Does protamine chloride neutralize low molecular weight heparin sufficiently?

The heparin neutralizing properties of protamine chloride on conventional heparin (porcine mucosa) and on low molecular weight heparin (Kabi 2165) were studied in vitro. Protamine chloride neutralized 99% of the delaying effect of conventional heparin on the activated partial thromboplastin time, whereas only 70% of the effect of low molecular weight heparin was neutralized. The neutralizing effect of protamine chloride on the inhibition of factor Xa (clot test) was 95% for conventional heparin and 55% for low molecular weight heparin, whereas the effect of both heparin preparations on the thrombin inhibition could be completely neutralized. We conclude that conventional heparin is neutralized more effectively in vitro by protamine chloride than is the low molecular weight heparin. The findings do not exclude that protamine chloride is able to suppress in vivo bleedings caused by low molecular weight heparin.     

Neutralisation of heparan sulphate and low molecular weight heparin by protamine

The neutralisation by protamine sulphate (PS) of heparan sulphate (HS), a low molecular weight heparin (LMWH), and a reference preparation of unfractionated heparin (UH), was studied by activated partial thromboplastin time (APTT) and anti-Xa clotting assays. UH was most easily neutralised in the APTT assay by PS (on a weight for weight basis), followed by LMWH and HS. The neutralisation of APTT activity by PS closely followed the loss of activity in the anti-Xa clotting assay, when plasma was used as the source of At III. When the anti-Xa clotting assay was carried out using purified At III in place of plasma, HS and LMWH were neutralised by much lower amounts of PS and resembled UH neutralisation more closely. Resistance of HS anti-Xa activity to PS neutralisation decreased with increasing plasma dilution. The presence of bovine albumin with purified At III concentrate increased the resistance of HS to PS neutralisation. It is concluded that PS binding to UH, HS and LMWH is probably related more to their degree of sulphation than molecular weight and that non-specific interactions between PS and plasma proteins inhibit the binding of PS to HS and LMWH.     

Inhibition of low molecular weight heparin by protamine chloride in vivo

To determine the antagonization of anticoagulant and lipolytic effects of a low molecular weight [LMW] heparin preparation protamine chloride was given intravenously after i.v. injection of LMW or normal heparin. The effects of normal heparin on factor Xa, thrombin, aPTT, lipoprotein [LPL] and hepatic triglyceride lipase [HTGL] activities were neutralized immediately by i.v. protamine. The inhibition of thrombin and aPTT by LMW heparin were also abolished, whereas the effects on LPL and HTGL were counteracted to 80% and on factor Xa only to 40% by i.v. protamine chloride. No rebound of the anticoagulant or lipolytic effect was detected. It is assumed that haemorrhagic complication during therapy can be antagonized by protamine chloride. The incomplete inhibitory effect of protamine chloride on LPL, HTGL and factor Xa activities of LMW heparin indicate that protamine chloride requires more than 14 saccharide units in the heparin molecule for interaction.     

Low molecular weight heparin and neuraxial anesthesia

Spinal and epidural anesthesia/analgesia provide several advantages over systemic opioids, including superior analgesia, reduced blood loss and need for transfusion, and decreased incidence of thromboembolic complications. However, patients hospitalized for major surgery often receive an anticoagulant and/or antiplatelet medication perioperatively to prevent venous thrombosis and pulmonary embolism, although the pharmacologic agent, degree of anticoagulation desired, and duration of therapy remain controversial. These patients are often not considered candidates for spinal or epidural anesthesia/analgesia because of a theoretically greater risk of spinal hematoma. Spinal hematoma is a rare and potentially catastrophic complication of spinal or epidural anesthesia. The incidence of neurologic dysfunction resulting from hemorrhagic complications associated with central neural blockade is estimated to be less than 1 in 150,000 epidural and less than 1 in 220,000 spinal anesthetics. The decision to perform neuraxial blockade on these patients must be made on an individual basis, weighing the risk of spinal hematoma from needle or catheter placement against the theoretical benefits gained. Familiarity with the pharmacology of hemostasis-altering drugs, as well as case reports and clinical studies involving patients undergoing neuraxial blockade while receiving these medications will guide the clinician faced with this difficult decision.     

Neutralization of a low molecular weight heparin (LHN-1) and conventional heparin by protamine sulfate in rats

The neutralization of a low molecular weight heparin (LHN-1) and conventional heparin (CH) by protamine sulfate has been studied in vitro and in vivo. In vitro, the APTT activity of CH was completely neutralized in parallel with the anti-Xa activity. The APTT activity of LHN-1 was almost completely neutralized in a way similar to the APTT activity of CH, whereas the anti-Xa activity of LHN-1 was only partially neutralized. In vivo, CH 3 mg/kg and LHN-1 7.2 mg/kg was given intravenously in rats. The APTT and anti-Xa activities, after neutralization by protamine sulfate in vivo, were similar to the results in vitro. In CH treated rats no haemorrhagic effect in the rat tail bleeding test and no antithrombotic effect in the rat stasis model was found at a protamine sulfate to heparin ratio of about 1, which neutralized APTT and anti-Xa activities. In LHN-1 treated rats the haemorrhagic effect was neutralized when APTT was close to normal whereas higher doses of protamine sulfate were required for neutralization of the antithrombotic effect. This probably reflects the fact that in most experimental models higher doses of heparin are needed to induce bleeding than to prevent thrombus formation. Our results demonstrate that even if complete neutralization of APTT and anti-Xa activities were not seen in LHN-1 treated rats, the in vivo effects of LHN-1 could be neutralized as efficiently as those of conventional heparin. The large fall in blood pressure caused by high doses of protamine sulfate alone was prevented by the prior injection of LHN-1.     

Low molecular weight heparin and unfractionated heparin in thrombosis prophylaxis: meta-analysis based on original patient data

A meta-analysis (MA) based on original patient data has been performed comparing low molecular weight heparins (LMWH) with unfractionated heparin (UFH) in thrombosis prophylaxis after major surgical interventions. The analyses have been done for the following prespecified groups of studies: all studies, studies in orthopaedic surgery (OS) and studies in general surgery (GS, with further separation into low-dose studies [GS-LD] and high-dose studies [GS-HD]). Deep vein thrombosis (DVT, all locations) and wound haematoma were used as primary endpoints for efficacy and safety, respectively. The analysis confirms the results of previous publication-based meta-analyses. In GS there is no relevant difference between LMWH and UFH regarding efficacy; the safety results strongly depend on the dosage: under low-dose LMWH the risk of wound haematoma is significantly lower, under high-dose LMWH it is significantly higher than under UFH. However, most of the studies in the last group used regimens of LMWH that are not considered appropriate any more. In OS there is a trend towards a better efficacy and safety of LMWH. In addition, LMWHs are superior to UFH, in OS, with respect to the secondary endpoints proximal DVT and pulmonary embolism. The rates of proximal DVT and pulmonary embolism, respectively, are consistently lower under LMWH than under UFH, whereas slightly smaller rates of distal DVT are observed under UFH.     

Low molecular weight heparin for deep vein thrombosis in glioma patients

The treatment and secondary prophylaxis of deep vein thrombosis (DVT) and pulmonary embolism, a common complication in patients with malignant glioma, has remained controversial. We treated 11 patients with malignant glioma and DVT prospectively with low molecular weight heparin (LMWH) at 175 IU/kg for 10 days and then for 3 months at 100 IU/kg. No patient developed bleeding complications or any other severe side effects of LMWH treatment. Two patients had a dose reduction of LMWH to 75 IU/kg because of chemotherapy-induced thrombocytopenia. One patient developed progressive DVT and nonlethal pulmonary embolism on day 14 of LMWH 100 IU/kg. After increasing the dose to 175 IU/kg he had no further recurrence. One patient had recurrence of DVT after a fracture of the leg affected by DVT at 8 months after the diagnosis of DVT and 5 months after the end of LMWH therapy. LMWH therapy may be safe and effective in the treatment and secondary prophylaxis of DVT in patients with malignant glioma. Received: 4 January 2002, Received in revised form: 18 April 2002, Accepted: 23 April 2002 Correspondence to Dr. F. Schmidt     

Low molecular weight heparin versus aspirin for acute ischemic stroke: A systematic review

Aspirin is the standard treatment for acute ischemic stroke, although heparins are widely prescribed. We performed a systematic review of randomized controlled trials to compare the safety and efficacy of low molecular weight heparins (LMWH) with aspirin in acute ischemic stroke. Two completed randomized controlled trials involving 1,933 patients were identified; 1 trial only included patients with presumed cardioembolic stroke. As compared with aspirin, treatment with heparin was associated with a significant reduction in symptomatic venous thromboembolism (odds ratio [OR] - 0.29, 95% confidence interval [CI] - 0.12-0.66) and an increase in major extracranial hemorrhage (OR - 2.57, 95% CI - 1.01-6.52). Nonsignificant increases in end-of-treatment case fatality (OR - 1.35, 95% CI - 0.87-2.08) and symptomatic intracranial haemorrhage (OR - 1.82, 95% CI - 0.68-4.87) were seen; symptomatic intracranial haemorrhage was significantly raised (OR - 4.26, 95% CI - 1.04-17.4) with heparin in patients treated within 24 hours of stroke onset. Stroke recurrence (OR - 1.24, 95% CI - 0.79-1.94) and deterioration (OR - 1.13, 95% CI - 0.85-1.50) during treatment and end-of-trial death (OR - 1.00, 95% CI - 0.77-1.30) or dependency and case fatality (OR - 1.03, 95% CI - 0.85-1.25) did not differ between the 2 treatments. No benefit of LMWH over aspirin was seen in patients with presumed cardioembolic stroke. Low molecular weight heparin should not replace aspirin in the routine management of patients with ischemic stroke, including those with presumed cardioembolic stroke. Copyright © 2002 by National Stroke Association     

Low molecular weight heparin administered once versus twice daily in patients with venous thromboembolism: a meta-analysis.

BACKGROUND: Low molecular weight heparin is as effective and safe as unfractionated heparin for treatment of acute venous thromboembolism. It is uncertain whether low molecular weight heparin should be administered once-daily or twice-daily in this setting. METHOD: A meta-analysis of randomized studies which directly compared once- and twice-daily administration of low molecular weight heparin for the treatment of acute venous thromboembolism was performed. A literature search was performed using Advanced Pub Med and the Cochrane library database, and abstracts from recent meetings were reviewed. Two investigators extracted data independently. RESULTS: Five studies, involving 1522 patients, were eligible. There were no statistically significant differences in the frequencies of symptomatic (odds ratio, 0.85 in favor of once-daily therapy at three months, p = 0.6), and asymptomatic, recurrent venous thromboembolism, total and major bleeds (odds ratio, 1.16 in favor of twice-daily therapy at 10 days, p = 0.8); and death, at 10 days, as well as at three months of follow-up. CONCLUSION: Once-daily low molecular weight heparin appears to be as effective and safe as twice-daily administration for the acute treatment of venous thromboembolism. However, there is inadequate data from studies that directly compared once-daily and twice-daily administration to be able to exclude the possibility of a higher frequency of fatal bleeding with once-daily therapy.     

Low molecular weight heparin as an anticoagulant for in vitro platelet function studies

We evaluated the suitability of low molecular weight (LMW) heparin as an anticoagulant for in vitro platelet function tests in 11 normal volunteers. Results with citrated platelets were considered as the standard. Spontaneous platelet aggregation and the aggregation responses to ADP, epinephrine, collagen, ristocetin and thrombin were measured turbidimetrically in an aggregometer. Dose-response and dose-rate curves were constructed for ADP- and epinephrine-induced aggregation. The maximum aggregation response (EDmax) and rate (EDRmax), and the estimated dose of agonist to induce 50% of the maximum response (ED50) and rate (EDR50) were calculated from these curves. The inhibition of ADP-induced aggregation with PGI2 was expressed as per cent inhibition. The release of ATP and TxA2, from platelets aggregated with collagen was measured. No spontaneous aggregation occurred with either anticoagulant. The ED50 and the EDR50 for heparinized platelets were significantly lower for ADP induced aggregation (0.8 +/- 0.3 microM vs 2.1 +/- 1.0 microM [p = 0.001] and 0.4 +/- 0.1 microM vs 0.8 +/- 0.3 microM [p = 0.003]). The EDRmax with ADP was significantly higher (p = 0.004) for heparinized platelets (64.6 +/- 17.0 units/ml vs 50.4 +/- 7.6 units/ml). The heparinized platelets aggregated slightly, but significantly, less in response to ristocetin than the citrated platelets. The response of washed heparinized and citrated platelets to thrombin was not significantly different. The per cent inhibition of ADP aggregation with PGI2, was significantly lower with heparinized platelets. The release of TxA2 and ATP was similar for both anticoagulants. These results indicate that LMW heparin is a satisfactory anticoagulant for platelet aggregation tests.     

Low molecular weight heparin and prevention of postoperative thrombosis in abdominal surgery.

In a prospective, double-blind, randomized multicenter trial the efficacy and safety of low molecular weight heparin and unfractionated heparin were compared for the prevention of postoperative deep vein thrombosis in patients undergoing abdominal surgery. Six hundred and seventy-three patients were randomly allocated to the two prophylaxis groups; 20 of these, however, did not undergo surgery and did not receive any prophylaxis. Of the remaining 653 patients 323 received one subcutaneous injection of 3,000 anti-Xa units of low molecular weight heparin and 330 received subcutaneously 5,000 U heparin three times a day. Treatment was initiated 2 h preoperatively and continued for 7 to 10 days. The occurrence of DVT was determined by the 125I-labelled fibrinogen uptake test and phlebography. Venous thrombosis was diagnosed in 24 of 323 patients (7.4%) treated with low molecular weight heparin and in 26 of 330 patients (7.9%) treated with low-dose heparin. DVT of proximal veins was detected in four patients of the low molecular weight heparin group and in three patients of the low-dose heparin group. During the observation period three pulmonary emboli - one fatal and two non-fatal - occurred in patients receiving prophylaxis with low-dose heparin. No pulmonary embolism was found in patients treated with low molecular weight heparin. Both prophylactic schemes were well tolerated. Intra- and postoperative blood loss, incidence of wound hematoma, frequency and volume of intra- and postoperative blood transfusion were similar in both groups with a slight advantage for the low molecular weight heparin group.(ABSTRACT TRUNCATED AT 250 WORDS)     

A low molecular weight heparin compared with unfractionated heparin

A 6000 daltons low molecular weight heparin (LMWH) was compared with unfractionated mucosal heparin in vitro and in vivo. Despite unimpressive specifications by clotting assays in vitro, the LMWH gave high and sustained activity in vivo by anti-Factor Xa assays, following subcutaneous injection. However, activity measured by APTT and calcium thrombin time assays was at least as high as occurred following unfractionated heparin. On the basis of clotting assays, there seems no reason to expect a lower incidence of haemorrhagic side-effects following the clinical use of this LMWH. The study also strikingly demonstrates the inadequacy of in vitro clotting assays for assessing the in vivo behaviour of LMWH.     

Low molecular weight heparin (Innohep) as thromboprophylaxis in outpatients with a plaster cast: a venografic controlled study

Introduction: The aim of this study was to investigate the incidence of deep vein thrombosis (DVT) in patients immobilized in plaster cast and the possible efficacy of prophylaxis with low molecular weight heparin (LMWH). Material and methods: The study was a randomized, assessor-blinded, open multicenter (three centers) study. All patients over 18 years of age with planned plaster cast on a lower extremity of at least 3 weeks were eligible for participation. Written informed consent was obtained from 300 patients and they were randomized to either 3.500 IU anti-Xa of tinzaparin (Innohep) subcutaneously once daily or no prophylaxis. On the day the cast was removed, ascending unilateral venography was performed. Two experienced radiologists, unaware of treatment, assessed the pictures independently. The radiologist had to obtain consensus as to whether DVT was present or not. Results: 300 patients were included (148 in the treatment group and 152 in the control group). Ninety-five were subsequently withdrawn. DVT was diagnosed in 10/99 patients in the treatment group and in 18/106 patients in the control group. This difference is not significant (P=.15, χ² test) and the odds ratio was 0.55 (95% confidence INTERVAL=0.34–1.26). Conclusion: DVT in legs after plaster casting is a big problem, with an incidence of almost 20%. An effective prophylactic regime is required. Once-daily dose of 3.500 IU anti-Xa of tinzaparin was not sufficient.     

Management of pregnant women with mechanical heart valve prosthesis: Thromboprophylaxis with Low molecular weight heparin

IntroductionPregnancy increases the risk of mechanical heart valve (MHV) thrombosis. Warfarin is protective, but implies risks to the fetus. Unfractionated heparin (UFH) is less effective but does not harm the fetus. In general, anticoagulation is more stable and predictable with low molecular weight heparin (LMWH) than with UFH.MethodRetrospective study of 12 pregnancies with MHV; 6 in aortic, 4 in mitral, and 2 in both positions, treated with therapeutic doses of subcutaneous LMWH twice daily throughout pregnancy. Doses were adjusted using anti-Xa monitoring. The frequency of thrombo-embolism with various anticoagulation regimes was calculated based on a literature review.ResultsMedian LMWH dose was 15500 IU/24 h, range 10000–20000 IU/24 h; median dose 257 IU/kg/24 h. Median peak LMWH in blood plasma ranged 0.54–0.92 anti-Xa U/mL. Thromboembolism developed in two women with aortic MHV despite LMWH levels in target range. One had systemic embolic episodes; in the other woman valve thrombosis was successfully thrombolysed. Both had initially received subtherapeutic doses. Thrombo-embolism was not observed in ten pregnancies treated as recommended. The pregnancies resulted in thirteen healthy babies; eight delivered by Cesarean section. Bleeding occurred in two women after Cesarean section due to preeclampsia.ConclusionTreatment with adjusted therapeutic doses of LMWH was successful in 10 of 12 pregnancies, and was not associated with fetal complications. Thromboembolism occurred in two pregnancies, possibly attributed to subtherapeutic doses of LMWH during the initial 3 weeks. Compared to UFH prophylaxis, therapeutic doses of LMWH appears to be more efficacious.