Low-molecular-weight heparin in outpatient treatment of DVT

Patients with a diagnosis of acute deep venous thrombosis have traditionally been hospitalized and treated with unfractionated heparin followed by oral anticoagulation therapy. Several clinical trials have shown that low-molecular-weight heparin is at least as safe and effective as unfractionated heparin in the treatment of uncomplicated deep venous thrombosis. The use of low-molecular-weight heparin in an outpatient program for the management of deep venous thrombosis provides a treatment alternative to hospitalization in selected patients. Use of low-molecular-weight heparin on an outpatient basis requires coordination of care, laboratory monitoring, and patient education and participation in treatment. Overlapping the initiation of warfarin permits long-term anticoagulation. Advantages include a decreased incidence of heparin-induced thrombocytopenia and fewer episodes of bleeding complications. Future clinical trials evaluating the safety and efficacy of low-molecular-weight heparin in the treatment of complicated deep venous thrombosis will further define appropriate indications for use and strategies for outpatient management.     

DVT and pulmonary embolism: Part II. Treatment and prevention

Treatment goals for deep venous thrombosis include stopping clot propagation and preventing the recurrence of thrombus, the occurrence of pulmonary embolism, and the development of pulmonary hypertension, which can be a complication of multiple recurrent pulmonary emboli. About 30 percent of patients with deep venous thrombosis or pulmonary embolism have a thrombophilia. An extensive evaluation is suggested in patients younger than 50 years with an idiopathic episode of deep venous thrombosis, patients with recurrent thrombosis, and patients with a family history of thromboembolism. Infusion of unfractionated heparin followed by oral administration of warfarin remains the mainstay of treatment for deep venous thrombosis. Subcutaneously administered low-molecular-weight (LMW) heparin is at least as effective as unfractionated heparin given in a continuous infusion. LMW heparin is the agent of choice for treating deep venous thrombosis in pregnant women and patients with cancer. Based on validated protocols, warfarin can be started at a dosage of 5 or 10 mg per day. The intensity and duration of warfarin therapy depends on the individual patient, but treatment of at least three months usually is required. Some patients with thrombophilias require lifetime anticoagulation. Treatment for pulmonary embolism is similar to that for deep venous thrombosis. Because of the risk of hypoxemia and hemodynamic instability, in-hospital management is advised. Unfractionated heparin commonly is used, although LMW heparin is safe and effective. Thrombolysis is used in patients with massive pulmonary embolism. Subcutaneous heparin, LMW heparin, and warfarin have been approved for use in surgical prophylaxis. Elastic compression stockings are useful in patients at lowest risk for thromboembolism. Intermittent pneumatic leg compression is a useful adjunct to anticoagulation and an alternative when anticoagulation is contraindicated.     

间歇气压疗法联合低分子肝素钙预防腰椎间盘突出症患者下肢静脉血栓形成的研究

目的：对比研究间歇气压疗法联合低分子肝素钙与单纯低分子肝素钙预防腰椎间盘突出症患者下肢静脉血栓形成的情况。方法：选取我科2009年1月～2010年6月期间收住的腰椎间盘突出症患者177例,将其随机分为A组89例和B组88例。A组使用间歇气压疗法联合低分子肝素钙预防血栓;B组单纯低分子肝素钙预防血栓形成。术后观察两组患者双下肢静脉血栓形成的情况。结果：A组没有出现下肢静脉血栓的病例,B组有5例出现下肢静脉血栓。结论：间歇气压疗法联合低分子肝素钙能有效预防下肢静脉血栓的形成。     

Heparin-associated thrombocytopenia and thrombosis syndrome in a rehabilitation patient

Heparin-associated thrombocytopenia and thrombosis (HATT) syndrome is a severe complication of heparin therapy. Since patients admitted for rehabilitation are at high risk for deep-vein thrombosis and pulmonary embolism, prophylactic doses of subcutaneous heparin are frequently used. We report the case of a 73-year-old woman with a history of heparin exposure, admitted to a comprehensive rehabilitation program for management of severe back pain. The patient was started on subcutaneous heparin. After 18 days of hospitalization, she developed marked thrombocytopenia and a massive venous thrombosis in the right lower extremity. On intravenous heparin therapy, the platelet count continued to decline. The thrombocytopenia resolved with discontinuation of heparin. This case illustrates a devastating complication of heparin therapy and emphasizes that physiatrists should be aware of this acute and preventable drug reaction.     

Normal saline versus heparin flush for maintaining central venous catheter patency during apheresis collection of peripheral blood stem cells (PBSC)

Thrombotic occlusion is frequently a complication of central venous catheters (CVCs). The original designers and producers of CVCs recommended heparin flush regimens to prevent thrombosis and maintain patency. This has become standard practice although no studies have demonstrated a relationship between heparin flushing and reduction of catheter thrombosis. Many consider the routine use of heparin flushing innocuous. However, serious complications including drug interactions and heparin induced thrombocytopenia and thrombosis syndrome (HITS) have been reported in association with heparin flushing. Numerous studies comparing heparin to saline flushing in peripheral devices suggest equal rates of thrombotic occlusions. The purpose of this study was to examine the incidence of thrombotic occlusions in CVCs using heparin compared to saline flushing. The study involved 78 cancer patients undergoing apheresis collection for peripheral blood stem cells; 29 received saline flushes and 49 received heparin (100 U/ml of saline) flushes. Study endpoints included slow apheresis flow rate (< 50 ml/min), urokinase use for thrombolysis, and radiographic evidence of catheter thrombosis. No significant differences were found for any endpoint between the two groups. These findings suggest saline may be as effective as heparin for maintaining patency of CVCs.     

Heparin-induced thrombocytopenia associated with collection of hematopoietic progenitor cells by apheresis

Heparin-induced thrombocytopenia (HIT) can occur following exposure to heparin and is characterized by thrombocytopenia with increased risk for thrombosis. This condition is mediated by formation of immunoglobulin G antibodies against platelet factor 4/heparin complexes that can subsequently lead to platelet activation. Herein, we detail the clinical and laboratory findings, treatments, and outcomes of two patients who developed HIT and thrombosis after undergoing collection of hematopoietic progenitor cells by apheresis (HPC-A) for autologous HPC transplant. Given that heparin may be used during HPC-A collections, these cases emphasize the importance of prompt consideration of HIT in patients that develop thrombocytopenia and thrombosis following HPC-A collection with heparin anticoagulation.     

Synthesis: certainties/uncertainties in the prevention of venous thrombosis in medical patients

In medical patients there are numerous and variable risk factors for deep vein thrombosis. Placebo-controlled clinical trials are rare. The efficacy of standard heparin or low molecular weight heparin for the prevention of deep vein thrombosis is clearly demonstrated for patients with recent myocardial infarction, ischaemic stroke with hemiplegia or severe pulmonary sepsis with lung failure. Pharmacological prophylaxis is probably also efficient in patients with a severe acute disease and a certain history of deep vein thrombosis. For all other medical and especially for bedridden elderly patients, use of low molecular weight heparin might decrease the incidence of deep vein thrombosis but might not modify the overall mortality. In these situations, placebo-controlled clinical trials are needed for best evaluation of the benefit-risk ratio.     

Oral heparins

The antithrombotic drug heparin is administered parenterally and believed not effective orally. Oral heparin would be most suitable for long term administration, often required for the prevention of thrombosis. Following parenteral administration, heparin is taken up by endothelial cells. Our laboratory has shown that heparin is similarly taken up by endothelium following oral administration, despite low plasma heparin concentrations. In a twenty-four hour period, endothelial heparin concentrations are greatest within 15 minutes of oral dosing although plasma levels never exceed one percent of dose. Endothelial uptake accounts for a considerable amount of absorption if the total body endothelium is considered. In support of oral heparin absorption, we demonstrated a dose-dependent decrease in thrombosis incidence in a rat jugular vein model following single oral doses of unfractionated heparins (bovine and porcine) or low molecular weight heparins (reviparin, logiparin and ardeparin). Low molecular weight heparins were effective at lower doses than unfractionated heparins where a fifty percent reduction in thrombosis was observed with 0.025 mg/kg reviparin, 0.1 mg/kg logiparin, versus 7.5 mg/kg bovine unfractionated heparin. These studies support the work of others demonstrating measurable systemic changes following oral heparin administration and suggest that heparin may be effective when administered by the oral route. It also indicates that the presence of heparin in plasma likely reflects a much greater amount associated with endothelium.     

Effect of heparins on thrombin generation in hemophilic plasma supplemented with FVIII, FVIIa, or FEIBA

Central venous catheters assist infusion of coagulation factors in hemophiliacs but can be problematic due to mechanical dysfunction, infection, and thrombosis. The effect of low molecular weight heparin, unfractionated heparin, or covalent antithrombin-heparin complex on thrombin generation in factor concentrate-supplemented hemophilic plasma were studied. Thrombin levels were similar to normal plasma after the addition of factor eight inhibitor bypassing agent to hemophilic plasma. At 0.2 U/ml of heparin, covalent antithrombin-heparin inhibited free thrombin generation to a greater degree than heparin and low molecular weight heparin. Covalent anti-thrombin-heparin may give a greater anticoagulant response in hemophilic plasma supplemented with factor VIII or factor VIIa than with factor eight inhibitor bypassing agent. Requirements for heparin in hemophilic patients with thrombosis may depend on the procoagulant treatment used.     

Efficacy of unfractionated heparin for thromboembolism prophylaxis in medical patients

A common mode of deep vein thrombosis prophylaxis in medical inpatients is unfractionated heparin 5000 U subcutaneously (s.q.) twice daily. We examined the evidence in favor of using this dose of heparin in this group of patients. MEDLINE was searched for studies using the words deep vein thrombosis prophylaxis and heparin. All randomized controlled trials comparing heparin and placebo or heparin and a low molecular weight heparin were used. Relative risk was 0.4 (95% confidence interval 0.22-0.73) in studies comparing heparin 5000 U s.q. b.i.d. with placebo. Relative risk was 0.28 (95% confidence interval 0.21-0.38) in studies comparing heparin 5000 units s.q. t.i.d. versus placebo. In studies comparing unfractionated heparin with enoxaparin relative risk was 1.42 (95% confidence interval 0.99-2.05). Heparin 5000 U s.q. b.i.d. is less efficacious than low molecular weight heparins and unfractionated heparin 5000 U s.q. t.i.d.     

Prothrombotic factors enhance heparin-induced thrombocytopenia and thrombosis in vivo in a mouse model

BACKGROUND: Heparin-induced thrombocytopenia/thrombosis (HIT/T) is a common cause of life- and limb-threatening thrombosis. The development of antibodies that react with complexes of heparin and platelet factor 4 (PF4) is fundamental to the development of the disease. However, anti-PF4/heparin antibodies are far more common than is HIT/T and there is less understanding of the factors that contribute to thrombosis in only a subset of patients. OBJECTIVES: Both qualitative and quantitative differences in multiple factors (e.g. antibodies, heparin and platelets) may influence the clinical course of patients who develop anti-PF4/heparin antibodies. We examined the hypothesis that host-specific factors, such as comorbid prothrombotic conditions, would exacerbate the pathologic effects of anti-PF4/heparin antibodies. METHODS AND RESULTS: A mouse model transgenic for human Fcgamma RIIa and PF4 and null for mouse PF4 was used to study the influence of prothrombotic conditions on the effects of anti-PF4/heparin antibodies in vivo. To simulate a prothrombotic milieu, mice were fed a hypercholesterolemic diet (HD). HD-fed mice had elevated plasma cholesterol, increased platelet reactivity and increased endothelial activation relative to mice fed a standard diet (SD). Age- and sex-matched mice from each diet group were treated with an anti-PF4/heparin antibody and heparin. HD-fed mice developed more severe thrombocytopenia than similarly treated SD-fed mice. Mice with moderate to severe thrombocytopenia had elevated plasma levels of thrombin-antithrombin complexes, indicative of increased thrombin generation in vivo. Platelet-fibrin thrombi were observed in multiple organs of HD-fed mice that developed severe thrombocytopenia. CONCLUSIONS: Host-specific factors, such as prothrombotic changes in platelet reactivity and/or endothelial activation, may influence the development of thrombosis in a subset of patients who develop anti-PF4/heparin antibodies.     

Low-molecular-weight heparin successfully treating a nephrotic patient complicated by renal and ovarian vein thrombosis and pulmonary embolism

Thromboembolic complications, frequently associated with idiopathic membranous glomerulonephritis, are frequent and serious problems associated with nephrotic syndrome. However, ovarian vein thrombosis associated with nephrotic syndrome has never been reported. This study describes the case of a 35-year-old woman with idiopathic membranous glomerulonephritis who developed left renal vein thrombosis with ovarian vein thrombosis and pulmonary embolism. The thromboembolic complications were successfully treated with low-molecular-weight heparin. Low-molecular-weight heparin thus appears safe and effective for treating thromboembolism in nephrotic patients.     

Heparin-induced thrombocytopenia: how to manage it, how to avoid it

Heparin therapy has two potential adverse effects: bleeding and heparin-induced thrombocytopenia (HIT). There are two types of HIT: type I is more common but less severe; type II occurs less frequently but involves severe thrombocytopenia and a high risk for thrombotic events. Treatment involves discontinuing heparin, allowing the platelet count to return to normal, and treating any thrombosis. Lepirudin (Refludan) is the only agent currently approved for the treatment of HIT-related thrombosis, but other agents may have a role in combination therapy. Prevention includes using low molecular weight heparin instead of unfractionated heparin and limiting unfractionated heparin therapy to less than 5 days.     

Successful treatment of cerebral venous sinus thrombosis by balloon venoplasty: a case report

Cerebral venous sinus thrombosis is a special cerebrovascular disease affecting young adult and middle-aged people. The clinical manifestations of cerebral venous sinus thrombosis are diverse and nonspecific; thus, imaging plays an important role in early diagnosis. Anticoagulation with heparin is the preferred treatment for cerebral venous sinus thrombosis. Endovascular treatment is also being increasingly used to achieve recanalization of the cerebral venous sinus. We herein describe a woman in her early 50s who was diagnosed with cerebral venous sinus thrombosis for which anticoagulation with heparin was ineffective. To improve her symptoms and prognosis, we selected balloon venoplasty to treat the right sigmoid sinus thrombosis. Her condition subsequently improved, and no recurrence was observed after several follow-ups.     

低分子肝素钙围术期应用预防老年髋部骨折术后深静脉血栓疗效观察

目的：为观察低分子肝素钙（low molecular weight heparins calcium injection,LMWH）围术期应用预防老年髋部骨折术后深静脉血栓（deep venous thrombosis,DVT）的疗效和安全性。方法：将50例接受手术的患者随机分为2组,每组25例。A组应用低分子肝素钙预防,B组运用普通血管活性药物,术后14～20d患侧下肢行彩超检查了解深静脉血栓发生情况。结果：A组0例（0%）发生深静脉血栓,B组为6例（24%）,两组比较差异有统计学意义（P〈0.05）;A组出血量（295±80）ml,B组（272±80）ml,两组比较差别无统计学意义（P〉0.05）,两组均未发生明显大出血。结论：表明低分子肝素钙围术期应用可安全有效预防下肢骨折术后深静脉血栓形成。     

Elevated pulmonary dead space and coagulation abnormalities suggest lung microvascular thrombosis in patients undergoing cardiac surgery

OBJECTIVE: Inflammation has been shown to trigger microvascular thrombosis. Patients undergoing cardiac surgery sustain significant inflammatory insults to the lungs and in addition are routinely given anti-fibrinolytic agents to promote thrombosis. In view of these risk factors we investigated if evidence of pulmonary microvascular thrombosis occurs following cardiac surgery and, if so, whether a pre-operative heparin infusion may limit this. DESIGN: Double-blind randomised controlled trial. SETTING: Tertiary university affiliated hospital. PATIENTS: Twenty patients undergoing elective cardiac surgery. INTERVENTIONS: Patients were randomised to receive a pre-operative heparin infusion or placebo. All patients were administered aprotinin. MEASUREMENTS AND RESULTS: Pulmonary microvascular obstruction was estimated by measuring the alveolar dead-space fraction. Pulmonary coagulation activation was estimated by measuring the ratio of prothrombin fragment levels in radial and pulmonary arterial blood. Systemic tissue plasminogen activator (t-PA) levels were also assessed. In the placebo group cardiac surgery triggered increased alveolar dead-space fraction levels and the onset of prothrombin fragment production in the pulmonary circulation. Administration of pre-operative heparin was associated with a lower alveolar dead-space fraction (p < 0.05) and reduced prothrombin fragment production in the pulmonary circulation (p < 0.05). Pre-operative heparin also increased baseline t-PA levels (p < 0.05). CONCLUSION: The changes in the alveolar dead-space fraction and pulmonary coagulation activation suggest that pulmonary microvascular thrombosis develops during cardiac surgery and this may be limited by a pre-operative heparin infusion.     

Low-molecular-weight Heparins for the Treatment of Venous Thromboembolism

Recent studies have indicated that certain low-molecular-weight heparins given subcutaneously may replace continuous intravenous unfractionated heparin for the treatment of venous thromboembolism. Low-molecular-weight heparins have a predictably high absorption rate when given subcutaneously and they do not require laboratory monitoring. These characteristics of low-molecular-weight heparin therapy raise the possibility of treating uncomplicated patients with deep venous thrombosis or pulmonary embolism in the outpatient setting. The advantages to the patient of avoiding in-hospital care and its associated hazards are obvious. Outpatient lowmolecular-weight heparin will likely prove to be highly cost-effective. At the present time, the findings associated with an individual low-molecular-weight heparin preparation cannot be extrapolated to different low-molecular-weight heparins and each must be evaluated in separate clinical trials. Recent randomized clinical trials indicate that low-molecular-weight heparin may be safer and more effective than continuous intravenous unfractionated heparin in the treatment of proximal venous thrombosis. A decreased mortality rate, which was particularly striking in patients with metastatic carcinoma, was unexpected and requires confirmation in further prospective randomized trials.     

Inhibitory effect of activated protein C and heparin on arterial thrombosis]

Activated protein C (APC) exerts an anticoagulant effect by inactivating coagulation factors Va and VIIIa, preferentially on the surface of the cell membrane, and may enhance fibrinolysis by inhibiting PAI-1. APC inhibits venous and microvascular thrombosis, as well as, platelet-rich thrombus formation on the Dacron graft inserted in the arteriovenous shunt. We examined the effect of APC and heparin on arterial thrombosis using small mesenteric arteries of the rat, in which platelet-rich thrombus formation was induced by segmental deep vessel injury and the changes were monitored using a video-microscope system. Both APC (0.9 and 3.0 mg/kg, iv) and heparin (300 and 1000 U/kg) inhibited thrombus formation similarly. APC did not prolong APTT compared with heparin. APC may inhibit arterial thrombosis after vascular damage without serious bleeding side effects.     

肾病综合征并发颅内静脉窦血栓的护理效果观察

目的探讨应用尿激酶与低分子肝素等联合治疗肾病综合征患儿并发颅内静脉窦血栓后的护理效果。方法采用尿激酶与低分子肝素等联合治疗,观察血压、神志、尿量、肢体色泽、温度及有无皮下出血情况。结果观察发现肾病综合者患儿在激素治疗的过程中易合并高凝状态,肾病综合征的高凝状态是静脉血栓形成的基础,临床上一旦患儿血压升高并发头痛、头昏、嗜睡、呕吐等症状时,应尽早进行头颅CT或MRI检查以便了解有无头颅静脉血栓,并常规运用尿激酶与低分子肝素联合治疗。结论早期应用尿激酶抗纤溶、低分子肝素抗凝及抗血小板凝聚药物综合治疗,其溶栓疗效较好。本文对儿童肾病综合征并发颅内静脉窦血栓的早期护理观察具有推广价值。     

Alternatives to heparin infusion.

This article offers an overview of the pathophysiology, diagnosis, and treatment of heparin-induced thrombocytopenia (HIT). This disorder is an immune-mediated reduction of platelets with subsequently increased generation of thrombin and increased risk of arterial and venous thrombosis. Heparin-induced thrombocytopenia can occur as an isolated incident or with acute thrombosis (HIT with thrombosis syndrome [HITTS]). Proper recognition, cessation of all forms of heparin (and compounds that cross-react with heparin), and rapid initiation of nonheparin anticoagulation are essential steps in reducing the risk of death, limb amputation, and new thrombotic events. Current alternatives to heparin are reviewed.