An anticoagulant dermatan sulfate proteoglycan circulates in the pregnant woman and her fetus.

Andrew, Maureen; Mitchell, Lesley; Berry, Leslie R.; Paes, Bosco; Delorme, Michael A.; Ofosu, Frederick A.; Burrows, Robert F.; Khambalia, B

doi:10.1172/jci115579

Cited by 78 publications

(35 citation statements)

References 44 publications

(16 reference statements)

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“…The incidence of VTE is significantly lower in children compared with adults. Young age has a protective role on developing thrombosis and could be explained by the reduced capacity to generate thrombin, 15,16 increased capacity of ␣ 2 macroglobulin to inhibit thrombin, 17 presence of a circulating anticoagulant at birth, [18][19][20] and enhanced antithrombotic potential by the vessel wall. 21,22 In addition, the vascular endothelium of children has not accumulated damage from diseases such as hypertension, diabetes, or hypercholesterolemia and therefore maintains its anticoagulant properties.…”

Section: Resultsmentioning

confidence: 99%

Pediatric venous thromboembolism in relation to adults

Spentzouris

Scriven

Lee

et al. 2012

Journal of Vascular Surgery

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Section: Resultsmentioning

confidence: 99%

Pediatric venous thromboembolism in relation to adults

Spentzouris

Scriven

Lee

et al. 2012

Journal of Vascular Surgery

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“…44 During pregnancy, both the maternal and fetal plasma contain trace amounts of a DS proteoglycan that stimulates inhibition of thrombin by HCII. 45 The placenta is rich in DS and may be the source of this proteoglycan. Whereas placental heparan sulfate has little or no anticoagulant activity when assayed with either HCII or antithrombin, DS appears to be the major anticoagulant glycosaminoglycan in this organ.…”

Section: Pregnancymentioning

confidence: 99%

Heparin Cofactor II Modulates the Response to Vascular Injury

Tollefsen

2007

ATVB

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Abstract-Heparin cofactor II (HCII) has several biochemical properties that distinguish it from other serpins: (1) it specifically inhibits thrombin; (2) the mechanism of inhibition involves binding of an acidic domain in HCII to thrombin exosite I; and (3) the rate of inhibition increases dramatically in the presence of dermatan sulfate molecules having specific structures. Human studies suggest that high plasma HCII levels are protective against in-stent restenosis and atherosclerosis. Studies with HCII knockout mice directly support the hypothesis that HCII interacts with dermatan sulfate in the arterial wall after endothelial injury and thereby exerts an antithrombotic effect. In addition, HCII deficiency appears to promote neointima formation and atherogenesis in mice. These results suggest that HCII plays a unique and important role in vascular homeostasis. Key Words: heparin cofactor II Ⅲ thrombin Ⅲ thrombosis Ⅲ atherogenesis Ⅲ restenosis T hirty years have elapsed since Briginshaw and Shanberge demonstrated that human plasma contains 2 heparindependent inhibitors of thrombin. 1,2 They reported that the 2 inhibitors could be separated by gel filtration and ionexchange chromatography. One of the inhibitors resembled the known protein antithrombin (formerly called antithrombin III) because it inactivated both thrombin and factor Xa and had easily detectable progressive (ie, heparinindependent) antithrombin activity. The second inhibitor did not react with factor Xa and had comparatively weak progressive antithrombin activity, yet it appeared to comprise a significant fraction of the total heparin cofactor activity in plasma. A few years later, Tollefsen and Blank demonstrated that 125 I-thrombin forms 2 SDS-stable complexes in plasma containing heparin, 3 and other investigators noted that the heparin cofactor activity of plasma exceeds the amount predicted from the antithrombin antigen concentration. 4,5 The existence of a second heparin cofactor (now called heparin cofactor II or HCII) was firmly established when the inhibitor was purified to homogeneity from human plasma and was shown to be distinct from antithrombin. 6 Although much has been learned about the structure, mechanism of action, and genetics of HCII, relatively little is known about its physiological function. This review summarizes our current knowledge of the biochemistry of HCII and then focus on recent insights gained from clinical studies and experiments with knockout mice. Biochemistry of HCIIThe HCII gene (designated SERPIND1 in humans) has been identified in a variety of vertebrate species, including humans, chimpanzee, rhesus monkey, house mouse, Norway rat, rabbit, cow, chicken, African clawed frog, European flounder, and zebrafish (http://www.ncbi.nlm.nih.gov/ entrez/). HCII mRNA is highly expressed in the liver, which appears to be the major source of plasma HCII. 7 Low levels of HCII mRNA are also detectable in other tissues, but the significance of extrahepatic expression of HCII is unclear. 8 HCII circulates in human plasma at...

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“…Several other studies have also identified similar molecules in human plasma [6][7][8][9]. Functional assays have been used to identify a heparin-like inhibitor of coagulation in cord blood [10], and it has been suggested that this was due to fetal fibrinogen or perhaps to dermatan sulfate (i.e., chondroitin sulfate B) operating through the heparin cofactor II pathway [37]. Our results confirm that functional fibrinogen was decreased significantly in cord blood, and this could explain, in part, the increased thrombin times for cord plasma as compared to adult plasma.…”

Section: Discussionmentioning

confidence: 99%

Protein-Bound Heparin/Heparan Sulfates in Human Adult and Umbilical Cord Plasma

Xiao

Miller

Bang

et al. 1999

Pathophysiol Haemos Thromb

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We used thrombin times and a competitive radiometric assay to identify, quantitate and characterize endogenous heparin-like molecules in umbilical cord (n = 58) and normal adult (n = 25) plasma. Thrombin times for cord plasma (29.6 ± 3.6 s) were significantly longer (p ≤ 0.0005) than those for adult plasma (18.9 ± 2.3 s), suggesting increased endogenous heparins. A radiometric assay based on the displacement of ¹²⁵I-heparin from protamine-Sepharose revealed that protease-digested plasma contained heparin/heparan sulfate, and plasma that was not digested with protease appeared not to contain heparin/heparan sulfate. More heparin/heparan sulfate was identified in cord than in adult plasma (p ≤ 0.05), but heparinase digestion produced significantly (p ≤ 0.001) reduced concentrations of heparin/heparan sulfate in only 39% of the samples. The lack of heparinase sensitivity in 61% of the protease-digested samples apparently was due to low molecular weight (LMW) heparins, for control heparin fragments of 5 kD that did not extend thrombin times were also less affected by heparinase, but the same LMW heparins were detected by radiometric assay. Despite normal thrombin times in all samples, the amounts of endogenous heparin/heparan sulfate identified in protease-digested samples by radiometric assay were of sufficient concentrations to produce inordinately prolonged thrombin times when compared with the same concentrations of unfractionated heparin. Collectively, these findings suggest the presence of a plasma reservoir of endogenous heparin/heparan sulfates in normal cord and adult plasma. These endogenous heparin/heparan sulfates are bound to plasma proteins, and an as yet undetermined proportion of these bound heparin/heparans are most likely LMW molecules.

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An anticoagulant dermatan sulfate proteoglycan circulates in the pregnant woman and her fetus.

Cited by 78 publications

References 44 publications

Pediatric venous thromboembolism in relation to adults

Pediatric venous thromboembolism in relation to adults

Heparin Cofactor II Modulates the Response to Vascular Injury

Protein-Bound Heparin/Heparan Sulfates in Human Adult and Umbilical Cord Plasma

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