Oral administration of dermatan sulphate reduces venous thrombus formation in vivo: potential use as a formulation for venous thromboembolism.

Dermatan sulphate (DS) is a sulphated polysaccharide that displays complexity in constituent sulphated disaccharides and interacts with proteins and signalling molecules to modulate numerous biological processes, including inhibition of the coagulation cascade and regulation of blood clotting and fibrinolysis. This study shows the antithrombotic and anticoagulant effects of DS prepared from bovine collagen waste liquor following oral and intravenous administrations in a deep vein thrombosis (DVT) rabbit model. In vitro, the prothrombin time, activated partial thromboplastin time, and thrombin citrated plasma clotting assays revealed that bovine DS had strong antithrombotic and anticoagulant effects comparable to low-molecular-weight heparin [Clexane® (enoxaparin sodium)]. In a DVT rabbit model, animals received intravenous and oral administrations of bovine DS and Clexane® providing further evidence that both agents had strong antithrombotic and anticoagulant effects by significantly reducing or preventing clot formation. Thromboelastography (TEG) assays revealed further that both bovine DS and Clexane® substantially prolonged the clotting time of recalcified citrated whole blood, but only bovine DS could retain clot strength suggesting that bovine DS had less effect on platelet-fibrin interactions. In conclusion, this is the first report that oral administration of DS from bovine collagen waste liquor reduces experimental venous thrombus formation warranting further research into bovine DS as an oral antithrombotic therapeutic.

A dermatan sulfate-functionalized biomimetic nanocarrier for melanoma targeted chemotherapy.

Melanoma is a malignant tumor of melanocytes that is a serious threat to human health. Dermatan sulfate (DS) is a natural glycosaminoglycan. Inspired by the origin of DS, we report a DS-functionalized biomimetic chitosan nanocarrier (DCNP) for melanoma targeted chemotherapy. DS can anchor to the surface of the chitosan nanocarrier (CNP) by forming amide bond. The SN38/DCNP can rapidly release the anti-tumor drug under acidic conditions. The functionalization of DS not only promoted the specific uptake behavior of melanoma cells, but also up-regulated cleaved caspase-3 and PARP promote tumor cell apoptosis. In vivo model, DCNP reduced the non-specific distribution of SN38 in the circulation and other tissues, while shows superior tumor targeting ability. SN38/DCNP significantly inhibit tumor growth and improved the survival rate. Moreover, SN38/DCNP has a milder myelosuppressive effect. The above results indicated that DS could be used as an excellent targeting unit for the treatment of melanoma.

Danaparoid is effective and safe for patients with obstetric antiphospholipid syndrome.

Objectives: The objective is to evaluate whether danaparoid is effective in improving the live birth rate in patients with obstetric antiphospholipid syndrome (oAPS).Methods: This prospective study included 91 pregnancies of 60 patients with oAPS diagnosed according to criteria of the International Congress on APS. Live birth rates, adverse pregnancies and perinatal outcomes were compared among patients treated with danaparoid and low dose aspirin (danaparoid group, LDA), unfractionated heparin (UFH) and LDA (UFH group) and LDA and/or prednisolone (LDA group).Results: After excluding 11 miscarriages with abnormal embryonic chromosomes, one chemical pregnancy and one ectopic pregnancy, live birth rates were 87.5% (14/16) for the danaparoid group, 90.0% (36/40) for the UFH group and 63.6% (14/22) for the LDA group, respectively. The live birth rates of patients treated with danaparoid and UFH were similar and tended to be higher than that of patients treated with LDA, respectively (OR 4.0, 95% confidence interval 0.72-22.22 and 5.15, 1.33-20.00). No patient given danaparoid and one patient with UFH developed heparin-induced thrombocytopenia which resulted in a stillbirth. Another patient with UFH suffered a lumbar compression fracture.Conclusion: Danaparoid is effective for improving the live birth rate and is safe for patients with oAPS.

Danaparoid use for haemodialysis in a morbidly obese patient with heparin-induced thrombocytopenia - Need for a higher than recommended weight-based dosing.

WHAT IS KNOWN AND OBJECTIVE: Heparin is widely used to prevent clotting of the extracorporeal circuit during haemodialysis (HD). Heparin-induced thrombocytopenia (HIT) is a potentially devastating immune mediated adverse drug reaction caused by the emergence of antibodies that activate platelets in the presence of heparin, leading to a pro-thrombotic state. Danaparoid is an alternative anticoagulant used in patients on HD with HIT but its dosing recommendations in obese patients on HD are relatively scarce. CASE SUMMARY: We report a case of a 48-year-old morbidly obese patient who received weight-based dosing of danaparoid for HD with monitoring of anti-Xa activity. However, despite the patient's anti-Xa level being within the therapeutic range at various time points, the circuit lines kept clotting during HD. WHAT IS NEW AND CONCLUSION: The report provides evidence that the manufacturer's recommendations on dosing danaparoid based on body weight may lead to sub-optimal therapeutic benefit and highlight the need for higher than recommended weight-based dosing in obese individuals on dialysis.

Persistent heparin-induced thrombocytopenia: danaparoid cross-reactivity or delayed-onset heparin-induced thrombocytopenia? A case report.

Clinical suspicion of immune heparin-induced thrombocytopenia (HIT) requires cessation of heparin and initiation of an alternative anticoagulant. The platelet count will subsequently recover. This case report describes the clinical course of a patient after a cardiovascular surgery. HIT was clinically and biologically confirmed. Unexpectedly, the platelet count did not recover despite the arrest of heparin. Danaparoid was initiated, and thrombocytopenia persisted. Danaparoid cross-reactivity was suspected, and laboratory assay was performed. Results were misinterpreted because no comparative buffer control was performed to ensure that the platelet aggregation was caused by danaparoid. Moreover, plasma/serum must be diluted to demonstrate this effect. Danaparoid cross-reactivity was incorrectly concluded, and the patient was switched to bivalirudin. The severe thrombocytopenia persisted. Plasmapheresis was started, and platelet count finally increased. The clinical course suggested a delayed-onset HIT. This case report illustrates the need for appropriate testing to differentiate drug cross-reactivity from delayed-onset HIT.

Design and characterization of core-shell mPEG-PLGA composite microparticles for development of cell-scaffold constructs.

Appropriate scaffolds capable of providing suitable biological and structural guidance are of great importance to generate cell-scaffold constructs for cell-based tissue engineering. The aim of the present study was to develop composite microparticles with a structure to provide functionality as a combined drug delivery/scaffold system. Composite microparticles were produced by incorporating either alginate/dermatan sulfate (Alg/DS) or alginate/chitosan/dermatan sulfate (Alg/CS/DS) particles in mPEG-PLGA microparticles using coaxial ultrasonic atomization. The encapsulation and distribution of Alg/DS or Alg/CS/DS particles in the mPEG-PLGA microparticles were significantly dependent on the operating conditions, including the flow rate ratio (Qout/Qin) and the viscosity of the polymer solutions (Vout, Vin) between the outer and the inner feeding channels. The core-shell composite microparticles containing the Alg/DS particles or the Alg/CS/DS particles displayed 40% and 65% DS release in 10 days, respectively, as compared to the DS directly loaded microparticles showing 90% DS release during the same time interval. The release profiles of DS correlate with the cell proliferation of fibroblasts, i.e. more sustainable cell growth was induced by the DS released from the core-shell composite microparticles comprising Alg/CS/DS particles. After seeding fibroblasts onto the composite microparticles, excellent cell adhesion was observed, and a successful assembly of the cell-scaffold constructs was induced within 7 days. Therefore, the present study demonstrates a novel strategy for fabrication of core-shell composite microparticles comprising additional particulate drug carriers in the core, which provides controlled delivery of DS and favorable cell biocompatibility; an approach to potentially achieve cell-based tissue regeneration.

Dermatan sulfate: an alternative to unfractionated heparin for anticoagulation in hemodialysis patients.

BACKGROUND: Unfractionated heparin (UFH) is the standard anticoagulant in regular dialysis treatments (RDTs), despite the fact that it may induce thrombocytopenia, dyslipidemia, allergy and osteoporosis. Dermatan sulfate (DS) selectively inhibits thrombin, does not inhibit F-Xa and does not interfere with platelets (PLTS). Here we described an original protocol for the use of DS as anticoagulant in RDT and compared its effects with those of UFH. METHODS: In 102 patients, 7,254 RDTs were performed using DS for anticoagulation (DS-phase) and 5,707 with UFH (UFH-phase). DS was supplied as initial bolus (80 ± 12 mg) and continuous infusion (14 ± 7 mg/hour). With UFH, the initial bolus was 1,475 ± 141 IU and continuous infusion 576 ± 349 IU/hour. Activated partial thromboplastin time and its ratio were measured at least monthly, both before (pre-RDT APTT ratio) and after (post-RDT APTT ratio) RDT sessions. With 41 of 102 patients, both DS and UFH doses were not changed during study phases (stable patients). In this subset, the coefficient of variation (CV) of all pre-RDT APTT ratio and post-RDT APTT ratio values was calculated. RESULTS: In DS and UFH phases, post-RDT APTT ratio increased by 61% and 50%, respectively, by comparison with pre-RDT APTT ratio (p<0.001). PLTS count was lower in the UFH than in the DS phase (p<0.01). In stable patients, post-RDT APTT ratio CV was lower in the DS than in the UFH phase (p<0.001), which indicates a more predictable anticoagulant effect of DS compared with UFH. CONCLUSIONS: DS appeared as effective as UFH for anticoagulation in RDT. It can reliably be considered as an alternative approach especially in cases of thrombocytopenia or other adverse effects of UFH.

Delivery of dermatan sulfate from polyelectrolyte complex-containing alginate composite microspheres for tissue regeneration.

Dermatan sulfate (DS) is a glycosaminoglycan (GAG) with a great potential as a new therapeutic agent in tissue engineering. The aim of the present study was to investigate the formation of polyelectrolyte complexes (PECs) between chitosan and dermatan sulfate (CS/DS) and delivery of DS from PEC-containing alginate/chitosan/dermatan sulfate (Alg/CS/DS) microspheres for application in tissue regeneration. The CS/DS complexes were initially formed at different conditions including varying CS/DS ratio (positive/negative charge ratio), buffer, and pH. The obtained CS/DS complexes exhibited stronger electrostatic interaction, smaller complex size, and more stable colloidal structure when chitosan was in large excess (CS/DS 3:1) and prepared at pH 3.5 as compared to pH 5 using acetate buffer. The CS/DS complexes were subsequently incorporated into an alginate matrix by spray drying to form Alg/CS/DS composite microspheres with a DS encapsulation efficiency of 90-95%. The excessive CS induced a higher level of sustained DS release into Tris buffer (pH 7.4) from the microspheres formulated at pH 3.5; however, the amount of CS did not have a significant effect on the release from the microspheres formulated at pH 5. Significant cell proliferation was stimulated by the DS released from the microspheres in vitro. The present results provide a promising drug delivery strategy using PECs for sustained release of DS from microspheres intended for site-specific drug delivery and ultimately for use in tissue engineering.

Parenteral anticoagulants: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.

This article describes the pharmacology of approved parenteral anticoagulants. These include the indirect anticoagulants, unfractionated heparin (UFH), low-molecular-weight heparins (LMWHs), fondaparinux, and danaparoid, as well as the direct thrombin inhibitors hirudin, bivalirudin, and argatroban. UFH is a heterogeneous mixture of glycosaminoglycans that bind to antithrombin via a unique pentasaccharide sequence and catalyze the inactivation of thrombin, factor Xa, and other clotting enzymes. Heparin also binds to cells and plasma proteins other than antithrombin causing unpredictable pharmacokinetic and pharmacodynamic properties and triggering nonhemorrhagic side effects, such as heparin-induced thrombocytopenia (HIT) and osteoporosis. LMWHs have greater inhibitory activity against factor Xa than thrombin and exhibit less binding to cells and plasma proteins than heparin. Consequently, LMWH preparations have more predictable pharmacokinetic and pharmacodynamic properties, have a longer half-life than heparin, and are associated with a lower risk of nonhemorrhagic side effects. LMWHs can be administered once daily or bid by subcutaneous injection, without coagulation monitoring. Based on their greater convenience, LMWHs have replaced UFH for many clinical indications. Fondaparinux, a synthetic pentasaccharide, catalyzes the inhibition of factor Xa, but not thrombin, in an antithrombin-dependent fashion. Fondaparinux binds only to antithrombin. Therefore, fondaparinux-associated HIT or osteoporosis is unlikely to occur. Fondaparinux exhibits complete bioavailability when administered subcutaneously, has a longer half-life than LMWHs, and is given once daily by subcutaneous injection in fixed doses, without coagulation monitoring. Three additional parenteral direct thrombin inhibitors and danaparoid are approved as alternatives to heparin in patients with HIT.

Dermatan sulfate reduces monocyte chemoattractant protein 1 and TGF-ß production, as well as macrophage recruitment and myofibroblast accumulation in mice with unilateral ureteral obstruction.

Selectins play an essential role in most inflammatory reactions, mediating the initial leukocyte-rolling event on activated endothelium. Heparin and dermatan sulfate (DS) bind and block P- and L-selectin function in vitro. Recently, we reported that subcutaneous administration of DS inhibits colon inflammation in rats by reducing macrophage and T-cell recruitment and macrophage activation. In the present study, we examined the effect of porcine intestinal mucosa DS on renal inflammation and fibrosis in mice after unilateral ureteral obstruction (UUO). Twenty-four adult male Swiss mice weighing 20-25 g were divided into 4 groups: group C (N = 6) was not subjected to any surgical manipulation; group SH (N = 6) was subjected to surgical manipulation but without ureter ligation; group UUO (N = 6) was subjected to unilateral ureteral obstruction and received no treatment; group UUO plus DS (N = 6) was subjected to UUO and received DS (4 mg/kg) subcutaneously daily for 14 days. An immunoblot study was also performed for TGF-ß. Collagen (stained area ~3700 µm(2)), MCP-1 (stained area ~1700 µm(2)), TGF-ß (stained area ~13% of total area), macrophage (number of cells ~40), and myofibroblast (stained area ~1900 µm(2)) levels were significantly (P < 0.05) higher in the UUO group compared to control. DS treatment significantly (P < 0.05) reduced the content of collagen (stained area ~700 µm(2)), MCP-1 (stained area ~160 µm(2)) and TGF-ß (stained area ~5% of total area), in addition to myofibroblast (stained area ~190 µm(2)) and macrophage (number of cells ~32) accumulation in the obstructed kidney. Overall, these results indicate that DS attenuates kidney inflammation by reducing macrophage recruitment, myofibroblast population and fibrosis in mice submitted to UUO.

Dermatan sulfate reduces monocyte chemoattractant protein 1 and TGF-β production, as well as macrophage recruitment and myofibroblast accumulation in mice with unilateral ureteral obstruction

Selectins play an essential role in most inflammatory reactions, mediating the initial leukocyte-rolling event on activated endothelium. Heparin and dermatan sulfate (DS) bind and block P- and L-selectin function in vitro. Recently, we reported that subcutaneous administration of DS inhibits colon inflammation in rats by reducing macrophage and T-cell recruitment and macrophage activation. In the present study, we examined the effect of porcine intestinal mucosa DS on renal inflammation and fibrosis in mice after unilateral ureteral obstruction (UUO). Twenty-four adult male Swiss mice weighing 20-25 g were divided into 4 groups: group C (N = 6) was not subjected to any surgical manipulation; group SH (N = 6) was subjected to surgical manipulation but without ureter ligation; group UUO (N = 6) was subjected to unilateral ureteral obstruction and received no treatment; group UUO plus DS (N = 6) was subjected to UUO and received DS (4 mg/kg) subcutaneously daily for 14 days. An immunoblot study was also performed for TGF-β. Collagen (stained area ~3700 µm²), MCP-1 (stained area ~1700 µm²), TGF-β (stained area ~13 percent of total area), macrophage (number of cells ~40), and myofibroblast (stained area ~1900 µm²) levels were significantly (P < 0.05) higher in the UUO group compared to control. DS treatment significantly (P < 0.05) reduced the content of collagen (stained area ~700 µm²), MCP-1 (stained area ~160 µm²) and TGF-β (stained area ~5 percent of total area), in addition to myofibroblast (stained area ~190 µm²) and macrophage (number of cells ~32) accumulation in the obstructed kidney. Overall, these results indicate that DS attenuates kidney inflammation by reducing macrophage recruitment, myofibroblast population and fibrosis in mice submitted to UUO.

The use of danaparoid to manage coagulopathy in a neurosurgical patient with heparin-induced thrombocytopenia type II and intracerebral haemorrhage.

This study presents a case of bifrontal intracerebral haemorrhage in a patient with heparin-induced thrombocytopenia type II (HIT II). HIT II was induced by treatment with low-molecular-weight heparin for recurrent deep vein thrombosis caused by essential thrombocytosis and accompanied by hepatic thromboembolism. This patient was treated with platelet substitution and neurosurgical haematoma evacuation. Anticoagulation with 2500 units danaparoid per day was sufficient for therapy of thrombosis and no rebleeding occurred.

An analysis of clinical outcomes of 91 pregnancies in 83 women treated with danaparoid (Orgaran).

UNLABELLED: Danaparoid case reports of 91 pregnancies in 83 patients with a history of thrombophilia and/or intra-uterine growth retardation have been analysed. All had intolerance to the heparins including HIT and acute or past thromboses or a history of repeated pregnancy loss (RPL). Danaparoid was started in the first, second and third trimesters in 60.2%, 19.3% and 20.5% pregnancies respectively at a dosing intensity of 1000 to 7500 U/day. Subcutaneous and/or intravenous administration was continued for a median 105 days (range 1-252) during pregnancy and 7 days (range 2 to 56) post-partum. The live birth rate was 90.4% (75/81) and danaparoid was restarted after 37 deliveries. Maternal adverse events in 46.2% of the pregnancies included 2 post cesarean deaths (a failed post-operative resuscitation and a major bleed in a patient refusing transfusion), 3 non-fatal major bleeds (associated with cesarean section and faulty placental implantation), 3 thrombo-embolic events unresponsive to danaparoid dose increase and 10 recurrent rashes. Seven early miscarriages, 1 therapeutic termination and 1 neonatal death occurred. In 13 reports a maternal, but no fetal, adverse event was attributed to danaparoid. Anti-Xa activity levels in maternal plasma were between 0.1 and 1.2 U/mL, absent from 6 fetal cord blood samples and 0 - 0.07 U/mL in the 5 maternal breast milk samples tested. CONCLUSION: The successful birth rate and adverse event profile indicates that danaparoid can be an effective and safe alternative anti-thrombotic in pregnancies complicated by HIT or intolerance or resistance to (LMW)heparins.

[Heparin-induced thrombocytopenia occurring after surgical treatment of atrial myxoma--a case report].

INTRODUCTION: Heparin-induced thrombocytopenia (HIT) is an acquired, prothrombotic disorder, caused by antibodies to a complex of heparin and platelet factor 4 (PF4) that activates platelets, resulting in the release of procoagulant microparticles, thrombocytopenia occurrence, generation of thrombin, and frequent thromboses. CASE OUTLINE: We present a case of severe HIT in a 68-year-old female, which occurred after cardiosurgery of the left atrial myxoma with the aim to point out the importance of differential diagnosis of thrombocytopenia in patients recently exposed to heparin. Platelet count dropped on the eleventh postoperative day, six days after unfractioned heparin and enoxaparine threatment, to 4x10(9)/I.The correct diagnosis failed to be made at first. Since thrombocytopenia remained refractory to a corticosteroid treatment and platelet transfusion, the patient was hospitalized on the 13th postoperative day at the Institute of Haematology. The diagnosis of HIT was confirmed with the high-probability clinical score (4T's) and strongly positive anti-heparin-PF4 (PaGIA) test as well as positive platelet aggregation test. The treatment started with a smaller therapeutic doses of danaparoid than recommended of 750 U intravenous bolus and was followed by continuous infusions of 100 U per 1 h and intravenous gammaglobulins in full dosage for four days. The platelet count started to rise on the third day and it was completely normalized on the 5th day of the therapy. CONCLUSION: Treatment of severe HIT with small doses of danaparoid supplemented by intravenous gamma globulin was successful. Additional awareness of heparin-induced thrombocytopenia is needed, especially of HIT in differential diagnosis of thrombocytopenia in patients recently exposed to heparin.

Heparin-induced thrombocytopenia. A contemporary clinical approach to diagnosis and management.

Thrombocytopenia following heparin administration can be associated with an immune reaction, now referred to as heparin-induced thrombocytopenia (HIT). HIT is essentially a prothrombotic disorder mediated by an IgG antiplatelet factor 4/heparin antibody, which induces platelet, endothelial cell, monocyte, and other cellular activation, leading to thrombin generation and thrombotic complications. Indeed, HIT can also be regarded as a serious adverse drug effect. Importantly, HIT can be a life-threatening and limb-threatening condition frequently associated with characteristically severe and extensive thromboembolism (both venous and arterial) rather than with bleeding. This article provides an overview of HIT, with an emphasis on the clinical diagnosis and management.

Danaparoid cross-reactivity with heparin-induced thrombocytopenia antibodies: report of 12 cases.

PURPOSE: Danaparoid is a safe and effective drug for the treatment of heparin-induced thrombocytopenia (HIT). We describe an uncommon complication: danaparoid cross-reactivity with HIT antibodies. DESIGN AND SETTING: A retrospective observational multicenter study on HIT was conducted in France. In this study concerning HIT patients treated with lepirudin, 12 patients were treated with lepirudin because danaparoid cross-reacted with the heparin-dependent antibodies. RESULTS: Three groups of situations can be separated. In a first group, four patients received a short course of danaparoid until their initial functional HIT assay showed a cross-reactivity between danaparoid and HIT antibodies. One patient presented a fatal thrombotic complication but the relationship between this thrombotic complication and danaparoid cross-reactivity cannot be certain. In a second group, four patients received for 4 days at least a danaparoid treatment while the initial functional test did not show any danaparoid cross-reactivity. During danaparoid treatment, no significant increase of platelet count was observed and two patients presented a fatal thrombotic complication. In a third group, cross-reactivity between danaparoid and HIT antibodies was not checked before danaparoid therapy. During danaparoid treatment, no significant increase of platelet count was observed and the four patients developed a venous thromboembolic complication. CONCLUSION: Absence of any increase in platelet count after 3 to 5 days of danaparoid therapy and/or the occurrence of a new thrombotic event should lead to danaparoid cross-reactivity suspicion. However, before attributing thrombotic complications to danaparoid cross-reactivity, it is crucial to verify that the patients received the recommended danaparoid dosage regimen.

Successful use of danaparoid in two pregnant women with heart valve prosthesis and heparin-induced thrombocytopenia Type II (HIT).

Anticoagulant therapy with heparin for the prevention of thromboembolism in pregnant women with prosthetic heart valves is associated with an increased risk to the mother and/or the fetus. A life-threatening complication of the therapy with heparin is heparin-induced thrombocytopenia type II (HIT). danaparoid has not yet been reported to be safe and effective for this indication. This study reports on a 26-year-old woman with tricuspidal valve prosthesis and a 37-year-old woman with a St. Jude Medical mitral valve prosthesis who were anticoagulated with danaparoid during pregnancy because of HIT. Anti-Xa levels were between 0.6 and 1.2 IU/mL during pregnancy with target levels of 1.0 IU/mL. Cesarean section was performed at anti-Xa levels of 0.3 and 0.7 IU/mL. One woman developed a placental hematoma at the 32nd week of gestation, which did not increase over the following week. Both patients delivered healthy boys. Heparin-induced thrombocytopenia in pregnant women with prosthetic heart valve can be successfully managed with danaparoid.

Management of allergy to heparins in postoperative care: subcutaneous allergy and intravenous tolerance.

Itching erythematous or eczematous plaques around injection sites are quite frequent side effects of heparin treatment and are clinical symptoms of a delayed-type hypersensitivity to heparins. In most cases, changing the subcutaneous therapy from unfractionated to low molecular weight heparin or treatment with heparinoids does not provide improvement, due to extensive cross-reactivity. Interestingly, it has been demonstrated that patients with delayed-type hypersensitivity to subcutaneously injected heparins tolerate intravenous application of heparin in controlled challenge tests. A patient with known delayed-type hypersensitivity to heparins received the heparinoid, danaparoid, subcutaneously for thrombosis prophylaxis after orthopedic surgery. After the first few injections, eczematous plaques developed; administration of the anticoagulant was continued and gradually resulted in generalized eczema despite treatment with topical and oral glucocorticoids. However, the patient required further anticoagulation. After discontinuation of subcutaneous injections and a switch to intravenous heparin, rapid improvement and clearing of skin lesions occurred. Therefore, in cases of delayed-type hypersensitivity to subcutaneously injected heparins, the switch from subcutaneous to intravenous heparin administration may be justified.