both, the level of fibrinogen was still higher in patients with diabetic nephropathy than in patients without nephropathy (p < 0.05), which suggests that inflammation is not the only mechanism that increases fibrinogen levels in patients with diabetic nephropathy.

Primary haemostasis in thyroid disease.

OBJECTIVES: There have been reports on a bleeding tendency in hypothyroidism resembling von Willebrand's disease. The aim of the present study was to investigate whether altered primary haemostasis is a general phenomenon in thyroid disease. DESIGN/SETTING: A total of 10 patients with hyperthyroidism and nine patients with hypothyroidism were studied at diagnosis, and during treatment with carbimazole or L-thyroxine, respectively, when euthyroidism had been achieved. RESULTS: In untreated hypothyroidism, template bleeding time was prolonged (median 9.3 min, range 3.8-20.0 min) compared to that in controls (median 4.0 min, range 3.0-6.0 min; P < 0.05), whereas maximal agglutination velocity induced by ristocetin was decreased (38% min-1, range 4-52% min-1 vs. 70% min-1, range 60-81% min-1, P < 0.05). The level of von Willebrand factor antigen in plasma from hypothyroid patients was less than half of the value in hyperthyroid patients. This difference disappeared after euthyroidism was achieved. CONCLUSIONS: We found that changed primary haemostasis is a general feature of hypothyroidism, and that it is resolved after levothyroxine treatment.

Aspects of haemostatic function in healthy subjects with microalbuminuria--a potential atherosclerotic risk factor.

Microalbuminuria, i.e., slightly elevated urinary albumin excretion rate (UAER), notifies increased risk for atherosclerotic disease and may reflect an early generalized vascular abnormality in healthy subjects. This study was designed in order to examine whether such abnormality is associated with a shift of the haemostatic balance in prothrombotic direction. The following haemostatic factors were measured in two representative groups of clinically healthy subjects, 28 with microalbuminuria (UAER of 6.6-150 micrograms/min) and 60 age- and sex-matched controls with normoalbuminuria (UAER < 6.6 micrograms/min): Coagulation factors: blood platelet count and mean volume, plasma Factor VII antigen concentration and coagulant activity, and plasma concentrations of prothrombin fragment 1 + 2, thrombin-antithrombin III complexes, fibrinogen, and fibrinopeptide A; fibrinolytic and endothelial factors: plasma concentrations of tissue plasminogen activator antigen and plasminogen activator inhibitor type 1 antigen; and endothelial factor: plasma von Willebrand factor antigen concentration. The fibrinolytic and endothelial factors were measured both before and after 10 minutes of venous occlusion of the arm. None of the haemostatic factors were significantly altered in the microalbuminuric group. Plasma fibrinogen concentration tended to be elevated but not statistically significant ((mean (95% C.I.) 7.8 (7.2-8.3) vs. 7.2 (6.9-7.5) mumol/l; p < 0.1). Neither did any of the haemostatic factors correlate with UAER in regression analyses. It is concluded that the haemostatic balance is unaltered in healthy subjects with microalbuminuria. It is unlikely that a prothrombotic state is present as an intermedial factor early in a causal chain between microalbuminuria and atherosclerotic vascular disease.

Effect of low-dose heparin on urinary albumin excretion in insulin-dependent diabetes mellitus.

We investigated the effect of heparin on urinary albumin excretion in patients with insulin-dependent diabetes mellitus. 39 patients with persistent urinary albumin excretion of 30-300 mg/24 h were randomly treated for 3 months with subcutaneous injections twice daily of isotonic saline, 5000 IU unfractionated heparin, or 2000 anti-Xa IU low-molecular-weight heparin. Unfractionated and low-molecular-weight heparin induced a significant reduction in urinary albumin excretion (p = 0.04 and p = 0.004). The mechanism and clinical relevance is unknown but deserve further attention.

Procoagulant activity and intimal dysfunction in IDDM.

The biological activity of thrombin and coagulation factor Xa was assessed in 62 insulin-dependent diabetic patients. A group of non-diabetic subjects of comparable age and urinary albumin excretion rate (< 30 mg/24 h) served as control subjects (group 1, n = 14). The patients were divided into three groups according to urinary albumin excretion rate. In group 2, albumin excretion rate was less than 30 mg/24 h (n = 17), in group 3 albumin excretion rate was in the range 30-300 mg/24 h (n = 20) and in group 4 albumin excretion rate was greater than 300 mg/24 h (n = 25). Compared to non-diabetic control subjects an increase in the biological activity of factor Xa was observed in all groups of diabetic patients (prothrombin fragment 1 + 2 levels were 1.14 +/- 0.38 nmol/l in group 2, p < 0.005; 1.06 +/- 0.45 nmol/l in group 3, p < 0.05 and 1.03 +/- 0.31 nmol/l in group 4, p < 0.05 vs 0.75 +/- 0.34 nmol/l in group 1). No difference in the level of antithrombin III was seen between the groups. We reconfirmed the presence of intimal dysfunction in diabetic nephropathy demonstrated by elevated transcapillary escape rate of albumin in group 4 compared with group 2 (8.9 +/- 2.0% vs 7.0 +/- 1.9%, p < 0.05). An overall positive correlation between transcapillary escape rate and prothrombin fragment 1 + 2 was found (r = 0.36, p < 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Endothelial function and serum lipids in the course of developing microalbuminuria in insulin-dependent diabetes mellitus.

Changed endothelial function and dyslipidemia are features of insulin-dependent diabetes mellitus complicated with clinical nephropathy. The time relationship between the appearance of these abnormalities is however not well known. We have therefore studied the coincidence of microalbuminuria, endothelial dysfunction and dyslipidemia during a 10 year prospective study of 209 insulin-dependent diabetic patients with normal urinary albumin excretion. Twenty-three patients developed progressing microalbuminuria defined as a median urinary albumin excretion > 30 mg/24-h in two consecutive years and a progression rate in albuminuria higher than 5% per year. Thirty patients who remained normoalbuminuric throughout the observation period were randomly selected to obtain a control group with comparable degree of glycaemic control. The mean level of von Willebrand factor before onset of microalbuminuria tended to be higher in patients developing microalbuminuria than in the control group (NS), but there was no increase in von Willebrand factor in the patients who developed microalbuminuria. Total cholesterol did not change, but a significant decrease in high density lipoprotein cholesterol was observed in patients who developed microalbuminuria. In conclusion, the study demonstrated coincidence of microalbuminuria and decreasing high density lipoprotein cholesterol, but no coincidence between onset of microalbuminuria and endothelial dysfunction assessed by von Willebrand factor.

Decreased platelet activity without change in fibrinolytic activity after low dosages of fish oil.

The effects of low-dose (350 mg daily) polyunsaturated fatty acids from fish oil, either in gelatine capsules or microencapsulated, were investigated in a non-blind, randomized, crossover study of 12 healthy male volunteers. The authors measured the incorporation of eicosapentaenoic acid (EPA) into platelets membranes, platelet aggregability by adenosine diphosphate (ADP) and adrenaline, and fibrinolytic activity as euglobulin lysis time, after two and six weeks of therapy. Both formulations resulted in increased incorporation of EPA into platelet membranes, and the microencapsulated formulation also significantly increased the platelet level of ADP for irreversible aggregation (by about 60%). Fish oil in gelatine capsules had a smaller, non-significant effect in the same direction. Both formulations reduced adrenaline-induced aggregability, but the effects did not attain significance. Neither formulation altered fibrinolysis. The data show that low doses of fish oil in microencapsulated form significantly lower platelet aggregability, without affecting fibrinolysis.

Cardiovascular risk factors during estrogen-norethindrone and cholecalciferol treatment.

The effect of cholecalciferol and estrogen-norethindrone treatment on total cholesterol level, high-density lipoprotein cholesterol level, blood pressure, and body mass index was investigated in 74 postmenopausal women in a double-blind, randomized trial. Blood pressure and body mass index did not change throughout the study. We demonstrated a decrease (11%) in serum cholesterol level after 1 year of treatment with estrogen-norethindrone. When this treatment was combined with cholecalciferol, a similar decrease (13%) was observed. The hypocholesterolemic effect was correlated to body mass index in a way that indicated the most pronounced decrease in lean women. The high-density lipoprotein cholesterol/total cholesterol fraction increased by 45% after 1 year of estrogen-norethindrone treatment, while an increase of 25% after 1 year was seen when cholecalciferol was added to the treatment. The latter increase was not different from a similar increase in the placebo group. The possible dyslipidemic effect of cholecalciferol, along with the risk of hypercalcemia, emphasizes the caution necessary in cholecalciferol treatment.

n-3 fatty acids in adipose tissue and coronary artery disease are inversely related.

The incidence of coronary heart disease is supposedly influenced by dietary fish-oil intake. The purpose of this study was to investigate the possible beneficial effect of fish consumption on coronary atherosclerosis. Adipose-tissue biopsies and segments of coronary arteries were sampled from 40 consecutive autopsies. Degree of coronary artery disease was estimated quantitatively by morphometry, and the fatty acid composition of adipose tissue was analyzed with gas-liquid chromatography. The group with the highest degree (68-92% stenosis, n = 13) of coronary artery disease had lower concentrations of docosahexaenoic acid in adipose tissue than did the group with the lowest degree (23-53% stenosis, n = 13) of coronary artery disease (P less than 0.05). Multiple-regression analysis showed that the degree of coronary artery disease was dependent on docosahexaenoic acid in adipose tissue (P less than 0.01) and body weight (P less than 0.05). The study supports the hypothesis that fish consumption is associated with a reduced risk of coronary heart disease.

Platelet aggregation and fatty acid composition of platelets in type 1 diabetes mellitus.

A raised content of arachidonic acid in platelets from diabetic patients with retinopathy was found without differences in platelet aggregation: platelet aggregability was not related to platelet fatty acid composition. In diabetes, platelet aggregation was inversely correlated to non-esterified fatty acids in plasma and may suggest an inhibiting effect. Mean platelet volume was raised in the diabetic patients, but without hyperaggregability. The findings do not exclude a relationship between platelet fatty acids and platelet aggregability, but suggest that variations in levels of non-esterified fatty acids in plasma might interfere with platelet aggregation.

[Deep-vein thrombophlebitis and pulmonary embolism as a sign of malignant disease]. / Dyb tromboflebit og lungeembolus som tegn på malign sygdom.

In five meticulously controlled investigations, the question of whether deep thrombophlebitis and pulmonary embolism may be signs of occult cancer was raised. One investigation was considered to be of doubtful value on account of selection. In two other investigations, an increased risk for cases of cancer was found among patients under the age of 50 years in whom suspicion of thrombophlebitis was confirmed and among patients with verified suspicion of pulmonary embolism. Two investigations reveal that the risk of cancer is particularly great if no risk factor for deep thrombophlebitis (so-called idiopathic deep thrombophlebitis) was found. In one of these investigations, problems concerning blinding were, however, present and the possible solution is not commented upon. On the present basis, arguments exist for a paraclinical investigation of patients with idiopathic deep thrombophlebitis or with pulmonary embolism. Investigation is probably only necessary in other patients with deep thrombophlebitis if symptoms suggestive of cancer are present and patients under the age of 50 years should be offered outpatient control in view of the possibility of cancer.