Therapeutic Doses Of Low Molecular Weight Heparin Research Articles

Half-dose enoxaparin vs. full-dose enoxaparin for postoperative bridging therapy in patients after cardiac surgery: Which dose regimen should be preferred?

Patients who require oral anticoagulation (OAC) after cardiac surgery due to an increased risk for thromboembolic events should receive bridging therapy with heparin until the INR is in a therapeutic range. For this purpose, unfractionated heparin (UFH) or low molecular weight heparin (LMWH) can be used. Recently published studies have demonstrated the safety and efficiency of therapeutic dose LMWH as bridging anticoagulant in cardiac surgery. The present study compares a full-therapeutic dose regimen with a half-therapeutic dose regimen of LMWH looking for safety and efficiency. This study represents a retrospective, single-center cohort study. In a period of 19 months all patients in whom a postoperative bridging therapy after cardiac surgery was necessary (atrial fibrillation, mechanical heart valve replacement, tricuspid valve repair, intracardiac patch implantation, excision of intracardiac tumors) were selected. In the first part of the study, patients received full-dose (FD = 1 mg/kg bodyweight twice daily) LMWH (Enoxaparin). Analogously, patients in the second part of the study were treated with half-dose (HD = 0.5 mg/kg bodyweight twice daily) LMWH. In case of renal insufficiency (GFR <30 ml/min) the dose was adjusted to one daily application. The duration of follow-up was the patients' entire stay in hospital. Main outcome parameters were bleeding, thromboembolic events, and death. The first dose of LMWH was given on the morning of the first postoperative day, considered that the bleeding risk was acceptable. OAC (Phenprocoumon) was started on the evening of the first postoperative day. Altogether 402 out of 3133 patients met the inclusion criteria (201 patients in each group). Despite a reduced renal function in the HD-group (p = 0.002) both groups were well matched. Mortality was significantly higher in the HD-group than in the FD-group (5.5% vs. 0.5%, p = 0.003) but not related to the anticoagulation regimen. We observed more bleeding events in the FD-group (11 vs. 5, p = 0.126) but vice versa more thromboembolic events in the HD-group (9 vs. 5, p = 0.277). In the HD-group postoperative dialysis was required more often (29 vs. 12, p = 0.011) and there was a higher incidence of patients who were psychic disorientated (42 vs. 26, p = 0.033). The hospital stay was longer in the FD-group (FD: 15.1 ± 9.3 days, HD 12.5 ± 8.1 days, p = 0.003). This study shows that a bridging therapy with LMWH is feasible and safe no matter which dose-regimen is used. The differences observed seem not to be related to the anticoagulation. The decision of using a full-dose or half-dose LMWH bridging regimen should be determined by the individual risk of the patient and the general bleeding risk of the procedure.

A multicentre national audit of the recording of patients weight: Implications for the prescription of gentamicin and therapeutic-dose low molecular weight heparin

A multicentre national audit of the recording of patients weight: Implications for the prescription of gentamicin and therapeutic-dose low molecular weight heparin

Accuracy of Point of Care Testing in Patients on Dual Anticoagulation During Initiation of Anticoagulation or Bridging,

Abstract 3360 Background:Point-of-care testing (POCT) is widely used for monitoring of the international normalized ratio (INR) in patients on oral anticoagulation with a vitamin-K antagonist (VKA) and numerous clinical studies have assessed the accuracy of this method in comparison with INR results from venous blood samples analysed in the laboratory. There is however a paucity of clinical data to support the use of POCT in patients on dual anticoagulation with low molecular weight heparin (LMWH) and a VKA during initiation of anticoagulation or bridging after a surgical procedure. Aim:To test the hypothesis whether therapeutic doses of LMWH interfere with INR measurements when using a POCT system during times of dual anticoagulation with LMWH and a VKA. To further investigate whether the effect is most pronounced once LMWH has reached peak plasma levels and less evident 10 hours and more after administration of LMWH. Methods:We prospectively collected 160 consecutive venous blood samples from patients on therapeutic doses of LMWH - Tinzaparin (175 IU/kg once daily) and a VKA commonly warfarin for INR testing in our laboratory. At the same time all patients had their INR determined on capillary blood collected by finger prick using a CoaguChek XS Pro and INR test strips with the same lot number (Roche Diagnostics Ltd, UK).60 blood samples were collected within 3–6 hours after administration of LMWH (group 1) and 100 samples were collected 10 hours or more after the last injection of LMWH (group 2). For each sample the dose and time of the last injection of LMWH was recorded along with the time of the venepuncture and the result of the capillary INR. To ensure that we had a wide variation in the plasma concentrations of LMWH we carried out anti-Xa testing on a cross-section of venous samplesThe dosing advice for Warfarin was based on the INR result of the venous blood sample processed in the laboratory. Results:The correlation coefficient between the POCT INR and the laboratory INR was 0.98 in group 1 and 0.97 in group 2.In the Bland Altman analysis for group 1 the mean 95% confidence interval (CI) was 0.03 (range+/− 1.96 SD: −0.26 to +0.32) and for group 2 the mean 95% CI was 0.00 (range −0.28 to +0.29). These results are comparable to results of our internal quality control between POCT INR and laboratory INR in patients on VKA alone with a mean 95% CI of −0.02 (range −0.26 to +0.29).The mean INR was 1.8 by both methods in group 1 and 1.7 by both methods in group 2 and anti-Xa levels ranged from 0 to1.19 U/mL.A variation in the result of the POCT INR and laboratory INR of 0.5 or greater is thought to affect dosing decisions for Warfarin. Such a variation was observed in 3% (2/60) in group 1 and 2% (2/100) in group 2. Conclusion:There was good accuracy of the INR obtained with the POCT system used and this was not affected by the timing of the administration of LMWH in relation to testing. Disclosures:No relevant conflicts of interest to declare.

Initiation and Reinitiation of Anticoagulation Therapy

A thorough understanding of the pharmacology, pharmacokinetics, and pharmacodynamics of the most commonly prescribed anticoagulants is necessary to ensure optimal therapeutic outcomes and patient safety. Evidence is available to guide some, but not all aspects of anticoagulation therapy initiation. Issues related to the initiation of anticoagulation therapy, including the resumption of therapy following interruption of anticoagulation for invasive procedures, are reviewed. Initiating unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), or fondaparinux is challenging for patients with renal dysfunction and obesity. UFH is preferred in patients with severe renal dysfunction. Morbidly obese patients may require higher than usual prophylactic doses of LMWH. Therapeutic doses of LMWH should be based on actual body weight, even in obese patients. Currently available evidence does not demonstrate the superiority of one initial warfarin dose over another. All anticoagulants increase the risk of bleeding and should therefore only be initiated in appropriately selected patients with sufficiently low underlying bleeding risk.

Guidelines on oral anticoagulation with warfarin – fourth edition

Guidelines on oral anticoagulation with warfarin – fourth edition

Perioperative bridging therapy with low molecular weight heparin for patients with inherited thrombophilia and antiphospholipid syndrome on long-term acenokumarol therapy

The aim of the study is to present our own perioperative bridging therapy with low molecular weight heparin (LMWH) for surgical patients with thrombophilia on long-term acenokumarol therapy [oral anticoagulant (OAC)]. In some European countries, the drug used in secondary antithrombotic prophylaxis is acenokumarol. Forty-two patients with inherited thrombophilia and 21 with antiphospholipid syndrome underwent surgery. All patients were on long-term OAC. This OAC was interrupted 2 days before elective surgery and since that day half of the individual therapeutic dose of LMWH was administered. On day of surgery, the LMWH therapeutic dose was divided into two parts. Starting with day 2 after surgery, the patient was again given half of the individual dose of LMWH every 24 h. On day 4, OAC was additionally included. Both drugs were administered until stabilization of international normalized ratio (INR) values within the therapeutic target for 2 consecutive days. LMWH was then interrupted, whereas OAC continued. No symptoms or episodes of venous thromboembolism were observed. No intraoperative or postoperative hemorrhagic complications were reported. The results suggest that our perioperative bridging therapy is safe and effective for prevention of thromboembolic and hemorrhagic complications.

Maternal Complications and Pregnancy Outcome in Women With Mechanical Prosthetic Heart Valves Treated With Enoxaparin

Obstetric Anesthesia Digest 30(4):p 223-224, December 2010. | DOI: 10.1097/01.aoa.0000389599.26353.cd

TTP-HUS klinikai képét utánzó és heveny veseelégtelenséggel szövődő krónikus DIC hátterében álló metasztatikus prosztatarák: patomechanizmus, differenciáldiagnózis és kezelés egy eset kapcsán

Disseminated intravascular coagulopathy (DIC) is characterized as activation of the clotting system resulting in fibrin thrombi, gradually diminishing levels of clotting factors with increased risk of bleeding. Basically two types of DIC are distinguished: (1) chronic (compensated) - with alteration of laboratory values and (2) acute (non-compensated) - with severe clinical manifestations: bleeding, shock, acute renal failure (ARF), transient focal neurologic deficit, delirium or coma. Chronic DIC related to metastatic neoplasia is caused by pancreatic, gastric or prostatic carcinoma in most of the cases. Incidence rate of DIC is 13-30% in prostate cancer, among those only 0.4-1.65% of patients had clinical signs and symptoms of DIC. In other words, chronic DIC is developed in one of eight patients with prostate cancer. DIC is considered as a poor prognostic factor in prostatic carcinoma. The similar clinical and laboratory findings of TTP-HUS (thrombotic thrombocytopenic purpura - hemolytic uremic syndrome) and DIC makes it difficult to differentiate between them. A 71 years old male patient with known chronic obstructive pulmonary disease, benign prostatic hyperplasia, significant carotid artery stenosis, gastric ulcer and alcoholic liver disease was admitted to another hospital with melena. Gastroscopy revealed intact gastric mucosa and actually non-bleeding duodenal ulcer covered by clots. Laboratory results showed hyperkalemia, elevated kidney function tests, indirect hyperbilirubinemia, increased liver function tests, leukocytosis, anemia, thrombocytopenia and elevated international normalized ratio (INR). He was treated with saline infusions, four units of red blood cells and one unit of fresh frozen plasma transfusions. Four days later he was transported to our Institution with ARF. Physical examination revealed dyspnoe, petechiae, hemoptoe, oliguria, chest-wall pain and aggressive behavior. Thrombocytopenia, signs of MAHA (fragmentocytes and helmet cells in the peripheral blood), normal INR, elevated lactate dehydrogenase (LDH) and ARF suggested TTP-HUS. Hemodialysis and six plasmaferesis (PF) were carried out. After the fifth PF, skin manifestations of thrombotic microangiopathy occurred on the feet. Clotting analysis revealed elevated D-dimer (>5 μg/mL), normal fibrinogen (3.2 g/L), a slightly raised INR (1.36) and activated partial prothrombin time (APTT) (45.8 sec), normal reticulocyte (57 G/L) and a slightly low platelet count (123 G/L), which proved to be chronic DIC. Therapeutic dose of low-molecular-weight heparin (LMWH) was started. Elevated prostate-specific antigen (PSA) (109.6 ng/mL) suggested prostatic carcinoma. Prostate biopsy revealed adenocarcinoma (Gleason: 4+4 for left lobe and 3+3 for right lobe). Elevated alkaline phosphatase suggested metastases in the bone, which were confirmed by bone scintigraphy. Combined androgen blockade (CAB) was started. After three months follow-up our patient's status is satisfactory. PSA is in the normal range (4.6 ng/mL). Thrombocytopenia of uncertain origin with normal or raised INR, APTT, elevated D-dimer, normal fibrinogen and reticulocyte count prove the diagnosis of chronic DIC. This process warrants searching for metastatic neoplasia. Due to the relatively low serum levels of circulating procoagulant factors (e.g. tissue factor), therapeutic dose of LMWH can be used with good efficiency in chronic DIC with low risk of bleeding. Severe DIC as a complication of metastatic prostate cancer can be treated by androgen deprivation therapy (ADT) or CAB in combination with ketokonazole and concomitant use of supportive treatment. Deme D, Ragán M, Kovács L, Kalmár K, Varga E, Varga T, Rakonczai E. Metastatic prostate cancer complicated with chronic disseminated intravascular coagulopathy causing acute renal failure mimicking thrombotic thrombocytopenic purpura and hemolytic uremic syndrome: pathomechanism, differential diagnosis and therapy related to a case.

Totally double laparoscopic colon resection with intracorporeal anastomosis and transvaginal specimens extraction

Dear Editor: Laparoscopic colorectal resection is equivalent to open resection in terms of oncologic outcomes, with superior perioperative results. Usually, an abdominal incision is required for anastomosis and specimen extraction. Recently, natural orifice specimen extraction (NOSE) and intracorporeal anastomosis have been proposed to improve the quality of laparoscopic colon resections. Transvaginal and transanal specimen extraction have been reported in association with right and left colic intracorporeal anastomosis and these two technical innovations may maximize the advantages of laparoscopic surgery. We present a case of double colon resection with intracorporeal anastomosis and transvaginal specimens extraction. A 73-year-old female obese patient was admitted for rectal bleeding and hypochromic microcytic anemia. Past medical history was significant for hypertension, COPD, myocardial infarction, treated with double stenting 4 years before, and sigmoid diverticular disease with several episodes of diverticulitis in the last 6 years. Her BMI was 36 kg/m. She denied any change in bowel habits, neither constipation nor diarrhea. She underwent colonoscopy revealing a gradually narrowing stenosis of the sigmoid with intact mucosa. Multiple biopsies were negative for cancer and confirmed the inflammatory disease. Due to the stenosing lesion, the procedure was incomplete and a virtual colonoscopy was performed. A right-colon mass, highly suspected for cancer but apparently not involving the lymph nodes, was found. Metastatic disease was excluded with contrast-enhanced total body CT scan. Preoperative carcinoembryonic antigen (CEA) level was normal (<5 ng/ml). Because of the patient’s general conditions and to reduce the risks related to anesthesia, we decided to treat both lesions at the same surgical time. In the aim to minimize complications and according to the patient willingness, we choose a minimally invasive approach with totally laparoscopic right colectomy and sigmoidectomy. Her low-dose aspirin therapy was stopped 7 days before surgery and therapeutic-dose of lowmolecular-weight heparin was administered. Mechanical bowel preparation was avoided, a single enema was given the night before. Broad-spectrum intravenous antibiotics were administered 30 min before the skin incision and postoperatively for 24 h. The patient underwent general endotracheal anesthesia and was positioned in the lithotomic position; nasogastric tube and urinary catheter were placed. The surgeon stood at the left side of the patient for the right colectomy and on the right for the sigmoidectomy. A medial to lateral right colectomy followed by a side to side ileocolic anastomosis with linear stapler was first performed. Subsequently, a sigmoidectomy with inferior mesenteric artery preservation and side to end colorectal anastomosis, using a circular stapler, was carried out. A colotomy was made just proximal to the transection site. The anvil was introduced inside the abdomen through one of the trocar incisions, and inserted in the proximal colon through the colotomy. The proximal colon was closed with a linear stapler, and an end to side anastomosis was established using a transrectal circular stapler. A 12-mm trocar was inserted through the posterior fornix under laparoscopic vision. The culdotomy F. Stipa :V. Giaccaglia : E. Santini : L. Tammaro Department of Surgery, San Giovanni Hospital, Rome, Italy

Antipsychotic Drug Use and the Risk of Venous Thromboembolism in Elderly Patients

Our aim was to investigate the relationship between exposure to antipsychotic drugs and the risk of venous thromboembolism (VTE) in elderly patients. A time-matched case-control analysis nested within a cohort of 111,818 patients with at least 1 antipsychotic drug prescription during 1998 to 2008. Data were used from the PHARMO institute's database, which contains drug dispensing data from community pharmacies and hospital admission data. The index date was for the cases defined as the date of hospital admission for VTE (deep venous thrombosis [DVT] or pulmonary embolism) or, for outpatient cases, the start of therapeutic dose low-molecular weight heparin therapy. For each case, 4 controls matched by age and sex were randomly sampled from the cohort. Two measures were used to evaluate the temporal relationship between antipsychotic drug use and the occurrence of VTE: being a current, recent, or past user and the duration of use up to the index date. The strength of the association was expressed as odds ratios with 95% confidence intervals, taking into account potential confounders. We identified 367 cases of hospital admission for DVT, 342 cases of hospital admission for PE, and 323 cases of outpatient treatment of DVT. Current exposure to antipsychotic drugs was not associated with an increased risk of VTE, compared with nonusers (odds ratio, 0.9; 95% confidence interval, 0.7-1.1). We found no association between dosage, the duration of use, or the type of antipsychotic drug and the risk of VTE. We found no evidence of an increased risk of VTE in elderly patients using antipsychotic drugs.

103 A SUCCESSFUL MANAGEMENT OF A PATIENT WITH SUBCLAVIAN VEIN THROMBOSIS AFTER IVF

The incidence of thromboembolic disease associated with the assisted reproductive techniques is considered to be rare. The aim of the report is to present a case of successful management of woman with subclavian vein thrombosis after IVF and embryo transfer. A 29-year-old smoking woman was refered to our programme for IVF and ICSI because of infertility associated with the male factor. Her past medical history didn’t report any serious disease. The treatment procedure consisted of a long protocol included administration of Diferelinum and Gonal F 75U/day. After 10 days of stimulation she received 6000 IU of hCG. At that point there were 16 follicles between 18 20mm in diameter. Oocyte recovery took place 36 hours later. 14 oocytes were collected and 9 were mature and underwent ICSI resulting in 6 embryos. Three embryos were transferred to the uterus 3 days later and three embryos were frozen. A dose of 40mg Dufaston per os, 600mg Utrozestan per vaginum and 1500U Pregnil in a day were given for luteal phase support. One day before embryo transfer the patent complained of slight shortness of breath, flatulence. Haematocrit was normal, ovaries were moderately enlarged at 85× 54 and 77x53mm. A diagnosis of moderate ovarian hyperstimulation syndrome was made and intravenous hydratation with HAES-sterile was administered. In two weeks triplets pregnancy was diagnosed. At 5th week of gestation (w.g.) the patient experienced pain and swelling of left arm and neck. Ultrasonography revealed thrombus in left internal jugular, subclavian and brachiocephalic veins. The patient started low molecular weight heparin (LMWH) and remained on therapeutic doses of LMWH until postpartum. Thrombophilia work-up (antiphospholipid antibody, lupus anticoagulant, total homocysteine, proteins C, S, antithrombin III, plasminogen, prothrombin G20210A, factor V Leiden and methyleneteterahydrofolatreductase (MTHFR) C677T) revealed high titer of antib2-GPI IgM (twice 14 weeks apart) and homozygosity for MTHFR C677T. At 11w.g. the patient passed prenatal ultrasound screening for Dawn syndrome and reduction of one fetus of triplets was made by method of Berkovich at 11 weeks of gestation. The procedure of reduction was simple. Patient’s pregnancy course was otherwise uncomplicated. Patient delivered female twins with Apgar 6 7 weighing 2200 and 1900 g via caesarian section at 37w.g. The pregnancy was ended via caesarian section at 37w.g. Female twins were born with Apgar 6 7 weighing 2200 and 1900. This case illustrates serious complication of assisted reproductive treatment. Early recognition and treatment of OHSS and thrombophilia is critical for prevention and effective therapy of thromboembolic complications in patients undergoing ovarian stimulation. 104 CLINICAL SIGNIFICANCE OF HIDDEN THROMBOPHILIA BEFORE IN VITRO FERTILIZATION AND EMBRYO TRANSFER A.M. Harutyunyan, Zh.K. Isentayeva. Moscow Centre of Urology, Andrology and Reproductive Gynecology, Moscow, Russia

Maternal Complications and Pregnancy Outcome in Women With Mechanical Prosthetic Heart Valves Treated With Enoxaparin

Anticoagulation therapy is recommended throughout pregnancy for women with mechanical heart valves, to reduce the risk of thromboembolic complications. Although warfarin is the preferred therapeutic agent for such patients when not pregnant, warfarin is teratogenic; during pregnancy, unfractionated or low molecular weight heparin (LMWH) may be considered because it is safer for the fetus, although it is not clear that it provides adequate anticoagulation. A large number of studies have reported a wide variation (3.9%–22%) in the percentage of thrombotic complications reported in pregnant women with mechanical heart valves managed with LMWH (enoxaparin), although most studies were small. When analysis was limited to studies including 5 or more pregnancies, a rate of 6.9% was reported. This retrospective single center study investigated the rate of maternal thrombotic and hemorrhagic complications and other maternal and fetal outcomes in 31 women with mechanical heart valves who were treated with therapeutic dose LMWH (enoxaparin) during pregnancy. Between 1997 and 2008, data were extracted from the medical records of these women and analyzed for the maternal primary endpoints of thromboembolism and hemorrhagic complications. Secondary maternal and fetal outcomes that were analyzed included miscarriage, stillbirth, neonatal or infant death, live birth, small for gestational age, warfarin embryopathy, and warfarin-associated fetal loss. Most patients received therapeutic dose enoxaparin (1 mg/kg BID) and aspirin 100 to 150 mg q day until planned delivery. A total of 47 pregnancies were evaluated in 31 subjects. Thirty-four (72.3%) were managed with enoxaparin as the primary anticoagulant and the remaining 13 (27.7%) received warfarin as the main anticoagulant, with enoxaparin used between 6 and 12 weeks of gestation and/or peridelivery. Thromboembolic complications occurred in 7 (14.9%) pregnancies; of these, 5 (10.6%) were directly related to enoxaparin therapy. Poor compliance with enoxaparin was a major factor in 3 of these events and failure to achieve therapeutic target anti-Xa levels was a major contributing factor in the other 2 cases. The other 2 thrombotic complications occurred because the patients electively stopped taking their anticoagulant (warfarin). Antenatal bleeding occurred in 17% (8/47) of the pregnancies; 5 of the 8 bleeds were associated with enoxaparin, and the other 3 occurred during treatment with intravenous unfractionated heparin. Primary or secondary postnatal hemorrhage complicated 32% (15/47) of the pregnancies; 6 were due to enoxaparin, one occurred on unfractionated heparin, one on unfractionated heparin and warfarin, and one on warfarin alone. Among the 35 pregnancies continued beyond 20 weeks of gestation, 96% (22/23) of the women taking mainly enoxaparin had a surviving infant compared with 75% (9/12) of those taking primarily warfarin (P = 0.11). There were 4 perinatal deaths; 3 due to warfarin. These findings suggest to the investigators that administration of therapeutic dose enoxaparin in combination with low-dose aspirin to pregnant women with mechanical heart valves can achieve a low risk of valve thrombosis and a high rate of infant survival, provided that there is close clinical follow-up and high compliance.

Using low molecular weight heparin in special patient populations

Clinical trials evaluating low molecular weight heparin (LMWH) for the prevention and treatment of venous thromboembolism and acute coronary syndromes have led to their regulatory approval for these indications in the general population. However, certain patient populations have been excluded from these landmark clinical trials, including patients with renal insufficiency, obese patients and pregnant women. In these special populations, data on safety and efficacy is limited and typically based on pharmacokinetic studies often performed in healthy subjects, or small cohort studies which are generally not powered to evaluate clinical outcomes such as bleeding or recurrent thrombosis. Because LMWH is mainly cleared renally, patients with severe renal insufficiency are at risk of LMWH accumulation and increased bleeding risks. In obese patients, there is concern regarding possible overdosing of therapeutic dose LMWH, since LMWH does not distribute in fat tissue. There are also concerns about possible underdosing of prophylactic dose LMWH in obese individuals using the standard fixed doses, particularly in the extremely obese individuals undergoing bariatric surgery. Last, pregnancy poses challenges with regards to the safety of LMWH during pregnancy and use of LMWH around delivery. This review summarizes the existing data in these special populations and proposes general recommendations for practice.

Anticoagulation: Low-Molecular-Weight Heparins in Renal Impairment and Obesity: Available Evidence and Clinical Practice Recommendations Across Medical and Surgical Settings

To develop practical recommendations for the use of low-molecular-weight heparins (LMWHs) as prophylaxis and treatment of venous thromboembolism and acute coronary syndromes in patients with impaired renal function or obesity. Multiple MEDLINE searches were performed (November 2008) to identify studies for inclusion, using a comprehensive list of search terms including, but not limited to, LMWH, enoxaparin, dalteparin, tinzaparin, obesity, weight, renal, kidney, elderly, monitoring, and anti-Xa. Only articles published in English that were relevant for this review were included. In the majority of patients, standardized prophylaxis or treatment doses of LMWHs can be used without the need for monitoring and adjusting regimens. For patients with severe renal impairment (estimated creatinine clearance [CrCl] <30 mL/min), doses of some LMWHs should be adjusted or unfractionated heparin should be used instead. CrCl should be estimated using the Cockcroft-Gault method. Differences are noted in the degree of accumulation of various LMWHs in patients with moderate-to-severe renal impairment, and thus, the degree of dose adjustment may differ among the various LMWHs. Increasing the prophylactic doses of LMWH may be appropriate in morbidly obese patients (body mass index > or = 40 kg/m(2)). The use of total body weight is appropriate for therapeutic doses of LMWH in obese patients. Laboratory monitoring of the anticoagulation effect of LMWHs is generally not necessary, but should be considered in patients with morbid obesity (weight >190 kg), those with severe renal impairment, and those with moderate renal impairment with prolonged (>10 days) LMWH use. When anti-Xa activity is monitored, it should be determined using a chromogenic method and a calibration curve based on the LMWH used. Additional data are needed for specific dose guiding in obese and renally impaired patients, who are often excluded from larger clinical trials. Practice recommendations are made based on available evidence and authors' clinical opinions.

Dose escalation of low molecular weight heparin to manage recurrent venous thromboembolic events despite systemic anticoagulation in cancer patients.

Cancer patients with venous thromboembolism (VTE) are at high risk of recurrent VTE despite standard anticoagulation. To date, very little published literature is available to guide the treatment of cancer patients with recurrent VTE. To evaluate the benefit and risk of low molecular weight heparin (LMWH) dose escalation in cancer patients with recurrent VTE. This was a retrospective cohort study of consecutive cancer outpatients referred for management of a symptomatic, recurrent VTE while receiving an anticoagulant. Confirmed episodes of recurrent VTE were treated with either dose escalation of LMWH in patients already anticoagulated with LMWH, or initiation of therapeutic dose LMWH in patients who were taking a vitamin K antagonist (VKA). All patients were followed for a minimum of 3 months after the index recurrent VTE unless they died during this period. Seventy cancer patients with a recurrent VTE despite ongoing anticoagulation were included. At the time of the recurrence, 67% of patients were receiving LMWH, and 33% were receiving a VKA. A total of six patients [8.6%; 95% confidence interval (CI) 4.0-17.5%] had a second recurrent VTE during the 3-month follow-up period, at an event rate of 9.9 per 100 patient-years (95% CI 2.0-17.8%). Three patients (4.3%; 95% CI 1.5-11.9%), or 4.8 per 100 patient-years (95% CI 0.0-10.3%) of follow-up, had bleeding complications. The median time between the index recurrent VTE to death was 11.4 months (range, 0-83.9 months). Cancer patients with recurrent VTE have a short median survival. Escalating the dose of LMWH can be effective for treating cases that are resistant to standard, weight-adjusted doses of LMWH or a VKA.

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

Introduction Pregnancy 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. Method Retrospective 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. Results Median 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. Conclusion Treatment 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.

Dose Escalation of Low Molecular Weight Heparin to Manage VTE Treatment Failure in Cancer Patients

Introduction: Cancer patients with venous thromboembolism (VTE) are at high risk of treatment failures (i.e. recurrent VTE while on therapeutic anticoagulants). Management of these treatment failures is controversial/poorly studied. Whereas some clinicians recommend inferior vena cava (IVC) filter insertion, others do not. We sought to assess the efficacy and safety of escalating the dose of low-molecular weight heparin (LMWH) in the management of treatment failure recurrent VTE in cancer patients.Methods: Retrospective cohort study of outpatients with cancer and treatment failure recurrent VTE seen at the Ottawa Hospital Thrombosis Unit from January 2007 to June 2008. Patients were followed for three months following the treatment failure event.Results: Thirty cancer patients had recurrent VTE despite ongoing anticoagulation. The mean age was 60.7 years. Twenty two patients (73.3%) were on LMWH treatment at the time of the recurrent event. Of these 22 patients, 4 (18.2%) were on full (100%) therapeutic doses, 15 (68.2%) on 75% of therapeutic doses and 3 (13.6%) on prophylactic doses of LMWH. All 4 patients on full therapeutic dose were treated by increasing the weight-adjusted dose of LMWH by 20% for 6 weeks. Patients on 75% of therapeutic doses were treated by increasing the weight-adjusted LMWH by 25% for 6 weeks (4/15 patients) or 3 months (11/15 patients). All three patients on prophylactic doses were treated with one month of full therapeutic doses of LMWH followed by 75% thereafter. No patients had an IVC filter inserted or a major bleeding episode. One patient had a minor bleeding episode (4.5%; 95% CI: 1.1–21.9%), 2 patients died (9.1%; 95% CI: 2.8–28.0) (no VTE-related death) and one patient (4.5%; 95% CI: 1.1–21.9%) had a second treatment failure event during the three-month follow-up period while on full therapeutic doses of LMWH.Eight patients (26.7%) were on vitamin-K antagonist at the time of the recurrent VTE due to treatment failure. Five (62.5) patients had a therapeutic INR on the day of the recurrent VTE. All patients were treated with LMWH at full doses for a month followed by 75% thereafter. One patient (12.5%; 95%CI 2.8–48.3) had a minor bleeding episode during follow-up.Conclusion: Escalading the dose of LMWH following a recurrent VTE due to treatment failure seems to be a safe and effective method to prevent further recurrence in cancer patients. Our data challenges the concept of using IVC filters in this setting.

Low-molecular-weight heparin in patients with chronic renal insufficiency

Low-molecular-weight heparin (LMWH) has largely replaced unfractionated heparin for the treatment of venous thromboembolism. The predictable anticoagulant effect of LMWH is seen across almost all patient populations, with few exceptions. However, because LMWH is primarily eliminated through the kidneys, patients with renal insufficiency are at risk of LMWH accumulation and bleeding complications. The risk of LMWH accumulation and bleeding is dependent on several factors including the degree of renal insufficiency, dose and type of LMWH. These risks are greatest when therapeutic doses of LMWH are used in patients with creatinine clearance less than 30 ml/min. Prophylactic dose LMWH does not appear to be associated with an increased bleeding risk, but has not been evaluated in large trials. LMWHs with a higher molecular weight may be less prone to accumulation and bleeding. LMWH must be used carefully in patients with renal insufficiency, particularly in those with severe renal impairment.

Heparin-induced thrombocytopenia: A stoichiometry-based model to explain the differing immunogenicities of unfractionated heparin, low-molecular-weight heparin, and fondaparinux in different clinical settings

IntroductionHeparin-induced thrombocytopenia (HIT) is caused by platelet-activating antibodies that recognize platelet factor 4 (PF4)/heparin complexes. The frequency of HIT is highly variable in different clinical settings, and is more frequent with unfractionated heparin (UFH) than with low-molecular-weight heparin (LMWH), despite the in vitro observation that HIT antibodies activate platelets similarly well with LMWH as with UFH. An important difference between UFH, LMWH, and fondaparinux is their widely differing plasma concentrations. We aimed to provide a model that included anticoagulant concentrations and PF4 availability as risk factors influencing the anti-PF4/heparin immune response. Materials and methodsBy photon correlation spectroscopy we determined the concentrations at which UFH, LMWH, and fondaparinux form complexes optimally with PF4. Plasma concentrations of UFH and LMWH were calculated based on ex vivo pharmacokinetic data, with information on fondaparinux and PF4 concentrations taken from the literature. Results and conclusionsThe main features of our model are: optimal complex formation occurs at prophylactic-dose UFH and high PF4 levels, whereas therapeutic-dose LMWH concentrations are too high for optimal complex formation; in contrast, concentrations of fondaparinux are usually below the optimal stoichiometric range. Thus, immunization should occur more often in situations with major rather than minor platelet activation, and—for a given degree of platelet activation (PF4 availability)—as: prophylactic-dose UFH>therapeutic-dose UFH>prophylactic-dose LMWH, fondaparinux>therapeutic-dose LMWH. Our model provides a framework for explaining empirical observations that LMWH induces less anti-PF4/heparin antibodies than does UFH, and that anti-PF4/heparin antibodies are more often found in patients undergoing major surgery than in medical patients.

Low-molecular-weight heparin in pregnancy: peripartum bleeding complications

To compare bleeding complications in pregnant patients treated with low-molecular-weight heparin (LMWH) to untreated controls. A case-control study of patients from 2001 to 2005 who received prophylactic or therapeutic doses of LMWH during pregnancy was carried out. Indications for LMWH included current or prior thromboembolism, thrombophilia, or heart valve replacement. Controls were chosen in a 2:1 ratio to cases, matched for delivery route, and selected as the next two consecutive deliveries. The primary outcome was postpartum hemorrhage (PPH). Odds ratios (ORs) were calculated with 95% confidence intervals (CIs). Forty-nine women treated with LMWH delivered 55 infants. Current or prior thromboembolic disease was the anticoagulation indication in 15/55 (27.3%) and 26/55 (47%) of pregnancies, respectively. There were more obese gravidas (OR 3.91, CI 1.70 to 9.09) and labor induction was more common in the LMWH group, 25/55 (45%) vs 29/110 (26%), P=0.01. There was no difference in estimated blood loss (295.7+/-145.7 vs 308.6+/-111.9 cm(3), P=0.62 vaginal; 687.5+/-251.8 vs 765.0+/-313.2 cm(3), P=0.34 cesarean), PPH (6/55, 11% vs 9/110, 8.2% OR 1.37, CI 0.16 to 11.5) or transfusion (3/55, 5.4% vs 4/110, 3.6% OR 1.50, CI 0.3 to 7.48) between the cases and controls. There were two cases of postpartum pulmonary emboli, one with a maternal mortality. Bleeding complications, including PPH and transfusion, in patients treated with LMWH during pregnancy were not increased when compared to normal controls matched for delivery route.