Haemodynamic and haematologic alterations with protamine reversal of anticoagulation: comparison of standard heparin and a low molecular weight heparin fragment

Reversal of anticoagulation with protamine sulfate causes many adverse haemodynamic and haematologic effects which could be due to differences in the mechanism of action of standard and low molecular weight heparin. Three groups of dogs were investigated: one group received normal saline pretreatment followed by heparinisation with standard heparin 150 IU/kg followed by protamine sulfate reversal 1.5 mg/kg after aortic interposition grafting: the second group were given normal saline pretreatment followed by heparinisation with low molecular weight heparin 150 U antiXa/kg and after grafting protamine sulfate reversal 1.5 mg/kg. The third group were given protamine sulfate pretreatment 2.25 mg/kg followed by low molecular weight heparin 150 U antiXa/kg and later protamine sulfate reversal 1.5 mg/kg after grafting. The same haemodynamic changes were seen regardless of the type of heparin or pretreatment with protamine given along with low molecular weight heparin. There was a suggestion that regular heparin cause a more pronounced increase in pulmonary artery pressure and a decrease in heart rate. On the other hand the systemic hypotension and reduction of cardiac output seemed more pronounced in the low molecular weight heparin group. Platelet count decreased less in the low molecular weight heparin group, but white blood cell count was equally reduced. Pretreatment with protamine did not abolish the adverse effects of protamine when reversing anticoagulation achieved with low molecular weight heparin, a finding not shared with standard heparin-protamine interactions.     

单剂量低分子量肝素在血液透析抗凝中的应用

对３０例血透患者进行随机交叉对照研究，比较血透前单剂量注射低分子量肝素（ＬＭＷＨ，速避凝）和持续输注普通肝素（ＳＨ）的疗效和安全性。结果：两组体外循环凝血发生率低且无明显差别，但ＬＭＷＨ组透析器复用次数明显延长（Ｐ＜０．０５），第四次透析２小时尿素氮、肌酐清除率及透析器血液间隙容量无明显下降；ＳＨ组则明显下降（Ｐ＜０．０５）。两组均无出血征象，但ＬＭＷＨ组穿刺点压迫时间明显缩短（Ｐ＜０．０５）；而两组透析２小时血浆肝素活性抗－低分子量肝素（ＦＸａ）水平无明显差别，透析４小时ＬＭＷＨ组明显高于ＳＨ组（Ｐ＜０．０５）；ＬＭＷＨ组部分凝血活酶活化时间（ＡＰＴＴ），凝血酶时间（ＴＴ）仅透析２小时轻度延长，透析４小时基本恢复到治疗前水平，ＳＨ组均明显延长（Ｐ＜０．００１）。我们认为血透前单剂量ＬＭＷＨ能有效、完全地代替ＳＨ。     

A single dose of a low molecular weight heparin fragment for anticoagulation during hemodialysis

A low molecular heparin fragment (Fragmin, mol. wt. 4-6000 d), given as a single injection (dose 5000 anti-Xa U), was used as an anticoagulant during hemodialysis in 11 patients. In comparison, our routine heparinization procedure was used; conventional heparin was given as a bolus injection at the start and then as continuous infusion during dialysis to prolong the whole blood activated clotting time (WBACT) 125-175%. Fibrin formation, followed by visual inspection and the measuring of fibrinopeptide A and fibrin monomer concentrations were equally suppressed by the two regimens. WBACT was less prolonged with Fragmin. Anti-Xa activity above 0.39 U/ml was maintained throughout the dialyses with Fragmin. In conclusion a single dose of Fragmin gives sufficient anticoagulation for hemodialysis lasting up to 4 hours.     

Influence of low molecular weight heparin compared to conventional heparin for anticoagulation during haemodialysis on low density lipoprotein subclasses.

BACKGROUND: In haemodialysis (HD) patients, low density lipoprotein (LDL) particle distribution is characterized by a higher proportion of more atherogenic dense LDL. Though clinical studies showed favourable effects of low molecular weight (LMW) heparin compared to standard heparin on triglycerides (TG) and cholesterol (CH) in HD patients with hypertriglyceridaemia, it is not known if LMW heparin influences LDL subfraction pattern. Thus, the aim of this pilot study was to investigate if a switch to LMW heparin influences LDL subfractions and apolipoproteins. METHODS: Ten outpatients with fasting TG >230 mg/dl in the chronic HD programme on heparin for anticoagulation (AC) were switched to dalteparin (80 IU/kg body weight as a bolus). Blood samples were drawn for CH, TG, LDL-CH, HDL-CH, apolipoproteins (apo), very low density lipoproteins (VLDL), intermediate density lipoproteins (IDL), and LDL subclasses at the beginning and after 12 months of therapy. Lipoproteins were isolated by preparative ultracentrifugation. Total LDL were fractionated into six density classes by equilibrium density gradient ultracentrifugation [(density in kg/l): LDL-1 1.019-1.031, LDL-2 1.031-1.034, LDL-3 1.034-1.037, LDL-4 1.037-1.040, LDL-5 1.040-1.044, LDL-6 1.045-1.063]. CH and TG were determined enzymatically, apolipoproteins by turbidimetry. RESULTS: In eight patients suitable for evaluation cholesterol decreased from 241 to 202 (P<0.05) and TG from 557 to 278 mg/dl (P<0.01), whereas LDL-CH and HDL-CH did not change significantly. A 28.2% decrease of VLDL (P<0.01) and a 19.3% decrease of IDL (P<0.05) paralleled by a significant drop of apoB were observed. Buoyant LDL subclasses increased (LDL-2, +34.3% and LDL-3, +20.3%) whereas dense LDL (LDL-5, -13.4% and LDL-6, -33.1%) decreased (P<0.05 for LDL-6). The ratio of buoyant LDL to dense LDL increased from 0.46+/-0.28 to 0.72+/-0.33 (P<0.05). CONCLUSION: In hypertriglyceridaemic HD patients, dalteparin improved metabolism of TG-rich lipoproteins, increased buoyant LDL and decreased potentially atherogenic dense LDL. Preservation of lipoprotein lipase by LMW heparin may be a possible mechanism to explain our findings.     

Retroperitoneal haematoma associated with low molecular weight heparin

Enoxaparin (a low molecular weight heparin) has been used extensively for its antithrombotic properties. Complications of its haemorrhagic side-effects have previously been described. We report two cases of extensive retroperitoneal haematoma requiring blood transfusion and inotropic support. One patient developed acute renal failure and did not respond to intensive resuscitative efforts.     

腰椎术后应用低分子肝素抗凝与硬膜外血肿形成的关联性研究

目的探讨腰椎术后硬膜外血肿形成与应用低分子肝素抗凝是否存在关联性。方法我科自2008-10起所有腰椎手术患者术后6 h皮下注射低分子量肝素钙注射液以预防深静脉血栓,将2008-10-2013-08患者作为治疗组,2003-08-2008-10患者作为对照组,统计两组硬膜外血肿发生率,分析应用低分子肝素与硬膜外血肿发生是否存在关联性。结果治疗组1128例患者,7例出现硬膜外血肿,发生率0.62%,对照组1060例患者,6例出现硬膜外血肿,发生率0.56%,结果 P0.05,两组数据无显著性差异。结论腰椎术后硬膜外血肿形成与应用低分子肝素抗凝无直接关系。     

Effective anticoagulation by a low molecular weight heparin (Fragmin) in hemodialysis with a highly permeable polysulfone membrane.

The efficacy and kinetics of a low molecular weight heparin fragment (LMWH-fragment, Fragmin) were studied during one hemodialysis session with a highly permeable polysulfone membrane and compared to a second dialysis session using a conventional cuprophane membrane. All patients received 5000 U of Fragmin given as an injection into the arterial line at start of dialysis. The anticoagulative efficacy was evaluated by measuring plasma fibrinopeptide A concentrations. LMWH-fragment concentrations in plasma and ultrafiltrate were determined by an amidolytic activity assay and by a radioimmunoassay using a monoclonal antibody. During hemodialysis with cuprophane and polysulfone membranes the fibrinopeptide A concentrations were low indicating adequate anticoagulation. LMWH concentrations in plasma did not differ in the two membranes at any time. The LMWH-fragment in the ultrafiltrate could neither be detected with the amidolytic assay nor with the radioimmunoassay. We conclude that a single injection of Fragmin effectively prevents clotting during hemodialysis with a highly polysulfone membrane. No significant amounts of the anticoagulant are lost over the dialysis membrane.     

Antiproliferative effects of low molecular weight heparin

AIM: To investigate the effect of low molecular weight heparins (LMWH) on the inhibition of intimal hyperplasia (IH) developing in prosthetic vascular patch graft implanted into sheep carotid artery. METHODS: A gelatin sealed Dacron patch graft was implanted into the common carotid artery of sheep, which were then allocated to a control group (n = 10) or to one of four treatment groups (each group n = 10) receiving either a low dose (LD) or high dose (HD) of one of two LMWH (enoxaparin 1 or 2 mg/kg/day, dalteparin 100 or 200 units/kg/day) administered subcutaneously for 4 weeks. Anti-activated factor X and activated partial thromboplastin time were assayed from blood collected prior to and at 1 and 2 h after LMWH administration on days 3, 7, 14, 21 and 28. Animals were killed on day 28 after taking blood samples prior to, then at 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 h following the last injection. Grafts were collected for analysis and measurements of intimal thickness obtained under light microscopy from eight transverse sections of each grafted artery aided by computer image analysis. An IH index was calculated by dividing the area of IH (mm2) by the width of the graft (mm). RESULTS: Intimal hyperplasia index measurements (mean +/- SD) were: controls 0.574 +/- 0.077, LD enoxaparin 0.471 +/- 0.056, LD dalteparin 0.404 +/- 0.025, HD enoxaparin 0.398 +/- 0.068, HD dalteparin 0.332 +/- 0.048. The reductions in IH index compared to controls were significant (P < 0.05) for both LD and HD dalteparin and for HD enoxaparin. CONCLUSION: Both LMWH dalteparin and enoxaparin reduced the amount of IH formation with dalteparin showing a greater effect in the present animal study. The possibility that different LMWH might exert differing antiproliferative effects requires further investigation.     

Rectus sheath haematoma associated with low molecular weight heparin: a case series

A report of three cases of spontaneous rectus sheath haematoma within a 1-month period in a single hospital. The common feature was the recent treatment with low molecular weight heparin. In contrast to the perceived benign nature of the classically-described haematoma, the cases described were life-threatening and required aggressive intervention.     

Thromboelastography to monitor the intra‐operative effects of low‐molecular weight heparin following bridging anticoagulation in a child with normal renal function*

Paediatric patients who require anticoagulation with therapeutic doses of low‐molecular weight heparin are at risk of having a residual anticoagulant effect at the time of surgery, even if managed according to current peri‐operative guidelines. Testing for residual effect is not currently recommended in such circumstances. A 15‐year‐old child with a mechanical aortic valve replacement requiring long‐term warfarin treatment, as well as underlying coagulation defects, was administered low‐molecular weight heparin for bridging anticoagulation before kyphoscoliosis surgery. Thromboelastography was used intra‐operatively to diagnose residual heparinisation, which was demonstrated by a prolonged reaction (R) time of 16.0 min in the plain cup, compared with 9.2 min in the heparinase cup. Subsequently, thromboelastography was also used to monitor haemostatic therapy, which consisted of protamine 2 mg.kg^?1 and 500 IU cryoprecipitate. Thromboelastography was used intra‐operatively to allow rapid testing of coagulation status and guide therapy, thereby minimising use of blood products and reducing complications.     

注射用血凝酶术前给药对低分子肝素抗凝患者髋关节置换术围术期出血量及凝血功能的影响

目的 探讨注射用血凝酶术前给药对低分子肝素抗凝患者髋关节置换术围术期出血量及凝血功能的影响.方法 本试验为随机、对照、单盲的临床研究.择期全麻下单侧髋关节置换术患者40例,美国麻醉医师协会(ASA)分级为Ⅰ或Ⅱ级,年龄60岁～75岁,体重45 kg ～75 kg.术前1d皮下注射低分子肝素(low-molecular-weight heparin,LMWH)4 000单位,采用随机数字表法,将患者随机分为2组(每组20例):注射用血凝酶组(H组)和生理盐水组(C组).切皮前10 min,H组静脉给予注射用血凝酶2单位(5ml生理盐水稀释),C组静脉注射等量生理盐水.记录术中出血量及术后24h引流量,记录术毕及术后24 h凝血功能的各项指标.术后第5d通过下肢深静脉彩超观察下肢深静脉血栓形成的发生情况. 结果 C组术中出血量及术后24h引流量分别为(629±97) ml和(273±87) ml,H组分别为(312±79) ml和(213±74) ml.与C组比较,H组术中出血量及术后24h引流量减少(P＜0.05).与术前比较,两组术毕、术后24h血红蛋白、红细胞、红细胞积压分别减少(P＜0.05).与术前比较,两组术毕及术后24 h凝血常规各项指标差异无统计学意义(P＞0.05).两组术后深静脉血栓形成发生率分别为13％和7％,差异无统计学意义(P＞0.05). 结论 注射用血凝酶术前给药能减少低分子肝素抗凝下髋关节置换术患者围术期出血量,并不影响患者的凝血功能.     

Low molecular weight heparin versus unfractioned heparin for anticoagulation during perioperative extracorporeal membrane oxygenation: A single center experience in 102 lung transplant patients

Extracorporeal membrane oxygenation (ECMO) is gaining importance in the perioperative management of lung transplant patients. To date, the ideal substance for anticoagulation of ECMO patients is still a matter of debate. In this study, we describe our experience with the use of low molecular weight heparin (LMWH) in comparison with unfractioned heparin (UFH) in lung transplant patients undergoing perioperative ECMO support. We retrospectively analyzed data from all lung transplant patients who underwent perioperative ECMO support at our institution between 2013 and 2017. Bleeding events served as primary outcome parameter. Secondary outcome parameters consisted of thromboembolic events. 102 patients were included in this study, of which 22 (21.6%) received UFH for anticoagulation, and 80 (78.4%) received LMWH. There was no difference between the two groups in regard to serious bleeding events (22.7% in the UFH group vs 12.5% in the LMWH group, P = .31). However, the proportion of patients experiencing thromboembolic events was significantly higher in the UFH group than in the LMWH group (50% vs 20%, P = .01). After adjusting for baseline differences between the two groups, we still observed a difference with respect to thromboembolic events. These data remain to be validated in future prospective, randomized trials.     

Persistence of thrombopenia induced by heparin despite replacement with low molecular weight heparin

A 42 year old man, treated for phlebitis with subcutaneous heparin, developed vascular occlusion in both legs with thrombocytopaenia. After surgery, heparin was discontinued and replaced by low molecular weight heparin (CY 216 Choay) without any success. Both commercial heparin and CY 216 Choay produced platelet aggregation in vitro. Heparin was stopped and replaced by dextran 40,000 with anti-aggregating drugs (flurbiprofen) followed by antivitamin K drugs. Thrombocytopaenia resolved three days later and the patient was discharged without sequelae. It therefore appeared necessary to carry out aggregation tests both with heparin and low molecular weight heparin if thrombocytopaenia occurs whilst heparin is being used.     

Thromboprophylaxis using a low molecular weight heparin delays fracture repair

Low molecular weight heparins are significantly superior to unfractionated heparin or warfarin in the prevention of thromboembolic episodes associated with orthopaedic surgery. Therapeutic doses of heparin and warfarin have been shown to delay bone repair in a rabbit model. The current study investigated the effect of prophylactic administration of a low molecular weight heparin, enoxaparin, on the healing of a closed rabbit rib fracture. Fracture healing was assessed using histomorphometric, histologic, and immunohistochemical methods at 3, 7, and 14 days, and biomechanical testing with torsional loading was assessed after 21 days. Bone repair was significantly attenuated at all times in animals receiving subcutaneous enoxaparin compared with that of the control animals. Numerous putative mechanisms for this phenomenon are discussed, and additional studies are proposed to elucidate the effects of this pharmacologically diverse group of compounds on all aspects of bone physiology and repair.     

Early antithrombotic prophylaxis with low molecular weight heparin in neurosurgery

Summary> ¶Background. Despite the high risk of venous thromboembolic events (VTE) in neuro-surgical patients, heparin prophylaxis has not been routinely established due to concern about bleeding complications. After initiating early low molecular weight heparin (LMWH) prophylaxis, we reviewed our patients in order to examine the viability of this practice. Method. Over a 3 year period, the records of patients admitted for elective neuro-surgery (ES), head injury (HI) or spontaneous intracranial haemorrhage (ICH) were analysed. Prophylaxis was performed with certoparin (3000 U anti-factor Xa s.c.) on the evening before ES and within 24 hours after surgery or admission whenever a CT did not show a progress-sive haematoma. Contraindications for LMWH were prothrombin time <70%, partial thrombo-plastin time >40s, platelet count <100.000/ml, and platelet aggregation test sum <60%. The incidence of bleeding complications, VTE, and resulting morbidity/mortality was assessed. Findings. 294 patients were admitted for ES, 344 for HI, and 302 for ICH. 155 of these were excluded because of contraindications. Intracranial bleeding was recorded in 1.5% (ES 1.1%, HI 3.5%, ICH 0%) and operative revision was performed in 1.1% (ES 0.7%, HI 2.8%) of patients. One case of moderate disability and no mortality occurred. The incidence of VTE and pulmonary embolism was documented in 0.2% and 0.1% of patients, with no associated mortality. No heparin induced thrombocytopenia was observed. Interpretation. In neurosurgical patients, antithrombotic prophylaxis with certoparin was determined to be safe and efficacious when contraindications are carefully considered and a 12-hour time interval before and after surgery was guaranteed. This retrospective analysis should encourage a prospective trial of early LMWH prophylaxis.     

Heparin/dihydroergotamine for venous thrombosis prophylaxis: comparison of low-dose heparin and low molecular weight heparin in hip surgery

In a prospective, double-blind controlled study we have compared the prophylactic efficacy against deep vein thrombosis of low-dose heparin + dihydroergotamine (A), low molecular weight heparin + dihydroergotamine (B) and placebo (C). A total of three hundred and fifty-six patients undergoing total hip replacement were randomized into three groups and 316 patients were analysed. All thrombi were verified by ascending phlebography. One-third of the patients developed deep vein thrombosis in group A and B, differing significantly from group C. The operative blood loss in group B was higher than that in groups A and C. However, the number of patients transfused and their transfusion requirements did not differ. Severe bleeding occurred in one patient in each group. No deaths were registered during the study. Our study indicates that prophylactic treatment against postoperative deep vein thrombosis with low molecular weight heparin + dihydroergotamine once daily is as effective and safe as conventional low-dose heparin + dihydroergotamine twice daily in patients undergoing total hip replacement. The once-daily regimen has the advantage of better patient acceptance and less nursing time.