Heparin‐induced thrombocytopenia and thrombosis: a prospective analysis of the incidence in patients with heart and cerebrovascular diseases

Kappers‐Klunne, M. C.; Boon, Denali; Hop, Wcj; Jj, Michiels; Stibbe, J.; Zwaan, Carmen van der; Koudstaal, P. J.; Vliet, H. H. D. M. Van

doi:10.1046/j.1365-2141.1997.d01-2056.x

Cited by 84 publications

(31 citation statements)

References 11 publications

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“…2b, to give increased specificity of binding and activation. There are good reasons for doing this, as current therapy with heparin is limited by its heterogeneity, with some of the oligosaccharide binding to blood platelets causing their aggregation by immune mechanisms to give the distressing disorder thrombotic thrombocytopenia (37). In the longer term, the new structures also open the prospect (38) of the design of nonsaccharide mimetics, which, unlike heparin, could be administered orally.…”

Section: ͚͚I͉i(h) ϫ I(h)i͉͚͚͞i͉i(h)i͉ Where I(h)mentioning

confidence: 99%

The anticoagulant activation of antithrombin by heparin

Jin

Abrahams

Skinner

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

669

740

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Antithrombin, a plasma serpin, is relatively inactive as an inhibitor of the coagulation proteases until it binds to the heparan side chains that line the microvasculature. The binding specifically occurs to a core pentasaccharide present both in the heparans and in their therapeutic derivative heparin. The accompanying conformational change of antithrombin is revealed in a 2.9-Å structure of a dimer of latent and active antithrombins, each in complex with the high-affinity pentasaccharide. Inhibitory activation results from a shift in the main sheet of the molecule from a partially six-stranded to a five-stranded form, with extrusion of the reactive center loop to give a more exposed orientation. There is a tilting and elongation of helix D with the formation of a 2-turn helix P between the C and D helices. Concomitant conformational changes at the heparin binding site explain both the initial tight binding of antithrombin to the heparans and the subsequent release of the antithrombin-protease complex into the circulation. The pentasaccharide binds by hydrogen bonding of its sulfates and carboxylates to Arg-129 and Lys-125 in the D-helix, to Arg-46 and Arg-47 in the A-helix, to Lys-114 and Glu-113 in the P-helix, and to Lys-11 and Arg-13 in a cleft formed by the amino terminus. This clear definition of the binding site will provide a structural basis for developing heparin analogues that are more specific toward their intended target antithrombin and therefore less likely to exhibit side effects.Heparin, a sulfated polysaccharide, is second only to insulin as a natural therapeutic agent and is the initial-choice anticoagulant in the treatment and prevention of thromboembolic disease. It functions in life as a component of the heparans that line the inner walls of the microvascular system (1), but heparin as a drug is a heterogeneous animal extract administered by injection to circulate in the bloodstream. Both heparin and the natural heparans contain a specific pentasaccharide fragment (2, 3) that binds and activates the plasma proteinase inhibitor antithrombin.In nature, this binding to heparans substantially localizes the function of antithrombin to inhibition of the serine proteases of the coagulation cascade within the bloodstream, allowing their coagulant activity in damaged tissue outside the vascular system. The heparans and the longer-chain heparins (4) activate the inhibition of thrombin by antithrombin by bringing them into close apposition, but there is also a direct activation of inhibition due to an overall conformational change (5) induced by the binding to the core pentasaccharide present in both heparin and heparans. This pentasaccharide-induced change alters the conformation of the reactive site loop of antithrombin (6, 7) and gives a 300-fold increase in inhibitory activity against the key coagulation protease factor Xa. Linked to this is a change in affinity at the heparin binding site (see Fig. 1), and as antithrombin contacts the pentasaccharide, it moves from an initial low-affinit...

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Section: ͚͚I͉i(h) ϫ I(h)i͉͚͚͞i͉i(h)i͉ Where I(h)mentioning

confidence: 99%

The anticoagulant activation of antithrombin by heparin

Jin

Abrahams

Skinner

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

669

740

View full text Add to dashboard Cite

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“…This low incidence of HIT was also seen in other studies involving medical in patients but the proportion of patients with HIT developing thrombosis was high (50-67%) (16)(17)(18). Analysis of renal patients on haemodialysis also indicate a low incidence of antibody formation (combined incidence 2.6%) with very few patients noted to be thrombocytopenic and none with thrombotic complications (19)(20)(21)(22)(23).…”

Section: Clinical Features Of Hitmentioning

confidence: 52%

Heparin-induced thrombocytopaenia/Thrombosis: a clinico-pathological review

Dave¹

2010

E Af Med Jrnl

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“…The incidence of HIT in patients treated systematically with high doses of unfractionated heparin lies between 0.3 and 2.7% [16, 19]. Fractionated, low–molecular–weight heparin seems to abolish the risk of HIT completely [16, 19]. …”

Section: Discussionmentioning

confidence: 99%

“…Many studies have been performed to elucidate the possible mechanism of HIT, which involves the binding of platelet factor–4/heparin complex to the heparin receptor on the platelet, and is dependent on heparin concentration [17, 18]. An autoantibody then triggers an immune response in some (but not all) patients [19]. The incidence of HIT in patients treated systematically with high doses of unfractionated heparin lies between 0.3 and 2.7% [16, 19].…”

Section: Discussionmentioning

confidence: 99%

Collection of Heparinized Plasma by Plasmapheresis

Meer¹,

Vrielink²,

Pietersz³

et al. 1999

Vox Sanguinis

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Background and Objectives: Heparinized plasma can be used for exchange transfusions in neonates and is usually collected by drawing whole blood using heparin as anticoagulant. The heparinized red blood cells and buffy coat cannot be used and are therefore discarded. To collect heparinized plasma more efficiently, a method was developed using an apheresis machine. Materials and Methods: With an MCS3p apheresis machine (Haemonetics), plasma was collected from volunteer donors as anticoagulant, heparin in saline (30,000 IU/l) was added in a 1:9 ratio. The activated partial thromboplastin time (APTT) of the donors was measured before and immediately after the procedure, and various parameters were determined in the collected plasma. Results: In 2 collection cycles, an average of 456±52 ml (mean ± SD; n = 20) of heparinized plasma was collected, and 504±57 ml (n = 2; donors with a high hemoglobin level) when 3 cycles were performed. The leukocyte and platelet contamination in the plasma (n = 22) was 1.11±0.92×10⁶ and 0.05±0.22×10⁹ per unit, respectively, which conformed to national specifications. Sodium levels were normal, but due to dilution of the plasma with heparin solution, potassium and calcium levels were about 20% lower than the serum levels in the donors. The donor APTT values were slightly longer after the procedure than before, but remained all within normal values. Conclusion: For the collection of heparinized plasma, apheresis has the advantage that (1) high–quality heparinized plasma can be harvested; (2) no blood components need to be discarded; (3) more plasma can be harvested with each donation, and (4) these procedures can be performed more often than whole blood donations.

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Heparin‐induced thrombocytopenia and thrombosis: a prospective analysis of the incidence in patients with heart and cerebrovascular diseases

Cited by 84 publications

References 11 publications

The anticoagulant activation of antithrombin by heparin

The anticoagulant activation of antithrombin by heparin

Heparin-induced thrombocytopaenia/Thrombosis: a clinico-pathological review

Collection of Heparinized Plasma by Plasmapheresis

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