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Inhibition of trypsin by heparin and dalteparin, a low molecular weight heparin  [PDF]
OLIVERA M. BOSNI？,KRISTINA R. GOP？EVI？,MIROSLAV M. VRVI？,IVANKA M. KARAD？I？
Journal of the Serbian Chemical Society , 2009,
Abstract: The interaction between trypsin, a prototype S1 serine protease, with heparin and its low molecular weight derivative dalteparin were investigated. Direct inhibition of the proteolytic activity of trypsin by heparin and dalteparin, used in concentrations typical for their clinical application, was detected. The half-maximum inhibition of the trypsin activity was achieved at 15.25±1.22 mg/mL for heparin and was estimated to be at 58.47±15.20 mg/mL for dalteparin. Kinetic analyses showed that heparin and its low molecular weight derivative dalteparin inhibited trypsin by occupation of an exosite, producing noncompetitive and mixed inhibition, respectively. Heparin as a noncompetitive inhibitor with constant of inhibition Ki1,2 = 0.151±0.019 mM and dalteparin with Ki1 = 0.202±0.030 mM and Ki2 = 0.463±0.069 mM in mixed inhibition both represent moderate inhibitors of serine protease trypsin. The obtained constants of inhibition indicate that under the clinically applied concentrations of heparin and dalteparin, trypsins and their homolog S1 serine proteases could be directly inhibited, influencing the delicate control of proteolytic reactions in homeostasis.
Recurrent Implantation Failure and Low Molecular Weight Heparin  [PDF]
Dalia Khalife, Ghina Ghazeeri
Open Journal of Obstetrics and Gynecology (OJOG) , 2018, DOI: 10.4236/ojog.2018.82018
Abstract: Implantation of the embryo into the endometrium is the first step in the establishment of pregnancy. This process is complex, and depends on many factors. Recurrent implantation failure is a source of distress to patients and specialists. It is defined as failure to achieve a viable pregnancy, following “>3 embryo transfers with high quality embryos or the transfer of ≥ 10 embryos in multiple transfers”. Thrombophilic conditions that contribute to recurrent implantation failure are the main concern in this review. The mechanism of implantation failure is believed to be due to decreased blood flow to the endometrium and placenta which can hinder normal endometrial receptivity leading to miscarriage. Defects in early placentation resulting in pregnancy failure, have focused attention on the therapeutic potential of low molecular weight heparin in the implantation process. Heparin has a role at all stages of implantation to improve pregnancy outcomes. There are controversies in literature regarding the association between thrombophilia and recurrent implantation failure and available literature regarding this issue is very heterogeneous. Various investigators, have shown that women with RIF are more likely to have a thrombophilia disorder, yet a clear cause cannot be acknowledged from these studies. Heparin treatment has been evaluated in several studies, showing conflicting evidence. However, several studies have pointed out that it may play a role in a subset of patients who presents a thrombophilia mutation, thus the group of patients that might benefit is needed to be identified. This review is dedicated to evaluate the published literature about the role of low molecular weight heparin in case of recurrent implantation failure with or without the presence of thrombophilia.
Intravitreal low molecular weight heparin in PVR surgery.
Kumar Atul,Nainiwal Sanjeev,Sreenivas B
Indian Journal of Ophthalmology , 2003,
Abstract: Purpose: To evaluate the efficacy of low molecular weight heparin (LMWH) in prevention of postoperative fibrin formation following vitreoretinal surgery with proliferative vitreoretinopathy (PVR). Material and Methods: Thirty consecutive patients of retinal detachment with advanced PVR were enrolled in the study. They were randomised to study and control groups (n = 15 each). Study group patients received vitreoretinal surgery with 5 IU/cc of LMWH in vitrectomy infusion fluid. The control group patients received vitroretinal surgery without heparin in the infusion fluid. Patients were followed up at 1 week, 1 month and 3 months after surgery. Postoperative bleeding, media clarity, best-corrected visual acuity and success of the surgery at the end of 3 months were compared between the two groups. Results: At each follow-up visit, the study group showed a better media clarity, which was statistically significant ( P = 0.0042). The study group had a 50% better chance of retinal reattachment compared to the control group. Five patients had intraoperative bleeding in the study group (33%) compared to 3 patients in the control group (20%). Conclusion: Use of intravitreal LMWH prevents postoperative fibrin formation and is beneficial in repair of retinal detachments with PVR.
Cerebral venous thrombosis: An experience with anticoagulation with low molecular weight heparin  [cached]
Pillai Lalitha,Ambike Dhananjay,Nirhale Satish,Husainy S
Indian Journal of Critical Care Medicine , 2005,
Abstract: Cerebral venous sinus thrombosis [CVST] is often an infrequent cause of neurological dysfunction resulting in admissions in Intensive care units [ICU]. Because of its myriad presentation it may be under diagnosed. Unfractionated Heparin [UFH] has been advocated in treatment but needs frequent monitoring. We studied the clinical profile of patients of cerebral venous sinus thrombosis, use of low molecular weight heparin [LMWH] with emphasis on safety in 64 patients of CVST.
Rates of clinically apparent heparin-induced thrombocytopenia for unfractionated heparin vs. low molecular weight heparin in non-surgical patients are low and similar
Charles FS Locke, John Dooley, Jonathan Gerber
Thrombosis Journal , 2005, DOI: 10.1186/1477-9560-3-4
Abstract: Heparin-induced thrombocytopenia (HIT) is recognized as a rare, but potentially devastating complication of heparin therapy because of its association with arterial and venous thrombosis [1]. HIT is mediated by antibodies which recognize an antigen formed by the binding of platelet factor 4 to heparin [2]. The now widespread use of low-molecular-weight heparins for a variety of indications previously reserved exclusively for unfractionated heparin has generated interest in comparing the relative rates of HIT between the two classes of heparin.In 1995 Warkentin examined rates of HIT in patients undergoing elective hip arthroplasty who had been randomized to receive either unfractionated heparin (UFH) or low molecular weight heparin (LMWH) for thromboprophylaxis [3]. Warkentin reported that HIT occurred in 9 of 332 patients who received UFH and in none of 333 patients who received LMWH (2.7 percent vs. 0 percent). In addition, development of heparin-dependent IgG antibodies and thrombotic events associated with thrombocytopenia were more common in patients treated with UFH than in those treated with LMWH.Recently, using different criteria for HIT (an absolute drop in platelet count of 50% or greater vs. platelet count less than 150,000 cells /ml), Warkentin reanalyzed these same data and found the difference in the observed rate of HIT was even more pronounced, 8 times greater (4.8% vs. 0.6%) in UFH compared to LMWH for prophylaxis of venous thromboembolism (VTE) in patients undergoing elective hip arthroplasty [4].Warkentin's results are supported by a recent study by Walenga et al which carefully evaluated sera from three clinical studies [5]. Walenga found that LMWH was less likely to generate H-PF4 antibodies than UFH and less likely to result in clinical HIT. Walenga also noted that LMWH were more likely to generate IgA and IgM antibodies rather than IgG antibodies, which are associated with clinical HIT. However, the sera reviewed by Walenga all were from orthop
Low Molecular Weight Heparin Induced Skin Necrosis without Platelet Fall Revealing Immunoallergic Heparin Induced Thrombocytopenia  [PDF]
Thomas Godet,Sébastien Perbet,Aurélien Lebreton,Guillaume Gayraud,Sophie Cayot,Aymeric Tremblay,Aurélie Ravinet,Sébastien Christophe,Renaud Guérin,Julien Pascal,Matthieu Jabaudon,Amr Hassan,Anne-Fran？oise Sapin,Jean-Etienne Bazin,Jean-Michel Constantin
Case Reports in Hematology , 2013, DOI: 10.1155/2013/849168
Abstract: Low molecular weight heparins (LMWH) are commonly used in the ICU setting for thromboprophylaxis as well as curative decoagulation as required during renal replacement therapy (RRT). A rare adverse event revealing immunoallergic LMWH induced thrombopenia (HIT) is skin necrosis at injection sites. We report the case of a patient presenting with skin necrosis witnessing an HIT after RRT, without thrombocytopenia. The mechanism remains unclear. Anti-PF4/heparin antibodies, functional tests (HIPA and/or SRA), and skin biopsy are of great help to evaluate differential diagnosis with a low pretest probability 4T’s score. 1. Introduction Renal failure is a frequent condition observed among ICU patients. Renal replacement therapy (RRT) is often required to treat this affection. Curative anticoagulation with heparin derivatives is mandatory to prevent filter clotting especially during proaggregant conditions such as sepsis. We wish to report a rare complication of heparin treatment with enoxaparin with a low pretest probability 4T’s score [1], due to an immunoallergic heparin induced thrombopenia (HIT): skin necrosis at injection site. 2. Case Report A 57-year-old woman with a history of severe melancholic state was hospitalized in psychiatric ward for 4 months before admission to our hospital. She presented in the emergency department with arterial hypotension and hypothermia due to severe dehydration because of severe feeding troubles with self-induced vomiting, anorexia, and loss of weight. The patient had no history of previous exposition to heparin derivatives. Platelet count was 490？G/L. Biological investigations found severe acute kidney injury (creatinine 720？μmol/L and urea 37？mmol/L), metabolic acidosis (pH 7.10, HCO3–14？mmol/L), and mild hyperkaliemia of 5.4？mmol/L. Abdominal scanning found no renal or digestive abnormality. First line treatment consisted of important fluid loading with crystalloids (5000？mL ringer lactate, 500？mL sodium bicarbonate 1,4%, and 500？mL sodium bicarbonate 4,2%) and parallel norepinephrine infusion to obtain satisfying hemodynamics. The patient was then transferred to our ICU. The hospitalization course was marked with an acute respiratory distress syndrome due to acute aspiration, cardiac failure with infusion of inotropic agent, and persistent anuric renal failure with the need of RRT (continuous venovenous hemofiltration (CVVHF), using the Aquarius System, Edwards Lifesciences, France, blood flow 200–250？mL/min, and ultrafiltrate flow 35？mL/kg/h, priming with 5000？UI unfractionated heparin (UFH) in 2000？mL saline
Prophylaxis of deep-vein thrombosis after lower extremity amputation: Comparison of low molecular weight heparin with unfractionated heparin
Lastória, Sidney;Rollo, Hamilton A.;Yoshida, Winston Bonetti;Giannini, Mariangela;Moura, Regina;Maffei, Francisco H. A.;
Acta Cirurgica Brasileira , 2006, DOI: 10.1590/S0102-86502006000300011
Abstract: purpose: to compare the efficacy and safety of a low molecular weight heparin (enoxaparin) with unfractionated heparin (uh) in this prophylaxis. methods: seventy five patients (59 men and 16 women), undergoing major lower extremity amputation (30 above-knee and 45 below-knee), were randomized to be treated with subcutaneous uh (5,000 iu t.i.d.) or enoxaparin (40mg/day) during hospitalization. prophylaxis was started 12 hours before surgery or, in emergency cases, in the first postoperative day. results: the two groups were comparable with regard to baseline characteristics. evaluation of dvt was performed by daily clinical examination and by duplex scanning before and 5 to 8 days after surgery. dvt was documented in the operated limb in 9.75% in patients treated with enoxaparin and in 11.76% in patients treated with uh (p=0.92) and there was one bilateral thrombosis in each group . bleeding complications were not observed in both groups. conclusion: enoxaparin and uh were both efficient and safe for the prophylaxis of dvt in patients submitted to lower extremity amputation.
Prophylaxis of deep-vein thrombosis after lower extremity amputation: Comparison of low molecular weight heparin with unfractionated heparin  [cached]
Lastória Sidney,Rollo Hamilton A.,Yoshida Winston Bonetti,Giannini Mariangela
Acta Cirurgica Brasileira , 2006,
Abstract: PURPOSE: To compare the efficacy and safety of a low molecular weight heparin (enoxaparin) with unfractionated heparin (UH) in this prophylaxis. METHODS: Seventy five patients (59 men and 16 women), undergoing major lower extremity amputation (30 above-knee and 45 below-knee), were randomized to be treated with subcutaneous UH (5,000 IU t.i.d.) or enoxaparin (40mg/day) during hospitalization. Prophylaxis was started 12 hours before surgery or, in emergency cases, in the first postoperative day. RESULTS: The two groups were comparable with regard to baseline characteristics. Evaluation of DVT was performed by daily clinical examination and by duplex scanning before and 5 to 8 days after surgery. DVT was documented in the operated limb in 9.75% in patients treated with enoxaparin and in 11.76% in patients treated with UH (p=0.92) and there was one bilateral thrombosis in each group . Bleeding complications were not observed in both groups. CONCLUSION: Enoxaparin and UH were both efficient and safe for the prophylaxis of DVT in patients submitted to lower extremity amputation.
Low Molecular Weight Heparin-Induced Skin Necrosis: A Case Report
Anastasios Katsourakis,George Noussios,George Kapoutsis,Efthimios Chatzitheoklitos
Case Reports in Medicine , 2011, DOI: 10.1155/2011/857391
Abstract: Low molecular weight heparins (LMWHs) are the standard agents used for antithrombotic therapy and prophylaxis. Despite their widespread use, reports about adverse effects from LMWHs are very scarce. Heparin-induced skin necrosis at the injection site is a rare adverse effect, more commonly associated with unfractionated heparin (UFH) rather than with LMWH, while its mechanism remains unclear. This paper deals with the enoxaparin induced skin necrosis.
Low-Molecular Weight Heparin Increases Circulating sFlt-1 Levels and Enhances Urinary Elimination  [PDF]
Henning Hagmann, Verena Bossung, Abdel Ali Belaidi, Alexander Fridman, S. Ananth Karumanchi, Ravi Thadhani, Bernhard Schermer, Peter Mallmann, Guenter Schwarz, Thomas Benzing, Paul T. Brinkkoetter
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0085258
Abstract: Rationale Preeclampsia is a devastating medical complication of pregnancy which leads to maternal and fetal morbidity and mortality. While the etiology of preeclampsia is unclear, human and animal studies suggest that excessive circulating levels of soluble fms-like tyrosine-kinase-1 (sFlt-1), an alternatively spliced variant of VEGF-receptor1, contribute to the signs and symptoms of preeclampsia. Since sFlt-1 binds to heparin and heparan sulfate proteoglycans, we hypothesized that the anticoagulant heparin, which is often used in pregnancy, may interfere with the levels, distribution and elimination of sFlt-1 in vivo. Objective We systematically determined serum and urine levels of angiogenic factors in preeclamptic women before and after administration of low molecular weight heparin and further characterized the interaction with heparin in biochemical studies. Methods and Results Serum and urine samples were used to measure sFlt-1 levels before and after heparin administration. Serum levels of sFlt-1 increased by 25% after heparin administration in pregnant women. The magnitude of the increase in circulating sFlt-1 correlated with initial sFlt-1 serum levels. Urinary sFlt-1 levels were also elevated following heparin administration and levels of elimination were dependent on the underlying integrity of the glomerular filtration barrier. Biochemical binding studies employing cation exchange chromatography revealed that heparin bound sFlt-1 had decreased affinity to negatively charged surfaces when compared to sFlt-1 alone. Conclusion Low molecular weight heparin administration increased circulating sFlt1 levels and enhanced renal elimination. We provide evidence that both effects may be due to heparin binding to sFlt1 and masking the positive charges on sFlt1 protein.
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