OBJECTIVE

To estimate the impact of adding low-molecular-weight heparin (LMWH) or unfractionated heparin to low-dose aspirin started ≤ 16 weeks' gestation on the prevalence of pre-eclampsia (PE) and the delivery of a small-for-gestational-age (SGA) neonate.

METHODS

A systematic review and meta-analysis of randomized controlled trials (RCTs) was performed by searching the medical databases PubMed, EMBASE, Web of Science and Cochrane Central. Pregnant women randomized to receive LMWH or unfractionated heparin in addition to low-dose aspirin were compared with those who received low-dose aspirin alone. Outcome measures were PE, severe PE, early-onset PE and SGA. Pooled relative risks (RRs) with 95% CI were calculated using a random-effects model.

RESULTS

Eight RCTs met the inclusion criteria; the indication for recruitment was previous recurrent miscarriage in five studies (three included women with thrombophilia) and a history of severe or early-onset PE in three studies (including women with thrombophilia in one). LMWH was administered in seven studies and unfractionated heparin in one. In women with a history of PE, treatment with LMWH and aspirin, compared with aspirin alone, was associated with a significant reduction in development of PE (three trials (n = 379); RR, 0.54 (95% CI, 0.31-0.92); P = 0.03) and in delivery of SGA neonates (two trials (n = 363); RR, 0.54 (95% CI, 0.32-0.91); P = 0.02). These outcomes were not significantly reduced in women with recurrent miscarriage who received LMWH and aspirin, compared with aspirin alone. The small number of studies precluded sensitivity analyses and the evaluation of publication biases. Blinding to the allocation treatment was absent in all RCTs.

CONCLUSIONS

Based on limited evidence, the addition of LMWH to low-dose aspirin could reduce the prevalence of PE and SGA in women with a history of PE. This observation should be the basis of a well-conducted future trial rather than a recommendation for immediate clinical application. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

The determination of molecular weight (M) and molecular weight distribution (MD) of heparins by a novel approach, consisting of a high performance size exclusion chromatography (HP-SEC) combined with a triple detector array (TDA) is described. HP-SEC/TDA permits the evaluation of MD of polymeric samples through a combined and simultaneous action of three on-line detectors, right-angle laser light scattering (RALLS), refractometer (RI), and viscometer. The method does not require any chromatographic column calibration, thus overcoming also the difficulty to obtain adequate reference standards. It permits the size determination also of small molecules, even when scattering dissimmetry is not observable. Unfractionated heparins, eight fractions of a size fractionated heparin, and dermatan sulfates were analyzed by HP-SEC/TDA. The M values found for the heparin fractions were used to build up a calibration curve of a conventional HP-SEC system: the results obtained analyzing unfractionated heparin samples with both HP-SEC/TDA and HP-SEC were in excellent agreement, suggesting the possibility to use the TDA data to generate standard samples with known MD and intrinsic viscosity [eta]. Moreover, HP-SEC/TDA can successfully be employed also for the determination of the Mark-Houwink a and k parameters.

Heparin is an anticoagulant agent known to have diverse effects on angiogenesis with some reports suggesting that it can induce angiogenesis while a few have indicated of its inhibitory property. Cancer patients treated for venous thromboembolism with low molecular heparin had a better survival than the unfractionated heparin (UFH). Heparin is known to interact with various angiogenic growth factors based on its sulfation modifications within the glycosaminoglycan chains. Therefore it is important to study the mechanism of action of heparin of different molecular weight to understand its angiogenic property. In this concern, we examined the angiogenic response of higher molecular weight Heparin (15 kDa) of different concentrations using late CAM assay. Growth of blood vessels in terms of their length and size was measured and thickness of the CAM was calculated morphometrically. The observed increase in the thickness of the CAM is suggestive of the formation of capillary like structures at the treated region. Analysis of the diffusion pattern showed internalized action of heparin that could affect gene expression leading to proliferation of endothelial cells. Angiogenesis refers to formation of new blood vessels from the existing ones and occurrence of new blood vessels at the treated area strongly confirms that heparin of 15 kDa molecular weight has the ability to induce angiogenesis on CAM vascular bed in a dose dependent manner. The results demonstrate the affinity of heparin to induce angiogenesis and provide a novel mechanism by which heparin could be used in therapeutics such as in wound healing process.

Heparin-induced thrombocytopenia (HIT) is a common adverse effect of unfractionated heparin (UFH) therapy. In contrast, only a few patients have been reported with HIT following low-molecular-weight heparin (LMWH) therapy (LMW-HIT). To define the clinical and biological characteristics of LMW-HIT, 180 patients treated for suspected HIT at 15 French centres were investigated. Clinical history was recorded and HIT was confirmed in 59 patients with positive serotonin release assay results: 57 of them had high levels of antibodies (Abs) to heparin-platelet factor 4 complexes (H/PF4) and two had Abs to interleukin 8. Eleven patients were treated exclusively with LMWH (LMW-HIT) and 48 with UFH either alone (UF-HIT, n = 34) or combined with LMWH (UF/LMW-HIT, n = 14). The LMW-HIT and UF-HIT groups were similar with respect to sex, age, platelet count before heparin therapy, frequency of bleeding and occurrence of disseminated intravascular coagulation. The interval to onset of HIT was longer in LMW-HIT patients compared with UF-HIT patients (P = 0.03). Severe thrombocytopenia (platelets < 15 x 10(9)/l) was more frequent in the LMW-HIT group (P = 0.04). Thrombosis occurred in three of 11 LMW-HIT patients, i.e. as frequently as in UF-HIT patients. LMW-HIT is potentially severe and may be observed after longer heparin treatment compared with UF-HIT. It is highly recommended, therefore, that platelet counts be monitored carefully whenever LMWH is administered.

BACKGROUND

Nonspecific binding to plasma proteins decreases the anti-factor Xa (anti-Xa) activity of unfractionated heparin (UFH) but not that of low-molecular-weight heparin (LMWH). However, plasma proteins could influence the anti-thrombin (anti-IIa) activity of LMWH. To explore this possibility, we compared the effects of plasma proteins on the anti-IIa activities of UFH and LMWH. We also examined their effects on the anti-IIa activity of dermatan sulfate (DS) because, like UFH, DS binds to plasma proteins.

RESULTS

There was almost complete recovery of anti-IIa activity when UFH, LMWH, or DS was added to plasma from each of 20 healthy volunteers. The addition of a chemically modified heparin with low affinity for antithrombin III to plasma containing UFH increased the anti-IIa activity in a concentration-dependent fashion by displacing UFH from plasma proteins. In contrast, addition of low-affinity heparin had no effect on the anti-IIa activity of LMWH. LMWH does not bind to plasma proteins because the bulk of the LMWH chains are < 6000 D, and only heparin fractions>> 6000 D bind nonspecifically to plasma proteins. As further evidence that plasma proteins do not influence the anti-IIa activity of LMWH, the rate of thrombin inhibition in plasma in the presence of LMWH is virtually identical to that in buffer containing physiological amounts of the major antithrombins. In contrast, with UFH or DS, the rate of thrombin inhibition is twofold slower in plasma than in buffer.

CONCLUSIONS

Nonspecific binding of UFH to plasma proteins most likely contributes to the variable anti-IIa response to UFH in patients with thromboembolic disease. Although DS also binds to plasma proteins, the clinical significance of this finding is unclear. In contrast, because LMWH does not bind to plasma proteins, the anti-IIa activity of LMWH should be just as predictable as its anti-Xa activity.

BACKGROUND

Little information is available about the prevalence of deep vein thrombosis (DVT) after discharge from cardiac surgery units and its impact on rehabilitation programs.

OBJECTIVE

To estimate the rate of DVT, in relation to different thromboprophylaxis strategies, in patients with a recent coronary artery bypass graft (CABG) entering cardiac rehabilitation.

METHODS

Two hundred seventy consecutive patients admitted to three rehabilitation facilities after CABG surgery from 19 cardiac surgery units (male patients, 81%; mean +/- SD age, 64 +/- 9 years; interval after operation, 4 to 19 days) underwent serial leg venous ultrasound examination on admission to three rehabilitative units.

RESULTS

At admission, antiplatelet treatment was present in all patients except 10 with absolute contraindications. In 171 patients (63%), heparin prophylaxis (low-molecular-weight heparin once daily, 87%; unfractionated heparin twice daily, 13%) was reported, limited to the early postoperative period (< or = 3 days) in 102 patients (38%). DVT was detected in 47 patients (17.4%). The rate of proximal and isolated distal DVT was 2.6% (7 cases) and 14.8% (40 cases), respectively. DVT was complicated in two cases (0.7%) by symptomatic pulmonary embolism, fatal in one case (0.4%). Clots were found in the leg contralateral to the saphenous vein harvest site in half of all DVT cases. Forty-three DVT cases (91%) were diagnosed at admission, while serial ultrasound testing allowed diagnosis of an additional 4 distal DVT cases. At multivariate analysis, female sex (p < 0.001) and length of stay in the surgery unit>> 8 days (p < 0.05) were independently associated with risk of DVT in the rehabilitation setting. The adoption of heparin prophylaxis until discharge predicted the absence of DVT after adjustment for immobility (p < 0.05).

CONCLUSIONS

This study showed a high rate of DVT in patients entering cardiac rehabilitation after CABG surgery. Wearing unilateral graded compression stockings after CABG surgery had limited efficacy, as clots were often localized in legs contralateral to the saphenous vein harvest site.

There is some evidence that Covid 19 pneumonia is associated with prothrombotic status and increased risk of venous thromboembolic events (deep venous thrombosis and pulmonary embolism). Over a two-week period we admitted in our Unit 25 patients with Covid-19 pneumonia, of these pulmonary embolism was diagnosed using computed tomography angiography in 7. We report on clinical and biochemical features of these patients. They were all males, with a mean age of 70.3 years (range 58-84); traditional risk factors for venous thromboembolism were identified in the majority of patients with pulmonary embolism, however not differently from those without pulmonary embolism. Clinical presentation of pulmonary embolism patients was usually characterized by persistence or worsening of respiratory symptoms, with increasing oxygen requirement. D-dimer levels were several fold higher than the upper threshold of normal; in patients in whom PE was recognized during hospital stay, a rapid and relevant increase of D-dimer levels was observed. Computed tomographic findings ranged from massive acute pulmonary embolism to a segmental or sub-segmental pattern; furthermore, thrombosis of sub-segmental pulmonary arteries within lung infiltrates were occasionally seen, suggesting local mechanisms. Six out of 7 patients were treated with unfractionated or low molecular weight heparin with clinical benefit within few days; one patient needed systemic thrombolysis (death from hemorrhagic complication).

Platelet adhesion to purified surface-immobilized fibronectin under flow conditions was investigated. Fibronectin was found to support attachment and spreading of platelets. The extent of platelet spreading depended on the amount of immobilized fibronectin. An antiglycoprotein (anti-GP) IIb/IIIa antibody and an Arg-Gly-Asp (RGD)-containing peptide inhibited adhesion almost completely, whereas antibodies directed against platelet GP Ic/IIa (very late antigen 5) inhibited by 50%. Similar results with the antibodies and the peptide were found in a static system. A comparison of different anticoagulants showed no difference in adhesion using citrate or hirudin. However, unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) as the only anticoagulant or in combination with citrate maximally inhibited adhesion by 80% and 60%, respectively. Preincubation of the immobilized fibronectin with UFH resulted in a maximal inhibition of 90%, whereas preincubation with LMWH had no effect. When we preincubated the surface with heparins of different size, we observed 40% inhibition of adhesion with heparins with an average MW of up to 18 kD, whereas a heparin with an average MW of 21 kD almost completely blocked adhesion. These results indicate that platelet adhesion to fibronectin in flow involves several receptors, is highly RGD-mediated, does not require physiologic levels of divalent cations, and can be inhibited by direct binding of heparin to the fibronectin surface.

OBJECTIVE

Heparin might possess anti-thrombotic properties other than anticoagulation. The aim of the present study was to test the effects of a low-molecular weight heparin, parnaparin, on adhesive molecule-mediated platelet-polymorphonuclear (PMN) leukocyte interactions and on PMN function.

METHODS

Platelets and PMN were isolated from citrated blood from healthy subjects. Pre-activated platelets incubated with PMN under dynamic conditions formed mixed cell aggregates. In previous experiments PMN were stimulated in vitro by purified P-selectin or formyl-methionyl-leucyl-phenylalanine (fMLP). Dual color flow cytometry was used to detect the formation of platelet-PMN mixed cell aggregates, and PMN activation was tested for by measuring L-selectin shedding, tissue factor expression and PMN degranulation. The effect of parnaparin was compared to that of unfractionated heparin.

RESULTS

Parnaparin, at a concentration of 0.3-0.8 IUaXa/mL, inhibited the formation of mixed cell aggregates (48.8+/-9.7% of total PMN population) by up to 60% in a concentration-dependent manner, while heparin inhibited aggregation up to 40%. Parnaparin, (0.3-0.8 IUaXa/mL), prevented L-selectin shedding from PMN, which was induced by purified P-selectin (5 mg/mL) or fMLP (0.5 mmol/L) by 65% and 67%, respectively. Inhibition was independent of incubation time (5-20 min). Parnaparin (0.8 IUaXa/mL) also inhibited tissue factor expression on PMN (% of positive cells), which was induced by P-selectin or fMLP (185+/-10 and 241+/-80% of basal value, respectively). Parnaparin protected PMN from degranulation after challenge with either stimulus (>95% inhibition). All the effects of parnaparin were observed with heparin at similar concentrations, although to a lesser extent and were often not significantly different from events in controls.

CONCLUSIONS

In conclusion, the process of depolymerization of heparin to obtain low molecular weight parnaparin resulted in an increased, anticoagulant-independent effect on PMN function. Thus, the overall anti-thrombotic properties of parnaparin may be partly due to a leukocyte-mediated anti-inflammatory effect.

BACKGROUND

Low-molecular-weight heparins (LMWHs), derived from unfractionated heparin (UFH) by different depolymerization procedures, vary in both their relative abilities to enhance the inhibition of FXa (anti-FXa) and thrombin (anti-FIIa), and in their physicochemical properties.

OBJECTIVE

We aimed to profile the inhibition of thrombin generation induced by bemiparin, enoxaparin, nadroparin, dalteparin and tinzaparin in platelet-rich plasma (PRP), and to compare them with UFH and fondaparinux (a synthetic pentasaccharide that specifically enhances FXa inhibition).

METHODS

Different LMWHs, UFH or fondaparinux were added to normal PRP. Thereafter, tissue factor-triggered thrombin generation was assessed using the Thrombogram-Thrombinoscope assay.

RESULTS

At equivalent anti-FIIa activity concentrations, LMWHs and UFH exhibited similar inhibitory effects upon thrombin generation. However, when used at equivalent anti-FXa activity concentrations, tinzaparin was significantly more active than the other LMWHs at inhibiting thrombin generation, and had similar activity to that of UFH. Enoxaparin, nadroparin and dalteparin all showed similar inhibitory activities. In these experiments, bemiparin exhibited the lowest inhibitory effect on thrombin generation of all the LMWHs. At 0.1 microg mL(-1) (0.093 anti-FXa IU mL(-1)), fondaparinux inhibited the rate of thrombin generation by 50%. A 7-fold higher concentration of fondaparinux was required to inhibit the endogenous thrombin potential by 50%.

CONCLUSIONS

LMWHs have a variable inhibitory effect on thrombin generation in vitro when compared by anti-FXa activity, but are similar when compared by their anti-FIIa activities. The rate of thrombin generation during the propagation phase, rather than the endogenous thrombin potential, is more sensitive to the anticoagulant activity of fondaparinux and the polysaccharide chains of LMWHs possessing only anti-FXa activity.

A recent clinical sepsis trial reported a significant reduction in 90-day mortality by antithrombin (AT) exclusively in the subgroup of patients without simultaneous heparin prophylaxis. Patients additionally receiving heparin did not benefit from AT treatment. Herein, we studied the microhemodynamic and cellular mechanisms of this adverse effect of heparin on AT actions by the use of intravital microscopy and granulocyte culturing. In Syrian golden hamsters normotensive endotoxemia was induced by 2 mg/kg endotoxin (LPS, E. coli) i.v. In a first group of animals, AT (AT, 250 IU/kg i.v., n = 6) was given 5 min before LPS administration. A second group of animals (Heparin + AT, n = 5) received AT (250 IU/kg i.v.) combined with unfractionated heparin (sodium heparin, 100 IU/kg/24 h, i.v.). Additional animals (LMWH + AT, n = 5) received AT (250 IU/kg i.v.) combined with LMWH (nadroparin 47.5 IU anti-Xa/kg, s.c., 2 h before LPS). LPS-treated animals, which received only saline, served as controls (control, n = 6). Using dorsal skinfold fold preparations, LPS-induced microvascular leukocyte-endothelial cell interaction (LE) and alteration of functional capillary density (FCD) were studied by intravital video fluorescence microscopy. In controls, LPS induced a massive increase in LE with a maximum at 8 h and an impressive decrease in FCD over a 24-hour period. Both LPS effects were effectively prevented by AT treatment (p < 0.01), whereas Heparin + AT and LMWH + AT animals showed microcirculatory alterations comparable to that in controls. In additional in vitro chemotaxis assays. AT blocked neutrophil chemotaxis, an effect reversed by both unfractionated heparin and LMWH. Thus, our study elucidates a relevant in vivo and in vitro unfractionated heparin and LMWH adverse effect in the microcirculatory actions of AT during endotoxemia. These results indicate that heparin should be avoided to permit AT to modulate LPS-induced inflammatory responses.

BACKGROUND

Low molecular weight heparins (LMWH) are increasingly used during haemodialysis (HD) to prevent clotting in the extracorporeal devices. It has been suggested that LMWH release endothelial-bound lipoprotein lipase (LPL) less efficiently than unfractionated heparin (UFH) does and thereby cause less disturbance of lipid metabolism. Evidence from in vitro studies and from animal experiments indicate, however, that both types of heparin preparations have the same ability to release endothelial LPL, but LMWH are less effective in preventing uptake and degradation of LPL in the liver. Model studies in humans indicate that LMWH cause as much depletion of LPL stores and impaired lipolysis of triglyceride (TG)-rich lipoproteins as UFH does.

METHODS

Two anticoagulant regimes based on present clinical practice were compared in nine HD patients. UFH was administered as a primed infusion, whereas the LMWH (dalteparin) was given only as a single bolus pre-dialysis. Blood was sampled regularly for LPL activity and TG.

RESULTS

LPL activity in blood was significantly lower during the dialysis with dalteparin. To explore the remaining activity at the endothelium, a bolus of UFH was given after 3 h of dialysis. The bolus brought out about the same amount of LPL, regardless of whether UFH or dalteparin had been used during dialysis. The increase in TG was significantly higher during dialysis with dalteparin.

CONCLUSIONS

This study indicates that a single bolus of dalteparin pre-dialysis interferes with the LPL system as much as, or more than an infusion of UFH does.

Patients undergoing major orthopedic surgery--hip or knee arthroplasty, or hip fracture repair--are in the highest risk category for venous thromboembolism (VTE) solely on the basis of the orthopedic procedure itself. Despite this, nearly half of patients undergoing these procedures do not receive appropriate prophylaxis against VTE, often due to a disproportionate fear of bleeding complications in this population. Guidelines from the American College of Chest Physicians (ACCP) provide evidence-based recommendations for many aspects of VTE risk reduction in the setting of orthopedic surgery, as detailed in this review. The ACCP recommends the use of either low-molecular-weight heparin (LMWH), fondaparinux, or adjusted-dose warfarin as preferred VTE prophylaxis in patients undergoing either hip or knee arthroplasty. Fondaparinux is the preferred recommendation for patients undergoing hip fracture repair, followed by LMWH, unfractionated heparin, and adjusted-dose warfarin as alternative options. Extended-duration prophylaxis (for 4 to 5 weeks) is now recommended for patients undergoing hip arthroplasty or hip fracture repair. Patients undergoing knee arthroscopy do not require routine pharmacologic VTE prophylaxis.

OBJECTIVE

To analytically discuss some protocols in Deep vein thrombosis (DVT)/pulmonary Embolism (PE) prophylaxis currently use in Neurosurgical Departments around the world.

METHODS

Analysis of the prophylaxis protocols in the English literature: An analytical and narrative review of literature concerning DVT prophylaxis protocols in Neurosurgery have been conducted by a PubMed search (back to 1978).

METHODS

80 abstracts were reviewed, and 74 articles were extracted.

METHODS

The majority of DVT seems to develop within the first week after a neurosurgical procedure, and a linear correlation between the duration of surgery and DVT occurrence has been highlighted. The incidence of DVT seems greater for cranial (7.7%) than spinal procedures (1.5%). Although intermittent pneumatic compression (IPC) devices provided adequate reduction of DVT/PE in some cranial and combined cranial/spinal series, low-dose subcutaneous unfractionated heparin (UFH) or low molecular-weight heparin (LMWH) further reduced the incidence, not always of DVT, but of PE. Nevertheless, low-dose heparin-based prophylaxis in cranial and spinal series risks minor and major postoperative haemorrhages: 2-4% in cranial series, 3.4% minor and 3.4% major haemorrhages in combined cranial/spinal series, and a 0.7% incidence of major/minor haemorrhages in spinal series.

CONCLUSIONS

This analysis showed that currently most of the articles are represented by case series and case reports. As long as clear guidelines will not be defined and universally applied to this diverse group of patients, any prophylaxis for DVT and PE should be tailored to the individual patient with cautious assessment of benefits versus risks.

BACKGROUND

The purpose of this study is to compare the effect of increasing concentrations of direct anti-Xa oral anticoagulants (DOAC) apixaban-, edoxaban-, and rivaroxaban-enriched plasma samples on various prothrombin time (PT), activated partial thromboplastin time (APTT), heparin calibrated anti-Xa methods, and other coagulation assays.

METHODS

Apixaban, edoxaban, or rivaroxaban was dissolved in dimethylsulfoxide and added to pooled normal plasma to obtain concentrations ranging from 0 ng/mL to approximately 600 ng/mL. The samples were tested using Innovin(®) , Neoplastine(®) CI Plus, Recombiplastin 2G, and Thromborel(®) S for PT testing and Actin, Actin(®) FS, Actin(®) FSL, APTT-Automate, and SynthaSIL for APTT. Samples were also tested using four different anti-Xa methods calibrated for unfractionated heparin or low molecular weight heparin. Special coagulation assays included antithrombin activity, lupus anticoagulant assays, and others. For special coagulation assays, the concentration of DOAC that resulted in a >15% change from baseline value was determined. DOAC quantification was performed using liquid chromatography-tandem mass spectrometry.

RESULTS

All PT and APTT reagents demonstrated a higher sensitivity for edoxaban and rivaroxaban than for apixaban. Anti-Xa methods were able to detect low concentrations of DOAC. DOACs effected special coagulation assays to differing degrees, with lupus anticoagulant testing using dilute viper venom, the most sensitive test to the presence of anti-Xa DOAC.

CONCLUSIONS

No PT or APTT reagent system effectively detected apixaban. All anti-Xa methods demonstrated sensitivity to low concentrations of DOAC. Dilute viper venom methods are exquisitely sensitive to anti-Xa DOAC, suggesting potential use of this assay for screening or measuring these drugs.

Heparin-induced thrombocytopenia (HIT) is a common immunological drug reaction. After exposure to heparin, some patients develop heparin dependent antibodies with no evidence of thrombosis, while others are at risk of thrombocytopenia, thrombosis, limb loss, and death. We conducted a retrospective chart review on all patients serologically positive for HIT by HPIA ELISA in a single tertiary-care hospital, to determine whether patients with malignancy had an increased risk of thrombotic complications. Medical records of 55 patients who tested positive for HIT and met clinical criteria for HIT were analyzed. All patients had been treated with unfractionated heparin. Malignancy was diagnosed in 11 patients, either at surgery or post-mortem examination. A higher rate of venous thrombosis and pulmonary embolism was observed in patients with HIT and malignant disease when compared to patients with no underlying malignancy (odds ratio 13.6, 95% CI 2.9-63.8).

Sulfated galactan from the red alga Botryocladia occidentalis has a potent anticoagulant activity, due to its ability to enhance thrombin and factor Xa inhibition by antithrombin and/or heparin cofactor II. It is less active than unfractionated heparin in arterial thrombosis, but in a venous thrombosis presents a dual effect, inhibiting thrombosis in low but not in high doses. This dual effect on venous thrombosis is a consequence of two actions, one that inhibits thrombin and factor Xa and one that induces factor XII activation. In order to dissociate these effects, we prepared derivatives of the sulfated galactan with low molecular weights. Two fractions that were similar in size to unfractionated heparin and low-molecular-weight heparin were obtained. As the molecular weight decreased, the ability to activate factor XII and to promote inhibition of coagulation proteases in the presence of antithrombin and heparin cofactor II diminished. At approximately 5 kDa, the sulfated galactan fragment had no effect on factor XII activation, and showed the same effect as unfractionated heparin in a venous thrombosis model. The approximately 5-kDa fragment is an antithrombotic with several advantages: i) It is as active as unfractionated heparin in venous thrombosis, but it has little activity in arterial thrombosis; ii) It inhibits venous thrombosis with very little anticoagulant effect; iii) It does not cause bleeding; and iv) It is not obtained from mammals.

OBJECTIVE

Investigate whether anti-Factor Xa levels are associated with the need for change of circuit/membrane oxygenator secondary to thrombus formation in pediatric patients.

METHODS

Retrospective single institution study.

METHODS

Retrospective record review of 62 pediatric patients supported with extracorporeal membrane oxygenation from 2009 to 2011.

METHODS

Data on standard demographic characteristics, indications for extracorporeal membrane oxygenation, duration of extracorporeal membrane oxygenation, activated clotting time measurements, anti-Factor Xa measurements, and heparin infusion rate were collected. Generalized linear models were used to associate anti-Factor Xa concentrations and need for change of either entire circuit/membrane oxygenator secondary to thrombus formation.

RESULTS

Sixty-two patients met study inclusion criteria. No-circuit change was required in 45 of 62 patients. Of 62 patients, 17 required change of circuit/membrane oxygenator due to thrombus formation. Multivariate analysis of daily anti-Factor Xa measurements throughout duration of extracorporeal membrane oxygenation support estimated a mean anti-Factor Xa concentration of 0.20 IU/mL (95% CI, 0.16, 0.24) in no-complete-circuit group that was significantly higher than the estimated concentration of 0.13 IU/mL (95% CI, 0.12, 0.14) in complete-circuit group (p = 0.001). A 0.01 IU/mL decrease in anti-Factor Xa increased odds of need for circuit/membrane oxygenator change by 5% (odds ratio = 1.105; 95% CI, 1.00, 1.10; p = 0.044). Based on the observed anti-Factor Xa concentrations, complete-circuit group had 41% increased odds for requiring circuit/membrane oxygenator change compared with no-complete-circuit group (odds ratio = 1.41; 95% CI, 1.01, 1.96; p = 0.044). Mean daily activated clotting time measurement (p = 0.192) was not different between groups, but mean daily heparin infusion rate (p < 0.001) was significantly different between the two groups.

CONCLUSIONS

Higher anti-Factor Xa concentrations were associated with freedom from circuit/membrane oxygenator change due to thrombus formation in pediatric patients during extracorporeal membrane oxygenation support. Activated clotting time measurements did not differ significantly between groups with or without circuit/membrane oxygenator change. This is the first study to link anti-Factor Xa concentrations with a clinically relevant measure of thrombosis in pediatric patients during extracorporeal membrane oxygenation support. Further prospective study is warranted.

OBJECTIVE

Low molecular weight heparin (LMWH) has largely replaced unfractionated heparin (UFH) in patients with venous thromboembolism because of its pharmacokinetic profile, ease of administration and lack of need for monitoring. The pharmacokinetic profile of LMWH is due to lower molecular weight and reduced charge resulting in less nonspecific protein binding than UFH. These same characteristics make LMWH more dependent on renal function compared with UFH. Consequently, care should be employed when LMWH is administered to patients with impaired renal function as reduced clearance and bioaccumulation may cause bleeding.

RESULTS

LMWHs vary in their likelihood of bioaccumulation in chronic renal failure. Enoxaparin bioaccumulates and causes bleeding if administered in therapeutic doses without dose adjustment to patients with impaired renal function. Less rigorous evidence suggests that tinzaparin does not bioaccumulate. Bioaccumulation appears to be greatest in patients with a creatinine clearance less than 30 ml/min, and when therapeutic LMWH doses are used.

CONCLUSIONS

Care should be used when LMWHs are administered to patients with impaired renal function, particularly those with severe impairment (creatinine clearance below 30 ml/min).

BACKGROUND

Low-molecular-weight heparins (LMWHs) are routinely given without the control of their effect on coagulation. The endogenous thrombin potential (ETP) is a sensitive detector of the heparin effect.

OBJECTIVE

What is the interindividual variation in TG after a fixed dose of LMWH in normal volunteers, is it explained by variation in weight?

METHODS

Subcutaneous (s.c.) injection, in 12 healthy volunteers, of 9000 aXa-units of unfractionated heparin (UFH) and of three heparins with narrow MW distribution around 10.5, 6.0 and 4.5 kD. Measurement of anti-thrombin (aIIa) and antifactor Xa (aXa)-activities and ETP at 11 time points over 24 h.

RESULTS

The coefficient of variation (CV) of the AUCs of aXa- and aIIa-activities is 50% for UFH and 22-37% for LMWHs. Because of the hyperbolic form of the dose-response curve, the CV of the inhibition of the ETP is lower: 32% for UFH and 13-21% for the LMWHs. Fixed dosage of LMWH caused under-dosage in 10-13% of the samples and over-dosage in 5-11%. High or low response is an individual property independent of the type of heparin injected and only partially explained by variation in body weight.

CONCLUSIONS

Optimized individual dosage of LMWH is possible through recognition of high and low responders, which requires one measurement of the heparin concentration or, preferably, the heparin effect on the ETP, 2-5 h after a first injection.

BACKGROUND

Anti-Factor Xa (Anti-Xa) assays specifically determine the anticoagulant activity of UFH by measuring the ability of heparin-bound Antithrombin (AT) to inhibit a single enzyme, Factor Xa (FXa). Recent improvements in the automation, cost-effectiveness and accessibility of the assay to clinicians, have resulted in the Anti-Xa assay becoming a part of daily clinical practice in many institutions.

OBJECTIVE

We hypothesized that different Anti-Xa assays have different applicability for use in clinical settings, depending on the amount of UFH administered. This was investigated in a tertiary paediatric institution.

METHODS

Samples were collected from children receiving Low-dose of UFH of at least 10 IU/kg/h, with or without a previous bolus of up to 25 IU/kg/h, within the previous 6 h in the PICU and HDU. High-dose UFH population consisted of children undergoing Cardiac Catheterization (CC), who received a bolus of UFH of 100 IU/kg body weight, 30 min prior to sampling.

CONCLUSIONS

The Anti-Xa activity for a given dose of UFH was found to vary significantly based on the Anti-Xa assay and the population being monitored. Our study suggests that the MODIFIED COMATIC Anti-Xa assay provides the best physiological measure of the UFH effect in children, as it does not introduce sources of error, such as exogenous AT, which may increase the measured ant Factor Xa activity, nor Dextran Sulphate which can displace plasma protein bound heparin and once again leading to falsely elevated assay results. Further studies that include assessment of clinical outcomes are required to confirm the applicability of use of this particular assay in monitoring UFH therapy.

The risk for venous thromboembolism (VTE) in medical patients is high, but risk assessment is rarely performed because there is not yet a good method to identify candidates for prophylaxis.

OBJECTIVE

To perform a systematic review about VTE risk factors (RFs) in hospitalized medical patients and generate recommendations (RECs) for prophylaxis that can be implemented into practice.

METHODS

A multidisciplinary group of experts from 12 Brazilian Medical Societies searched MEDLINE, Cochrane, and LILACS.

METHODS

Two experts independently classified the evidence for each RF by its scientific quality in a standardized manner. A risk-assessment algorithm was created based on the results of the review.

RESULTS

Several VTE RFs have enough evidence to support RECs for prophylaxis in hospitalized medical patients (eg, increasing age, heart failure, and stroke). Other factors are considered adjuncts of risk (eg, varices, obesity, and infections). According to the algorithm, hospitalized medical patients>> or =40 years-old with decreased mobility, and>> or =1 RFs should receive chemoprophylaxis with heparin, provided they don't have contraindications. High prophylactic doses of unfractionated heparin or low-molecular-weight-heparin must be administered and maintained for 6-14 days.

CONCLUSIONS

A multidisciplinary group generated evidence-based RECs and an easy-to-use algorithm to facilitate VTE prophylaxis in medical patients.

Early diagnosis of infective endocarditis (IE) is based on the yielding of blood cultures and echocardiographic findings. However, they have limitations and sometimes the diagnosis is inconclusive, particularly in patients with prosthetic valves (PVs) and implantable cardiac electronic devices (ICEDs). The primary aim of this study was to evaluate the diagnostic accuracy of 18F-FDG PET/CT in patients with suspected IE and ICED infection.

METHODS

A prospective study with 80 consecutive patients with suspected IE and ICED infection (65 men and 15 women with a mean age of 68 ± 13 y) between June 2013 and May 2015 was performed in our hospital. The inclusion criteria were clinically suspected IE and ICED infection at the following locations: native valve (NV) (n = 21), PV (n = 29), or ICED (n = 30) (automatic implantable defibrillator [n = 11] or pacemaker [n = 19]). Whole-body 18F-FDG PET/CT with a myocardial uptake suppression protocol with unfractionated heparin was performed in all patients. The final diagnosis of infection was established by the IE Study Group according to the clinical, echocardiographic, and microbiologic findings.

RESULTS

A final diagnosis of infection was confirmed in 31 patients: NV (n = 6), PV (n = 12), and ICED (n = 13). Sensitivity, specificity, positive predictive value, and negative predictive value for 18F-FDG PET/CT were 82%, 96%, 94%, and 87%, respectively. 18F-FDG PET/CT was false-negative in all cases with infected NV. 18F-FDG PET/CT was able to reclassify 63 of 70 (90%) patients initially classified as possible IE by modified Duke criteria. In 18 of 70 cases, 18F-FDG PET/CT changed possible to definite IE (26%) and in 45 of 70 cases changed possible to rejected IE (64%). Additionally, 18F-FDG PET/CT identified 8 cases of septic embolism and 3 of colorectal cancer in patients with a final diagnosis of IE.

CONCLUSIONS

18F-FDG PET/CT proved to be a useful diagnostic tool in suspected IE and ICED infection and should be included in the diagnostic algorithm for early diagnosis. 18F-FDG PET/CT is not useful in the diagnosis of IE in NV but should be also considered in the initial assessment of this complex scenario to rule out extracardiac complications and possible neoplasms.

Unfractionated heparin and low molecular weight heparin are the most commonly used antithrombotic and thromboprophylactic agents in hospital practice. Extended out-of-hospital treatment is inconvenient in that these agents must be administered parenterally. Current research is directed at development of a safe and effective oral antithrombotic agent as an alternative for the effective, yet difficult to use vitamin K antagonists. A novel drug delivery technology that facilitates transport of drugs across the gastrointestinal epithelium has been harnessed to develop an oral dosage form of unfractionated heparin. Combining unfractionated heparin with the carrier molecule, sodium N-(8 [2-hydroxybenzoyl]amino) caprylate, or SNAC has markedly increased the gastrointestinal absorption of this drug. Preclinical and clinical studies to-date suggests that oral heparin-SNAC can confer a clinical efficacious effect; further confirmation is sought in planned clinical trials.