Hans Kræmmer Nielsen

Anticoagulant therapy in deep venous thrombosis. A randomized controlled study

Ninety patients with venographically proven deep venous thrombosis(DVT) but without clinical signs of pulmonary embolism(PE) were randomized into two different treatment regimens to compare the safety and efficacy of continuous intravenous heparin and oral anticoagulant(AC) treatment versus non-AC treatment. All patients in the two treatment groups were actively mobilized from the day of admission and wore graduated compressing stockings. In the non-AC-group the patients were treated with phenylbutazone for ten days. Treatment with heparin was maintained for 6 days and oral AC treatment was given from the third day and continued for 3 months. Venography was repeated after 30 days. A perfusion-ventilation lung scan was performed on day 1-2, 10 and 60. In fifty-nine patients a revenography was performed, twenty nine in the AC-group and thirty in the non-AC group. For distal veins regression was found in nine and eight respectively (4.4% in favour of AC, 95% confidence limit 27.5% to -18.7%) and in proximal veins regression was found in five and eight, respectively (10.9% in favour of AC, 95% confidence limit 32.0% to -10.1%). No difference in lung scans was found after 10 days (0.8% in favour of AC, 95% confidence limit 21.5% to -19.9%) or after 60 days (3.3% in favour of non-AC treatment, 95% confidence limit 21.8% to -28.5%). In the AC group the incidence of bleeding complications was 8.3%. No side-effects of phenylbutazone was found. The present controlled clinical study demonstrated no effect of AC-treatment on DVT progression in actively mobilized patients wearing graduated compressing stockings when compared to a non-AC treated group receiving analgetic therapy with phenylbutazone. However, the patient population of the study is relatively small with wide confidence intervals for differences between groups. Before more general recommendations can be made, a large scale placebo-controlled study is needed to evaluate the possible effect of AC-treatment in DVT patients, who can be mobilized from the first day.

Platelet-Derived Growth Factor Release and Antiplatelet Treatment with Low-Dose Acetylsalicylic Acid:

Platelet-derived growth factor (PDGF) and β-thromboglobulin (β-TG) are released from alpha granules during platelet activation. PDGF may play a role in the development of atherosclerosis and the late restenosis after percutaneous transluminal coronary angioplasty (PTCA). The effect of acetylsalicyclic acid (ASA) on PDGF release was studied in healthy volunteers before and twelve hours after ingestion of 300 mg ASA. PDGF, β-TG, and thromboxane B2(TxB 2) were measured by radioimmunoassay (RIA) in serum and in platelet rich plasma (PRP) after submaximal stimulation with collagen. TxB2 decreased sig nificantly from 0.9 ± 0.3 ng/(mL x 106 platelets) to 0.006 ± 0.005 ng/(mL x 10 6 platelets) (mean ± SD) in serum after ASA ingestion while PDGF and β-TG remained unchanged. Measurements in PRP after stimulation with collagen showed a significant decrease in PDGF (from 21.5 ± 1.4 pg/(mL x 106 plate lets) to 1.8 ± 4.1 (pg/mL x 106 platelets)), in β-TG (from 21.0 ± 13.3 ng/(mL x 10 6 platelets) to 2.2 ± 1.4 ng/(mL x 106 platelets)) and in TxB2 (from 143.6 ± 80.7 pg/(mL x 106 platelets) to 0.5 ± 0.6 pg/(mL x 106 platelets)) after treat ment with ASA. In conclusion low-dose ASA inhibits collagen-induced release of both β-TG and PDGF in PRP and TxB2-synthesis in PRP and serum.

Incomplete thromboxane inhibition with 100 mg of intravenous acetylsalicylic acid in patients with acute ST elevation myocardial infarction: a placebo-controlled pilot trial.

BACKGROUND Acetylsalicylic acid (ASA) is now a standard treatment of acute myocardial infarction (AMI). ASA inhibits thromboxane A(2) (TXA(2)) production by blocking the constitutive cyclooxygenase (COX)-1 enzyme, but only to a small degree the inducible COX-2. COX-2 is induced by increased concentrations of cytokines, which is related to an enhanced inflammatory response. Previously, we have found a complete inhibition of TXA(2) synthesis in healthy volunteers after intravenous administration of 50 mg of ASA. We measured in a randomized, placebo-controlled pilot trial the effect of 100 mg of ASA injected intravenously on TXA(2) synthesis in AMI patients treated with streptokinase. METHODS AND RESULTS Nineteen patients with AMI treated with streptokinase were randomized to 100 mg of ASA or placebo injected intravenously. Se-TXB(2) and bleeding time were measured before and after drug administration. One hundred and eighty minutes after intravenous ASA administration, treatment with oral ASA was initiated. We found a significant decrease in serum concentrations of TXB(2) after 30, 60 and 180 min following ASA injection compared to placebo, but in none of the patients was complete inhibition of TXA(2) production achieved. No significant change in bleeding time could be demonstrated. CONCLUSION Intravenous ASA in a dosage of 100 mg did not completely prevent TXA(2) production in AMI patients treated with streptokinase. This may be due to synthesis of TXA(2) by the inducible COX-2 enzyme and/or to a transcellular metabolism in platelets of prostanoids generated by endothelial cells.

A new automated technique for platelet aggregation measurement

A Multistat III Centrifugal Analyser (MCA) was used to measure platelet aggregation in vitro. It has a capacity of about 40 samples per h. In the analyser platelet-rich plasma and collagen-reagent were mixed, and the turbidity was measured as a function of time. The results were presented in arbitrary units ( arb . units), i.e. change in turbidity per min X 1000. The estimated 0.95 reference range was 50-95 arb . units, (n = 46) and the coefficient of correlation between MCA results and results obtained by conventional aggregometry ( Fibromat ) was 0.85 (P less than 0.001). The MCA method registered 50-75% reduction of platelet aggregation after intake of low dose acetylsalicylic acid (ASA) (1.2-4.0 mg/kg) during 3 days in 19 subjects. The MCA method is suitable to monitor ASA treatment routinely in order to establish an individual appropriate ASA dose during prophylactic treatment of arterial thromboembolic disease.

Observer variation in the interpretation of ventilation-perfusion lung scintigraphy

The diagnosis of pulmonary embolism (PE) remains one of the most difficult in clinical medicine, and the diagnostic value of lung scintigraphy has been questioned. To evaluate the observer variation in the interpretation of ventilation-perfusion lung scanning in the diagnosis of PE, 87 lung scintigrams from consecutive patients with phlebography-proven deep venous thrombosis and without clinical signs of PE were randomly mixed with 50 reference lung scintigrams from patients with PE symptoms. The scintigrams were reevaluated blind by two experienced clinical physiologists. Each observer evaluated each lung scintigram twice and recorded whether the lung scan was normal or abnormal. If it was abnormal, the location and number of segment defects were registered. The intraobserver agreement, including number and location of segments, ranged from 0.77 to 0.85 and for the diagnosis of PE from 0.88 to 0.92 with a kappa of 0.80 – 0.84. The values for the interobserver agreement for the diagnosis of PE were 0.73 – 0.80 with a kappa of 0.56 – 0.67. It is concluded that in the interpretation of ventilation-perfusion lung scintigraphy the use of a simple scheme — deciding whether there is segmental ventilation-perfusion mismatch or not — has a good reproducibility with a high kappa for inter- and intraobserver variation and can serve as a simple routine method for diagnosing PE.

Bepridil versus verapamil in stable angina pectoris — a controlled clinical trial

The calcium antagonist bepridil (bepridil monohydrochloride monohydrate, Org 5730, Cordium) was investigated in comparison with verapamil in a double-blind cross-over design in patients with angina pectoris. Exercise parameters, frequency of anginal attacks, consumption of nitroglycerin and subjective preference were analysed for 36 patients. The exercise capacity, estimated by exercise time and total work load during standard bicycle testing, was significantly more improved with bepridil treatment than with verapamil treatment. No significant differences were observed in frequencies of anginal attack, consumption of nitroglycerin and subjective preference. Side effects were mild and equally divided over both treatment groups.

Effect of Low-Molecular-Weight Heparin (Tinzaparin) and Unfractionated Heparin on Platelet Aggregation

A low-molecular-weight heparin (LMWH), when anti-IIa activity was compared. In the ex vivo part Tinzaparin, was compared with unfractionated heparin of the study, a significant enhancement of ADP-induced (UFH) for their effects on platelet aggregation in vitro and platelet aggregation was observed after i.v. administra ex vivo. Both heparins showed a dose-dependent proag- tion of both Tinzaparin and UFH with no difference in gregatory effect on ADP- and collagen-induced platelet potency. Subcutaneous administration of Tinzaparin in aggregation in vitro, but LMWH was less potent. The two different doses did not have any effect on platelet differences in potency between Tinzaparin and UFH de- activity. In conclusion, Tinzaparin appears, like other pended on how the compounds were compared. The most LMWHs, to have less proaggregatory effect on platelets pronounced difference was found when molar concentra- than UFH both in vitro and ex vivo.

The imbalance of coagulation and fibrinolysis in coronary heart disease and its relation to traditional risk factors

Two major hypotheses to explain the pathogenesis of atherosclerotic disease — the thrombogenic and the lipid hypothesis — have dominated in the past century. The thrombogenic theory was postulated by Rokitansky, who in 1844 described intimai thickening resulting from fibrin deposition with subsequent organization by fibroblast and lipid accumulation. He deduced that the deposit derived from the arterial blood, reviving the idea of dyscrasia, which had been popular in antiquity [1]. The lipid theory was proposed by Virchow in 1856, who observed that the intimai thickening in atherosclerosis was located in the subendothelial layer, and therefore could not be derived from surface deposits [2]. Both theories have been integrated into one single multifactorial theory that involves the common step — endothelial dysfunction as a reponse to injury — developed by Ross [3]. One or more risk factors (hyperlipidemia, smoking, obesity, hypertension, diabetes etc.) plus local factors such as shear stress or injury are hypothesized to contribute to the development of endothelial lesions.

Dipyridamole and Platelet Release of Platelet-derived Growth Factor

Platelet-derived growth factor (PDGF) and β-thromboglobulin (β-TG) are released from platelet alpha-granules during platelet activation. PDGF is a potent chemoattractant and mitogen for human vascular smooth muscle cells, and may be important in the development of late restenosis following angioplasty and in atherogenesis. In recent studies, where PDGF release into serum was evaluated indirectly by measuring (3)H-thymidine incorporation into fibroblasts, it was reported that the antiplatelet drug dipyridamole (DPM) decreased serum levels of PDGF. Such selective inhibition of the PDGF-release would have potential important implications for patients with atherosclerosis and for patients undergoing angioplasty. We therefore measured platelet content of PDGF and β-TG as well as platelet release of PDGF using a newly developed radioimmunoassay in healthy volunteers before and immediately after ingestion of DPM 100 mg t.i.d. for 3 days. We found no significant differences in platelet content of PDGF or β-TG before and after DPM. PDGF release from platelets isolated from plasma by gel filtration and stimulated with thrombin as well as platelet release of PDGF into serum was also unaffected by DPM. In conclusion, treatment with DPM does not affect platelet content of PDGF or β-TG. The treatment did not inhibit the platelet-release of PDGF as previously reported, neither via direct effects on platelets nor on inhibitory plasma components. DPM may, however, inhibit (3)H-thymidine incorporation into fibroblasts.