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This study was made to evaluate assays for monitoring of low dose heparin thromboprophylaxis and to evaluate its efficacy in reduction of hypercoagulation. Patients with medical diseases scheduled for routine thromboprophylaxis were subcutaneously treated with either 5.000 anti XaU low molecular weight (LMW) heparin once daily (n=20) or 5.000 IU standard (ST) heparin 3 times daily (n= 19). On days 1,2,3, before, 1 and 4 hours after heparin injection APTT, TCT, anti Xa, Heptest, thrombin-antithrombin complexes (TAT), and D-Dimer levels were measured. In the LMW heparin group, median values of APTT and TCT slightly increased after heparin and the ranges of pre- and postinjection values showed extensive overlap. However, values of anti Xa and Heptest markedly increased, showing complete separation of ranges. In the ST heparin group neither APTT, TCT, anti Xa, nor Heptest were significantly different comparing pre- and postheparin values. Half of the patients in both groups had subclinical hypercoagulation at baseline (TAT>5ng/ml, D-Dimer>200ng/ml). On day 3 of prophylaxis this percentage was not significantly decreased. Moreover, several patients in both groups increased in TAT and D-Dimer. In the LMWheparin group, negative correlations between body weight and 4 h postinjection heparin levels were found (anti Xa R=−0.50, Heptest R=−0.31) and between 1 h postinjection heparin and TAT and D-Dimer levels 3 h later (TAT-anti Xa R=−0.58, TAT-Heptest R=−0.64, D-Dimer-anti Xa R=−0.32, D-Dimer-Heptest R=−0.33). These results show that low dose LMW but not ST heparin therapy can be monitored by the anti Xa test or the Heptest.

In a prospective randomised trial patients receiving multiple-day chemotherapy and heparin had significantly fewer local complications at the site of venous access than patients who had chemotherapy alone. The need to move peripheral venous catheters to other sites was decreased significantly, from 36% to 6%. Prophylaxis of phlebitis with low-dose continuous heparin is safe, simple, cheap and effective. It facilitates administration of multiple-day chemotherapy for the patients, the nurses and the physicians.

Introduction: There is strong evidence from experimental data that heparin influences the course of acute pancreatitis by improving pancreas microcirculation and inhibition of pancreatic proteases. The aim of the study was to determine if heparin has a beneficial effect on post-ERCP pancreatitis and any influence on oxidative stress. Methods: 55 consecutive patients between 1/98 and 2/99 were analyzed prospectively. 17 patients who received low-dose heparin for at least 7 days prior to ERCP were compared with 38 patients not receiving any heparin in the last 4 weeks prior to ERCP. Various labor parameters prior to, and 9 h after ERCP and physical complaints following ERCP were determined. Results: Labor analysis prior to and after ERCP are shown in table 1. Patients receiving heparin prior to ERCP had a significantly lower concentration of amylase/lipase after ERCP and tended to have less post- ERCP pancreatitis. Physical complaints, indirect markers of oxidative stress and the concentration of zinc, copper, manganese, vitamins A and E did not differ significantly between the two groups. Conclusion: Previous administration of heparin may improve the course of post-ERCP pancreatitis, but not because of any influence on oxidative stress. A prospective randomised study is being undertaken to answer the question post in the heading.

EDITORőRandolph et al's meta-analysis suggests that continuous infusions of low dose heparin prolong the patency of arterial and venous peripheral catheters.1 This is encouraging for both patients with needle phobia and junior doctors. The authors do not, however, emphasise the risks of invasive vascular devices, particularly the infective risks. Although some studies disagree, it is widely accepted that rates of phlebitis and infection (both local and systemic) …

We appreciate the comments of Drs Hughes and Gonzalez. However, it seems that they have misunderstood the mechanism of action of LMWH and made an incorrect conclusion in their letter. Increasing the dose of heparin compensates for the reduced bioavailability of antithrombin III, not the reduced bioavailability of heparin. Therefore, even though LMWH have a more predictable bioavailability than unfractionated heparin, the anticoagulant effect of the LMWH is dependent on the bioavailability of antithrombin III. In fact, because LMWH have a greater concentration of the pentasaccharide chain responsible for antithrombin III activation and fewer high-molecular-weight fractions (responsible for the minor direct heparin antithrombotic effect), they are even more critically dependent on the presence of antithrombin III for their effect. To state this another way, if there is inadequate antithrombin III, both unfractionated heparin and LMWH are ineffective. We understand that different LMWH preparations have different ratios of anti-IIa

Antioxidants such as superoxide dismutase (SOD) protect tissues from injury by inactivating oxygen free radicals. Extracellular SOD (EC-SOD) is bound to heparan sulfate, a structural component of the vascular extracellular matrix(ECM). In adults, high doses of heparin (H) competitively release EC-SOD from the vascular matrix into the blood, where it is rapidly degraded. In our previous study we showed that a high dose of H (175 units/ml) releases SOD from umbilical veins. The purpose of this study is to determine whether SOD is released by a lower dose of H (1 unit/ml), routinely used for catheter patency.

Objective: To determine a rational approach to heparin dosing for thromboembolism prophylaxis. Design: Literature review. Results: Three commonly used heparin dosing regimens were identified: (1) standard low-dose heparin (5000 U administered subcutaneously 2-3 times per day); (2) adjusted-dose heparin (adequate to elevate the activated partial thromboplastin time to 5 seconds above the upper limit of normal); and (3) low-molecular-weight heparin (30 mg subcutaneously twice daily without monitoring). Conclusions: Adjusted-dose heparin thromboembolism prophylaxis is both the safest and most reliable method currently available. Arch Surg. 1996;131:1069-1073

A total of 4352 patients were admitted to a prospective' randomised multicentre trial comparing the prophylactic efficacy of dextran 70 and low-dose heparin against fatal pulmonary embolism after elective operations for general, orthopaedic, urological, and gynaecological conditions. Out of 3984 patients correctly admitted, 1993 were allocated to receive dextran 70 and 1991 to receive low-dose heparin. Withdrawal of prophylaxis because of bleeding or technical difficulties occurred more often in the heparin group, but allergic reactions were more common in the dextran group. Of the 75 patients who died within 30 days after operation, 38 had been given dextran and 37 low-dose heparin. Necropsy was performed in 33 and 32 of these cases respectively. In six patients in each group pulmonary embolism was the sole or a contributory cause of death. Of these, five patients in the dextran group and two in the heparin group had received a full course of prophylaxis. There was no statistically significant difference between the two treatment groups in the incidence of fatal pulmonary embolism after a full course of prophylaxis.

56 patients undergoing elective major surgery received low dose heparin prophylaxis, 5,000 IU 2 h before surgery and every 8 h for 7 days. The patients were tested by the 125I-fibrinogen uptake test, which, if positive, was controlled by venography. The heparin concentrations were measured by the method of Denson and Bonnar and by the chromogenic method of Teien et al. in blood samples drained immediately before and after surgery and on the 1st and 5th postoperative day 2 and 4 h after the injection of heparin. The values were found higher when estimated by the method of Denson and Bonnar than by the chromogenic method. Deep vein thrombosis (DVT) developed in 11 patients, and in 10 of them within the first 48 after the operative procedure, in 1 after 4 days. The preoperative values were not lower in the patients who developed DVT, and the heparin concentrations found on the 1st and 5th postoperative day were at the same level as in those who did not develop DVT.

The manubrio-sternal joints (MSJs) of 10 male and 10 female non-rheumatoid subjects and of 11 subjects with RA were studied. Microradiography often revealed herniation of the intra-articular fibrocartilaginous disc into the cancellous bone and osteo-arthritic changes. In RA, erosive destruction of the articular surfaces was seen in six cases and in one subject the joint was ankylotic. Histologically the MSJ presented degenerative phenomena but no inflammatory changes in old non-rheumatic subjects. Active inflammation was visible in four joints from rheumatoid subjects, and in another four fibrous replacement suggestive of earlier inflammation was seen. The joints from non-rheumatoid subjects presented a histological joint cavity in nine cases, with or without synovial-like cells lining the cavity. A similar cavity was present in only one of the joints taken from rheumatoid subjects and there were inflammatory changes in the synovial tissue in this joint. It is suggested that involvement of the MSJ in RA m...

Low-dose heparin has achieved wide use for the prevention of deep vein thrombosis. Full-dose heparin (20,000 U/day or more) has a well-documented suppressive effect on adrenal aldosterone production. To determine whether this effect may also occur with low-dose heparin, 5 healthy male volunteers were given heparin, 5,000 U subcutaneously every 12 h for 10 days, and their renin-aldosterone axis was studied. Plasma aldosterone fell from a mean of 17.2 ng/dl at baseline to 6.6 on day 5 and 4.3 on day 10. The 24-hour urinary aldosterone fell from 11.5 micrograms/day at baseline to 5.3 and 6.8 on days 4-5 and 9-10, respectively. After stimulation with furosemide (60 mg orally) and 4 h ambulation, plasma aldosterone remained suppressed on heparin: 22.4 ng/sl at baseline, 7.0 on day 5 and 6.2 ng/dl on day 10. Plasma renin activity, serum and urinary electrolytes, and body weight were unchanged during the study. Hence, low-dose heparin can inhibit aldosterone production. Patients receiving this treatment should be observed (during and after therapy) for impaired electrolyte homeostasis.

An ischemic bowel model was used to stimulate adhesion formation in eight ponies. Heparin (40 USP u/kg) or saline was administered intravenously at surgery and was continued subcutaneously every 12 hours for 48 hours to evaluate the efficacy of heparin in preventing intraabdominal adhesions. Ponies were euthanatized after 6 weeks, and postmortem examinations were performed. A statistically significant difference was found between the heparin-treated and the control groups. Adhesions developed in three of four control ponies, and adhesions did not develop in three of four heparin-treated ponies. None of the adhesions resulted in clinical disease. In this study, heparin decreased the formation of adhesions in ponies after experimentally induced intestinal ischemia.

SummaryThe activated partial thromboplastin time has been used to monitor the effects of low-dose subcutaneous heparin in two groups of patients undergoing hip surgery. The study was performed to determine the degree of anticoagulation required to protect these high-risk patients from post-operative deep vein thrombosis. The patients were randomised to receive a fixed regimen of subcutaneous calcium heparin (5,000 units eight-hourly) or a dose of calcium heparin monitored by maintaining the standardised APTT at 50 secs. In the adjusted group the APTT achieved the target figure in 46% of observations compared to 27% in the fixed group (p μ0.005). Nine patients showed positive 125I-fibrinogen scans and in all, the APTT was below the target value the day before the scan became positive. In contrast, in six of the nine thrombotic patients heparin was detected by antifactor Xa clotting assay. The APTT, therefore, appears to give a better guide to the antithrombotic effect of heparin than the antifactor Xa clotting assay. These preliminary observations suggest that prolonging the standardised APTT method to just above 50 secs improves prophylaxis in high-risk cases. Furthermore, an increased dose of heparin is required than is provided during the conventional low-dose regime of 5,000 units tds. With regular control using the standardised APTT, increasing the dose to the target value does not increase postoperative haemorrhage.Further studies with larger numbers of patients are required in order to show a significant reduction in the incidence of postoperative deep vein thrombosis in hip surgery patients receiving low-dose adjusted heparin.

The aim of this investigation was to study the beneficial role of low-dose heparin in peritonitis. Peritonitis was induced in 20 dogs by the technique of Rosato and co-authors, 10 of which received low-dose heparin subcutaneously for 5 days in a dose of 100 units/kg body weight. Decreased mortality as well as decrease in the formation of intra-abdominal abscesses and adhesions were observed in the heparin-treated dogs. Some of the possible underlying mechanisms for beneficial effects of heparin in peritonitis are discussed.

SummaryThe efficacy of topical thrombin in prevention of wound haematoma inpatients receiving subcutaneous low-dose heparin was studied in a randomized, controlled trial. One hundred and two patients undergoing elective abdominal surgery were included in the trial. Haematological studies were carried out in the last 42 patients to determine whether introduction of thrombin into the wound resulted in any systemic effect via the coagulation pathways. The frequency of post-operative wound haematoma was significantly lower in the thrombin-treated group as compared to the control group and its action appeared to be independent of any change in coagulation parameters.

• Carotid artery ligation, whether elective or an emergency, is an operation that most head and neck surgeons do with some trepidation because of the possible neurologic consequences. Of 440 major head and neck operations for cancer in which the carotid artery was exposed, 20 (4.5%) patients suffered a carotid rupture or had the vessel ligated just prior to rupture. We describe the typical patient and his management. Of these 20 patients, five died as a direct result of rupture or ligation, ten survived rupture and/or ligation with neurologic sequelae, and five survived rupture and/or ligation without neurologic sequelae. Of the ten patients with neurologic problems, four had immediate strokes, and six had delayed strokes, ie, these occurred greater than eight hours after ligation. Seven patients who required carotid artery ligation, separate from the previously mentioned group, received 5,000 units of heparin sodium subcutaneously every 12 hours in a prospective study. Of these seven patients, one died immediately postoperatively, and six survived without any neurologic sequelae. We discuss the cause of delayed neurologic problems and the rationale for the use of low-dose heparin. (Arch Otolaryngol104:307-310, 1978)

We investigated whether the dosage of heparin injected subcutaneously for the postoperative prophylaxis of thromboembolism influences efficacy. We considered prospective, controlled or comparative, randomized studies in which heparin was administered in a dosage of 5,000 U b.i.d. or t.i.d. subcutaneously. In major surgical procedures in general surgery, gynecology, urology and chest surgery, 2 × 5,000 and 3 × 5,000 U of heparin/day lower the frequency of postoperative deep venous thrombosis from about 30% to about one-fourth and one-third that amount, respectively. With regard to orthopedic/ traumatic surgery, in a study of only 40 patients, 2 × 5,000 U/day reduced the incidence of thrombosis by one-half. The use of the higher dosage resulted in a decrease in DVT in 5 of 7 reports, but the other two authors measured no prophylactic effect at all. Proof that subcutaneous heparin prophylaxis is also able to reduce the number of fatal postoperative pulmonary emboli has been produced only in the case of the higher dosage. In our own group of patients there is no correlation between body weight and frequency of hemorrhagic complications. In our patients there is no relation between malignant tumor as the primary disease and the occurrence of hemorrhagic complications. There is no evidence that the lower dosage causes fewer hemorrhagic complications than the higher dosage.

The effect of heparin, 5000 units every 8 hours, on deep venous thrombosis in patients with proximal femoral fractures was investigated in a controlled, double blind, randomised study. Heparin or placebo was administered as soon as possible after the fracture, and before 6 hours had passed, and was continued for 14 days. The diagnosis of deep venous thrombosis was made using daily I125 fibrinogen scans. A total of 130 patients endured the trial and the results were registered on a sequential diagram. This showed that the 0-hypothesis could not be rejected, and that consequently no difference in the frequency of deep-vein thrombosis was detected.

Since 1973 a prospective trial of antithrombotic agents for the prophylaxis of deep venous thrombosis and pulmonary embolism was undertaken in 386 high risk patients. Five drugs were employed: 1. A combination of aspirin and dipyridamol (95 patients); 2. Dextran 60 (43 patients); 3. Dihydroergotamine (61 patients); 4. Low dose heparin (63 patients); 5. A combination of dihydroergotamine and low dose heparin (twice daily in 61 patients and three times daily in 63 patients). The patients were investigated by I125 fibrinogen uptake test, phlebography, lung scan and careful clinical evaluation before and after operation. In cases of established thrombosis simultaneous anticoagulation with heparin and coumadin was started. In the first group, 32 (34%) thromboses and three pulmonary emboli were detected of which one patient died. In the dextran group, 24 patients (54%) developed thrombosis and there were no fatal pulmonary emboli. In the low dose heparin group we detected 29 (46%) thromboses and three pulmonary emboli. Only the combination of low dose heparin and dihydroergotamine significantly reduced the incidence of thromboembolic complications-15 (25%) thromboses and no pulmonary emboli. The application of this combination three times a day showed no further improvement but more haemorrhagic complications appeared. Since 1975 no fatal pulmonary emboli have occurred in 720 patients undergoing total hip replacement.

A prospective study of pulmonary embolism utilizing low dose heparin in 125 postoperative patients failed to demonstrate a significant reduction in deep venous thrombosis diagnosed by fibrinogen scanning. However, the incidence of probable pulmonary emboli diagnosed by pulmonary scanning in the absence of chronic lung disease appeared to be reduced by the low dose heparin regimen.

Increasing awareness of the dangers of low dose heparin therapy has stimulated interest in mechanical methods for decreasing the incidence of thromboembolism. Plantar flexion and dorsiflexion of the feet while the patient is on the operating table by the use of a mechanical device (the Pedi-Pulsor) significantly decreases the incidence of deep vein thrombosis (45 percent in control patients versus 18 percent with the Pedi-Pulsor [p = 0.05]). In addition, use of this machine during the postoperative period should further aid in decreasing the incidence of thromboembolism.

In 100 patients who underwent major cranial or spinal operations, the incidence of lower extremity deep vein thrombosis was 29%. Of importance was the presence of known risk factors, particularly leg weakness and a long operation. The subject of deep vein thrombosis and its complications in neurosurgical disorders is reviewed and its prophylaxis is discussed. The administration of low dose heparin based on an epidemiological analysis of the risks involved would seem to be an effective method of prophylaxis.

3.6 g acetylsalicylic lysin was injected into 30 patients daily after operative replacement of the hip-joint. Pulmonary embolism and (or) deep-vein thrombosis were diagnosed in 19 patients. Low-dose heparin (3 X 5000 IU/24 h) significantly reduced the incidence of deep-vein thrombosis (ten of thirty patients: P less than 0.05) compared with the acetylsalicylic acid group. The results demonstrate not only the inadequate thrombosis prophylaxis provided by acetylsalicylic acid, but also that low-dose heparin prophylaxis in these specially at risk patients is of limited efficacy.

In a double blind study, three different methods of prophylaxis of thromboembolism were compared in surgical patients. Each group received either acetylsalicylic acid or low dose heparin or a combination of both drugs. The groups were comparable for type of surgery, sex, age, weight, and other risk factors. A significantly lower incidence of thromboembolism was found in the combined prophylaxis group than in the two other groups. The total rate of complications attributable to prophylaxis was low except for a mild but significantly increased bleeding tendency in the combined prophylaxis group. Hemorrhagic complications in most cases were slight side effects which permitted to continue prophylaxis.

The laboratory control of low-dose heparin therapy is generally regarded as unnecessary. A laboratory study of the effects of low-dose heparin was performed using different methods: an amidolytic method and a method involving the inhibition of factor Xa in a coagulation test. Variations in partial thromboplastin time, recalcification clotting time, thrombin time and the plasma antithrombin HI levels were also studied. These tests were repeated (days 0, 1, 3, 8) in 27 women between the ages of 27 and 62 years who were undergoiing gynecological surgery. They received 5,000 IU of heparin either twice or thrice daily. There was no correlation between heparin levels in the blood and global clotting tests simultaneously performed. The plasma heparin levels varied between 0 and 0.15 IU/ml with both methods. A detectable heparin concentration on days 1, 3 and 8 was present in only half of the cases receiving the twice daily regimen. The plasma antithrombin III activity and concentration were not modified during treatment.

The study was carried out on 75 patients undergoing hip joint surgery. The efficacy of a prophylaxis of deep vein thrombosis (DVT) by acetylsalicylic lysine (ASL) and by a low dose heparin (LDH) combined with the ASL treatment was investigated using the 125I-fibrinogen test. DVT was not significantly decreased by the ASL application (53%) compared to the controls (60%). DVT occurred significantly less under the combined administration (27 %) than in the other two groups.