低分子肝素治疗抗磷脂综合征疗效及对骨代谢的影响的探讨
|
摘要
目的：比较低分子肝素与强的松和阿司匹林治疗APS的疗效及副作用，探讨低分子肝素是否能替代强的松和阿司匹林治疗APS。
方法：将ACA阳性患者80例(已孕40例，未孕40例)随机分为研究组及对照组，每组为40例。研究组予以低分子肝素(克塞)，对照组予以强的松与阿司匹林治疗，观察治疗后两组ACA转阴率，对血液流变学、骨代谢及妊娠结局的影响。
结果：(1)研究组治疗1疗程、2疗程、3疗程ACA转阴数分别为5例、25例、32例，ACA转阴率分别为12.5％、62.5％和80％，对照组ACA转阴数分别为8例、32例、36例，转阴率分别为20％、80％、90％，随治疗时间延长，两组转阴率均增加，各疗程间转阴率差异有统计学意义(p＜0.05)。研究组与对照组治疗1疗程、2疗程、3疗程ACA转阴率，差异均无统计学意义(p＞0.05)。
(2)研究组血浆黏度治疗前、1疗程、2疗程后分别为1.84±0.42、1.49±0.16、1.41±0.13，两两比较，差异均有统计学意义(p＜0.05)；对照组治疗前、1疗程、2疗程后分别为1.87±0.33、1.62±0.30、1.50±0.20，两两比较，差异均有统计学意义(p＜0.05)。研究组治疗1疗程、2疗程后血浆黏度均比对照组下降幅度大，差异均有统计学意义(p＜0.05)。
(3)研究组血钙浓度治疗前、1疗程、2疗程后分别为2.49±0.18mmol／l、2.47±0.27mmol／l、2.50±0.26mmol／l，两两比较，差异均无统计学意义(p＞0.05)；对照组治疗前、1疗程、2疗程后分别为2.51±0.26mmol／l、2.48±0.30mmol／l、2.64±0.17mmol／l，两两比较，治疗前和1疗程与2疗程比较，均有显著差异(p＜0.05)。研究组治疗2疗程后血钙浓度均比对照组上升幅度小，差异有统计学意义(p＜0.05)。
(4)研究组TRAP浓度治疗前、1疗程、2疗程后分别为4.35±0.53u／l、4.60±0.74u／l 4.55±0.56u／l，两两比较，差异均无统计学意义(p＞0.05)；对照组治疗前、1疗程、2疗程后分别为4.28±0.70u／l、5.16±0.59u／l、6.52+0.51u／l，两两比较，差异均有统计学意义(p＜0.05)。研究组治疗1疗程、2疗程后TRAP浓度均比对照组上升幅度小，差异均有统计学意义(p＜0.05)。
(5)治疗后研究组与对照组妊娠成功率为分别50％和70％，两者相比，差异无统计学意义(p＞0.05)。
结论：
1、低分子肝素治疗APS，其ACA转阴率、妊娠结局与强的松和阿司匹林相当。
2、低分子肝素治疗APS降低血浆黏度优于强的松和阿司匹林。
3、低分子肝素治疗APS对骨代谢影响比强的松和阿司匹林小。
4、TRAP检测可作为早期诊断骨质疏松的指标。
Objects: To compare the therapeutic effect of low molecular heparinwith prednisone and aspirin in antiphospholipid syndrome and observethese influence of bone metabolism、hemorheology and pregnancyoutcome during the therapy.
Metheods: A prospective observational study included 40patients(20 pregnancy patients, 20 unpregnancy patients) withanticardiolipin antibody in the study group who received low-molecularheparin. The control group of 40 patients(20 pregnancy patients, 20unpregnancy patients)received prednisone and aspirin. We comparedthese groups according to the pregnancy outcomes、the negative rate ofanticardiolipin antibody(ACA)and the influence of bone metabolism、hemorheology and pregnancy outcome during the therapy, using standardstatistical tests.
Results: 1.The number of people with negative anticardiolipinantibody were 5、25 and 32 in the study group,the Clearance rate ofanticardiolipin antibody after one course of treatment、two courses oftreatment、two courses of treatment in the study group were 12.5%、62.5% and 80% and the number of people with negative anticardiolipinantibody were 8、32 and 36 and the Clearance rate of anticardiolipinantibody after one course of treatment、two courses of treatment、twocourses of treatment in the control group were 20%、80%、90%,with theprolonged treatment the Clearance rate of anticardiolipin antibody raisedup,there was significant difference (p<0.05). There was no significantdifference in the Clearance rate of anticardiolipin antibody after onecourse of treatment、two courses of treatment、two courses of treatmentbetween the study group and control group (p>0.05).
2. The plasma viscosity of study group were 1.84±0.42、1.49±0.16and 1.41±0.13 before the treatment and after one course and two courses of treatment, there was significant difference in them (p<0.05).Theplasma viscosity were 1.87±0.33、1.62±0.30、1.50±0.20 before thetreatment and after one and two courses of in control group, there wassignificant difference in them (p<0.05). The plasma viscosity of studygroup were lower than the control group, there was significantdifference(p<0.05).
3. The concentration of and blood calcium of the study group were2.49±0.18mmol/l、2.47±0.27 mmol/l、2.50±0.26 mmol/l before thetreatment and after one course and two courses of treatment,there was nosignificant difference in them (p>0.05), the concentration of bloodcalcium of the control group were 2.51±0.26 mmol/l、2.48±0.30mmol/l、2.64±0.17mmol/l before the treatment and after one course and twocourses of treatment,there was significant difference between one courseand two courses of treatment (p<0.05),the concentration of blood calciumof the control group before the treatment was different with two coursesof treatment (p<0.05). The concentration of blood calcium of study groupwere lower than the control group after two courses of treatment, therewas significant difference(p<0.05).
4.The concentration of and tartrate-resistand acid phosphatase(TRAP)of the study group were 4.35±0.53u/l、4.60±0.74u/l, 4.55±0.56u/l beforethe treatment and after one course and two courses of treatment,there wasno significant difference in them (p>0.05), the concentration of TRAP ofthe control group were 4.28±0.70u/l、5.16±0.59u/l、6.52±0.51 u/l beforethe treatment and after one course and two courses of treatment,there wassignificant difference in them (p<0.05). The concentration of TRAP ofstudy group was lower than the control group after one course and twocourses of treatment, there was significant difference(p<0.05).
5. The pregnancy outcomes were 50% and 70% and no differencewas noted for pregnancy outcomes between the study group and controlgroup (p>0.05).
Conclusions:
1. There was no significant difference in the Clearance rate ofanticardiolipin antibody and pregnancy outcomes between the the therapy with low-molecular heparin and prednisone and aspirin.
2. The therapy with low-molecular heparin is better thanprednisone and aspirin to cut down plasma viscosity.
3. The influence of low-molecular heparin to bone metabolismwas lower than prednisone and aspirin.
4. Tartrate-resistand acid phosphatasewe should test to diagnoseosteoporosis.
方法：将ACA阳性患者80例(已孕40例，未孕40例)随机分为研究组及对照组，每组为40例。研究组予以低分子肝素(克塞)，对照组予以强的松与阿司匹林治疗，观察治疗后两组ACA转阴率，对血液流变学、骨代谢及妊娠结局的影响。
结果：(1)研究组治疗1疗程、2疗程、3疗程ACA转阴数分别为5例、25例、32例，ACA转阴率分别为12.5％、62.5％和80％，对照组ACA转阴数分别为8例、32例、36例，转阴率分别为20％、80％、90％，随治疗时间延长，两组转阴率均增加，各疗程间转阴率差异有统计学意义(p＜0.05)。研究组与对照组治疗1疗程、2疗程、3疗程ACA转阴率，差异均无统计学意义(p＞0.05)。
(2)研究组血浆黏度治疗前、1疗程、2疗程后分别为1.84±0.42、1.49±0.16、1.41±0.13，两两比较，差异均有统计学意义(p＜0.05)；对照组治疗前、1疗程、2疗程后分别为1.87±0.33、1.62±0.30、1.50±0.20，两两比较，差异均有统计学意义(p＜0.05)。研究组治疗1疗程、2疗程后血浆黏度均比对照组下降幅度大，差异均有统计学意义(p＜0.05)。
(3)研究组血钙浓度治疗前、1疗程、2疗程后分别为2.49±0.18mmol／l、2.47±0.27mmol／l、2.50±0.26mmol／l，两两比较，差异均无统计学意义(p＞0.05)；对照组治疗前、1疗程、2疗程后分别为2.51±0.26mmol／l、2.48±0.30mmol／l、2.64±0.17mmol／l，两两比较，治疗前和1疗程与2疗程比较，均有显著差异(p＜0.05)。研究组治疗2疗程后血钙浓度均比对照组上升幅度小，差异有统计学意义(p＜0.05)。
(4)研究组TRAP浓度治疗前、1疗程、2疗程后分别为4.35±0.53u／l、4.60±0.74u／l 4.55±0.56u／l，两两比较，差异均无统计学意义(p＞0.05)；对照组治疗前、1疗程、2疗程后分别为4.28±0.70u／l、5.16±0.59u／l、6.52+0.51u／l，两两比较，差异均有统计学意义(p＜0.05)。研究组治疗1疗程、2疗程后TRAP浓度均比对照组上升幅度小，差异均有统计学意义(p＜0.05)。
(5)治疗后研究组与对照组妊娠成功率为分别50％和70％，两者相比，差异无统计学意义(p＞0.05)。
结论：
1、低分子肝素治疗APS，其ACA转阴率、妊娠结局与强的松和阿司匹林相当。
2、低分子肝素治疗APS降低血浆黏度优于强的松和阿司匹林。
3、低分子肝素治疗APS对骨代谢影响比强的松和阿司匹林小。
4、TRAP检测可作为早期诊断骨质疏松的指标。
Objects: To compare the therapeutic effect of low molecular heparinwith prednisone and aspirin in antiphospholipid syndrome and observethese influence of bone metabolism、hemorheology and pregnancyoutcome during the therapy.
Metheods: A prospective observational study included 40patients(20 pregnancy patients, 20 unpregnancy patients) withanticardiolipin antibody in the study group who received low-molecularheparin. The control group of 40 patients(20 pregnancy patients, 20unpregnancy patients)received prednisone and aspirin. We comparedthese groups according to the pregnancy outcomes、the negative rate ofanticardiolipin antibody(ACA)and the influence of bone metabolism、hemorheology and pregnancy outcome during the therapy, using standardstatistical tests.
Results: 1.The number of people with negative anticardiolipinantibody were 5、25 and 32 in the study group,the Clearance rate ofanticardiolipin antibody after one course of treatment、two courses oftreatment、two courses of treatment in the study group were 12.5%、62.5% and 80% and the number of people with negative anticardiolipinantibody were 8、32 and 36 and the Clearance rate of anticardiolipinantibody after one course of treatment、two courses of treatment、twocourses of treatment in the control group were 20%、80%、90%,with theprolonged treatment the Clearance rate of anticardiolipin antibody raisedup,there was significant difference (p<0.05). There was no significantdifference in the Clearance rate of anticardiolipin antibody after onecourse of treatment、two courses of treatment、two courses of treatmentbetween the study group and control group (p>0.05).
2. The plasma viscosity of study group were 1.84±0.42、1.49±0.16and 1.41±0.13 before the treatment and after one course and two courses of treatment, there was significant difference in them (p<0.05).Theplasma viscosity were 1.87±0.33、1.62±0.30、1.50±0.20 before thetreatment and after one and two courses of in control group, there wassignificant difference in them (p<0.05). The plasma viscosity of studygroup were lower than the control group, there was significantdifference(p<0.05).
3. The concentration of and blood calcium of the study group were2.49±0.18mmol/l、2.47±0.27 mmol/l、2.50±0.26 mmol/l before thetreatment and after one course and two courses of treatment,there was nosignificant difference in them (p>0.05), the concentration of bloodcalcium of the control group were 2.51±0.26 mmol/l、2.48±0.30mmol/l、2.64±0.17mmol/l before the treatment and after one course and twocourses of treatment,there was significant difference between one courseand two courses of treatment (p<0.05),the concentration of blood calciumof the control group before the treatment was different with two coursesof treatment (p<0.05). The concentration of blood calcium of study groupwere lower than the control group after two courses of treatment, therewas significant difference(p<0.05).
4.The concentration of and tartrate-resistand acid phosphatase(TRAP)of the study group were 4.35±0.53u/l、4.60±0.74u/l, 4.55±0.56u/l beforethe treatment and after one course and two courses of treatment,there wasno significant difference in them (p>0.05), the concentration of TRAP ofthe control group were 4.28±0.70u/l、5.16±0.59u/l、6.52±0.51 u/l beforethe treatment and after one course and two courses of treatment,there wassignificant difference in them (p<0.05). The concentration of TRAP ofstudy group was lower than the control group after one course and twocourses of treatment, there was significant difference(p<0.05).
5. The pregnancy outcomes were 50% and 70% and no differencewas noted for pregnancy outcomes between the study group and controlgroup (p>0.05).
Conclusions:
1. There was no significant difference in the Clearance rate ofanticardiolipin antibody and pregnancy outcomes between the the therapy with low-molecular heparin and prednisone and aspirin.
2. The therapy with low-molecular heparin is better thanprednisone and aspirin to cut down plasma viscosity.
3. The influence of low-molecular heparin to bone metabolismwas lower than prednisone and aspirin.
4. Tartrate-resistand acid phosphatasewe should test to diagnoseosteoporosis.
引文
[1] Rai RS, Clifford K, Cohen H, et al. High prospective fetal loss rate in unt reated pregnancies of women with recurrent miscarriage and antiphospholipid antibodies[J]. Hum Reprod, 1995, 10: 3301-3304.
[2] Wechsler B, Huong Du LT, Piette JC. Is there a role for antithrombotic therapy in the prevention of pregnancy loss? [J]Haemostasis. 1999 Dec; 29 Suppl S1: 112-20
[3] Dobado-Berrios PM, Lopez-Pedrera C, Velasco F, et al. Increased levels of tissue factor mRNA in mononuclear blood cells of patients with primary antiphospholipid syndrome[J]. Thromb Haemost 1999; 82: 1578—82.
[4] De Bandt M, Palazzo E, Belmatoug N. Outcome of pregnancies in lupus: experience at one centerAnn Med Interne (Pads) [J]. 2000 Mar; 151 (2): 87-92
[5] Luis H. Chris L. Luis J. Prevention of anticardiolipin antibody-related pregnancy losses with prednisone and aspirin[J]. The American Journal of Medicine, Volume 93, Issue 4, October 1992, Pages 403-411.
[6] Harger JH, Laifer SA, Bontempo FA. Low-dose aspirin and prednisone treatment of pregnancy loss caused by lupus anticoagulants[J]. J Perinatol. 1995 Nov-Dec; 15(6): 463-9
[7] Fatquharson RG, Quenby S, GreavesM. Antiphospholid syndrome in pregnancy: a controlled treatment trial [J]. Journal of Obstetrics and Gynecology, 2001, 21 (Supplement): 22.
[8] Triolo G, Ferrante A, Ciccia F, et al. Randomized study of subcutaneous low molecular weight heparin plus aspirin versus intravenous immunoglobulin in the treatment of recurrent fetal loss associated with antiphospholipid antibodies[J]. Arthritis and Rheumatism 2003; 48(3): 728—31.
[9] Sipak-Szmigiel O, Ronin-Walknowska E, Miklaszwicz A, et al. Application of intravenous immunoglobulin therapy (IVIG) in pregnant patients with recurrent spontaneous abortions 2003 May; 74(5): 350-5..
[10] Harris EN, Pierangeli SS. Utilization of intravenous immunoglobulin therapy to treat recurrent pregnancy loss in the antiphospholipid syndrome[J]. Scand J Rheumatol Suppl. 1998; 107: 97-102..
[11] Jeremic K, Pervulov M, Gojnic Met al. Comparison of two therapeutic protocols in patients with antiphospholipid antibodies and recurrent miscarriages[J]. Vojnosanit Pregl. 2005Jun; 62(6): 435-9.
[12] Farquharson RG, Quenby S, Greaves M. Antiphospholipid syndrome in pregnancy: a randomized, controlled trial of treatment[J]. Obstetrics and Gynecology 2002; 100(3): 408—3.
[13] Triolo G, Ferrante A, Ciccia F, et al. Randomized study of subcutaneous low molecular weight heparin plus aspirin versus intravenous immunoglobulin in the treatment of recurrent fetal loss associated with antiphospholipid antibodies[J]. Arthritis and Rheumatism 2003; 48(3): 728—31.
[14] Chamley LW. Antiphospholipid antibodies: biological basis and prospects for treatment [J]. J Reprod Immunol, 2002, 57 (1): 185-202.
[15] 谈蕴珏，林其德，赵爱民．复发性流产与抗心磷脂抗体关系探讨[J]．中国生埴免疫学杂志，1999，12(9)：545-547．
[16] Gautam N. Allahbadial S, Swati G. Low Molecular Weight Heparin in Immunological Recurrent Abortion-The Incredible Cure. Journal of Assisted Reproduction and Genetics[J], February 2003 Vol. 20, No. 2: 82-90.
[17] Lash G. E., Warren A. Y., Underwood S., et al. Vascular endothelial growth factor is a chemoattractant for trophoblast cells[J]. Placenta 2003. 24, 549-556..
[18] Gharavi AE, Pierangeli SS, Levy RA, et al. Mechanisms of pregnancy loss in antiphospholipid syndrome[J]. Clin Obstet Gynecol, 2001, 44: 11-19..
[19] Van Horn J. T., Craven C, Ward K. et al. Histologic features of placentas and abortion specimens from women with antiphospholipid and antiphospholipid-like syndromes[J]. Placenta2004. 25, 642-648.
[20] Girardi G., Berman J., Redecha P. et al., Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome.[J]Clin. Invest. 2003(112) 1644-1654.
[21]. Hamatani, T., Daikoku, T., Wang, H. et al. Global gene expression analysis identifies molecular pathways distinguishing blastocyst dormancy and activation[J]. Proc. Natl. Acad. Sci. USA 2004.101, 10326-10331.
[22] Fiedler, K., Wurfel, W. Effectivity of heparin in assisted reproduction. [J]Eur. J. Med. Res. 2004.(9), 207-214..
[23] Stavreus-Evers A, Aghajanova L, Brismar H, etal. Co-existence of heparin-binding epidermal growth factor-like growth factors and pinopodes in human endometrium at the time of implantantion[J]Mol Hum Reprod, 2002, 8(8): 765-769.
[24] Gonzalez-Timon B, Francis J, Cloke N et al.. Heparin prevents programmed cell death in human trophoblast. Mol Hum Reprod[J]. 2006 Mar 23.
[25] Leach, R. E., Kilburn, B., Wang, J., Liu, Z., Romero, R., Armant, D. R., 2004. Heparin-binding EGF-like growth factor regulates human extravillous cytotrophoblast development during conversion to the invasive phenotype[J]. Dev. Biol. 266, 223-237..
[26] Leach, R. E., Kilburn, B., Wang, J., Liu, Z., Romero, R., Armant, D. R., 2004. Heparin-binding EGF-like growth factor regulates human extravillous cytotrophoblast development during conversion to the invasive phenotype[J]. Dev. Biol. 266, 223-237.
[27] Meroni PL, DI Simone N, Testoni C, D'Asta M, Acaia B, Caruso A. Antiphospholipid antibodies as cause of pregnancy loss[J]. Lupus. 2004; 13(9): 649-52.
[28] Ensom MH, Stephenson MD. Pharmacokinetics of low molecular weight heparin and unfractionated heparin in pregnancy[J]. J Soc Gynecol Investig. 2004 Sep; 11 (6): 377-383.
[29] Bats AS, Lejeune V, Cynober E, et al. Antiphospholipid syndrome and secondor third-trimester fetal death: follow-up in the next pregnancy. [J] Eur J Obstet Gynecol Reprod Biol. 2004 Jun 15; 114(2): 125-9.
[30] 丰盛梅，金慰芳，高建军．．破骨细胞RANK激活后的信号通路[J]．中国骨质疏松杂志，2004，10(4)：507-509．
[31] 甘洁民，朱汉民．抗酒石酸酸性磷酸酶测定及应用[J]．上海医学检验杂志，1997；12(1)：31．
[32] 陈航，高燕，王梅．糖皮质激素对骨密度及骨折发生的影响[J]．中国综合临床2006，22(12)：1149-1151．
[33] Folwarczna J, Janiec W, Gawor M. Effects of enoxaparin on histomorphometric parameters of bones in rats[J]. Pol J Pharmacol. 2004 Jul-Aug; 56(4): 451-7.
[34] Handschin AE, Trentz OA, Hoerstrup SP. Effect of low molecular weight heparin (dalteparin) and fondaparinux (Arixtra) on human osteoblasts in vitro. [J] Br J Surg.2005 Feb; 92(2): 177-83.
[35] Agard C, Barrier JH. Complicated Horton's syndrome: therapeutic modalities[J]. Presse Med. 2004 Jan 24; 33(1): 51-9.
[36] 孟迅吾．全方位地关注原发性骨质疏松症的研究[J]中华内分泌代谢杂志，2000，4(16)：201-202．
[1] Akanli LF, Trasi SS, Thuraisamy K, et al. Neonatal middle cerebral artery infarction; association with elevated maternal anticardiolipin antibodies[J]. Am J Perinatol 1998; 15: 399—402.
[2] Pavan L, Tsatsaris V, Hermouet A, et al. Oxidized low-density lipoproteins inhibit trophoblastic cell invasion[J]. J Clin Endocrinol Metab 2004; 89: 1969—72.
[3] Del Papa N, Guidali L, Sala A, et al. Endothelial cells as target for antiphospholipid antibodies. Human polyclonal and monoclonal anti-h2glycoprotein 1 antibodies react in vitro with endothelial cells through adherent h2glycoprotein 1 and induce endothelial activation[J]. Arthritis Rheum 1997; 40: 551—61.
[4] Blank M, Cohen J, Toder V, et al. Induction of antiphospholipiod syndrome in naive mice with mouse lupus monoclonal and human polyclonal anti-cardiolipin antibodies[J]. Proc Natl Acad Sci USA 1991; 88: 3069-73.
[5] di Simone N, Meroni PL, Del Papa N, et al. Antiphospholipid antibodies affect trophoblast gonadotropin secretion and invasiveness by binding directly and through adhered beta2-glycoprotein I[J]. Arthritis Rheum 2000; 43: 140—50.
[6] Giradi G, Berman J, Redecha P, et al. Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome[J]. J Clin Invest 2003; 112: 1644—54.
[7] Del Papa N, Guidali L, Spatola L, Bonara P, Borghi MO, Tincani A, et al. Relationship between anti-phospholipid and anti-EC antibodies; h2glycoprotein 1 mediates the antibody binding to endothelial membranes and induces the expression of adhesion molecules. Clin Exp Rheumatol 1995; 13:179—85.
[8] Horkko S, Miller E, Dudl E, et al. Antiphospholipid antibodies are directed against epitopes of oxidized phospholipids. Recognition of cardiolipin by monoclonal antibodies to epitopes of oxidized low density lipoprotein[J]. J Clin Invest 1996; 98: 815—825.
[9] Dobado-Berrios PM, Lopez-Pedrera C, Velasco F, et al. Increased levels of tissue factor mRNA in mononuclear blood cells of patients with primary antiphospholipid syndrome[J]. Thromb Haemost 1999; 82:1578—82.
[10] Meroni PL, DI Simone N, Testoni C, et al. Antiphospholipid antibodies as cause of pregnancy loss[J]. Lupus. 2004; 13(9): 649-52.
[11] Go rsk i A, W asik M, Nowaczyk M, et al. Immunomodulating activity of heparin. FA SEB J, 1991; 5: 91.
[12] Kupferminc IJ, Fait G, IanyA, et al. Low-molecular-weight heparin for the prevention of obstetric comp lications in women with thrombophilias [J]. Hypertens Pregnancy, 2001, 20: 35-44.
[13] 闰凤亭，李大金，孙晓漠．环孢素A对正常早孕期细胞滋养细胞体外生长的调节作用[J]．中华妇产科杂志2002，37(2)：74-76．
[14] Konova E, Ivanova I, Petrova P, et al. Effect of intravenous gamma-globulin therapy on lymphocyte population in pregnant women with antiphospholipid antibodies[J]. Akush Ginekol (Sofiia). 2004; 43(2): 3-10.
[15] Jeremic K, Pervulov M, Gojnic M, et al. Comparison of two therapeutic protocols in patients with antiphospholipid antibodies and recurrent miscarriages. Vojnosanit Pregl[J]. 2005 Jun; 62(6): 435-9.
[16] Walenga JM, Bick RL. Heparin-induced thrombocytopenia, paradoxical thromboembolism, and other side effects of heparin therapy[J]. Med Clin North Am, 1998, 82, 635-658.
[17] Walton KJ, Duncan JM, Deschamps P, et al. Heparin acts synergistically with interleukin-11 to induce STAT3 activation and in vitro osteoclast formation[J]. Blood, 2002, 100, 2530-2536.
[18] Takahashi N, Udagawa N, Tanaka S, Suda T: Generating murine osteoclasts from bone marrow. In: Methods in Molecular Medicine. Ed. Helfrich MH, Ralston SH, Vol. 80, Bone Research Protocols, Humana Press, Totowa, NJ, 2003, 129-144.
[19] Walton KJ, Duncan JM, Deschamps P, et al. Heparin acts synergistically with interleukin-11 to induce STAT3 activation and in vitro osteoclast formation[J]. Blood, 2002, 100, 2530-2536.
[20] Mutoh S, Takeshita N, Yoshino T, et al. Characterization of heparin-induced osteopenia in rats[J]. Endocrinology, 1993, 133, 2743-2748.
[21] Folwarczna J, Janiec W, Barej M, et al. Effects of nadroparin on bone histomorphometric parameters in rats[J]. Pol J Pharmacol, 2004, 56, 337-343.
[22] Laurent P, Dussarat GV, Bonal J, et al. Low molecular weight hepadns: a guide to their optimum use in pregnancy[J]. Drugs, 2002, 62, 463-477.
[23] Erduran E, Tekelioglu Y, Gedik Y, et al. Apoptotic effects of heparin on lymphoblasts, neutrophils, and mononuclear cells: results of a preliminary in vitro study[J]. Am J Hematol, 1999, 61, 90-93.
[24] Karti SS, Ovali E, Ozgur O, et al. Induction of apoptosis and inhibition of growth of human hepatoma HepG2 cells by heparin[J]. Hepatogastroenterology, 2003, 50, 1864-1866.
[25] Shaughnessy SG, Young E, Deschamps P, et al. The effects of low molecular weight and standard heparin oncalcium loss from fetal rat calvaria[J]. Blood, 1995, 86, 1368-1373.
[26] Muir JM, Andrew M, Hirsh J, et al. Histomorphometric analysis of the effects of standard heparin on trabecular bone in vivo[J]. Blood, 1996, 88, 1314-1320.
[27] Barbour LA, Kick SD, Steiner JF, et al.. A prospective study of heparin-induced osteoporosis in pregnancy using bone densitometry[J]. Am J Obstet Gynecol, 1994, 170, 862-869.
[28] Nishiyama M, Itoh F, Ujiie A. Low-molecular-weightheparin (dalteparin) demonstrated a weaker effect on rat bone metabolism compared with heparin[J]. Jpn J Pharmacol, 1997, 74, 59-68.
[29] Mutoh S, Takeshita N, Yoshino T, et al. Characterization of heparin-induced osteopenia in rats. Endocrinology[J], 1993, 133, 2743-2748.
[30] Muir JM, Andrew M, Hirsh J, et al. Histomorphometric analysis of the effects of standard heparin on trabecular bone in vivo[J]. Blood, 1996, 88, 1314-1320.
[31] Muir JM, Hirsh J, Weitz JI, et al. A histomorphometric comparison of the effects of heparin and low-molecular-weight heparin on cancellous bone in rats[J]. Blood, 1997, 89, 3236-3242.
[32] Murray W J, Lindo VS, Kakkar VV, Melissari E: Longterm administration of heparin and heparin fractions and osteoporosis in experimental animals. Blood Coagul Fibrinolysis, 1995, 6, 113-118.
[33] Bhandari M, Hirsh J, Weitz JI, et al. The effects of standard and low molecular weight heparin on bone nodule formation in vitro[J]. Thromb Haemost, 1998, 80, 413-417..
[34] Eriksen EF,. K Brixen, P Charles. New markers of bone metabolism: clinic use in metabolic bone disease[J]. Eur J Endocrinol, 1995; 132: 251-263.
[35] Gamero P, Delmas PD. Measurement of biochemical markers: methods and limitations. Principles of bone biology[J], 1996, 1277-1291.
[36]. Yaziji H, Jankila AJ, Lear SC, et al. Immunohistochemical detection of tartrate-resissues[J]. AmJ Clin Patho1, 1995, 104: 397-402.
[37] Nakasato YR, Janckila AJ, Halleen JM, et al. Clinical significance of immunoassays for type 5 tartrate2resistant acid phosphatase[J]. Clin Chem, 1999, 445: 2150-2157.
[38] Hallen JM, Alatalo SL, Ivaska KK, et al. Serum tartrate-resistant acid phosphatase 5b is a useful marker for monitoring alendronate therapy. J Bone Miner Res, 2001, 16 (suppl): S534.
[39] Riss B J, Hansen A M, Jensen K, et al. Low bone mass and fast rate of boneloss at menopause: Equal risk factors for future fracture. A 15-years follow-up study[J]. Bone, 1996, 19: 9-17.
[2] Wechsler B, Huong Du LT, Piette JC. Is there a role for antithrombotic therapy in the prevention of pregnancy loss? [J]Haemostasis. 1999 Dec; 29 Suppl S1: 112-20
[3] Dobado-Berrios PM, Lopez-Pedrera C, Velasco F, et al. Increased levels of tissue factor mRNA in mononuclear blood cells of patients with primary antiphospholipid syndrome[J]. Thromb Haemost 1999; 82: 1578—82.
[4] De Bandt M, Palazzo E, Belmatoug N. Outcome of pregnancies in lupus: experience at one centerAnn Med Interne (Pads) [J]. 2000 Mar; 151 (2): 87-92
[5] Luis H. Chris L. Luis J. Prevention of anticardiolipin antibody-related pregnancy losses with prednisone and aspirin[J]. The American Journal of Medicine, Volume 93, Issue 4, October 1992, Pages 403-411.
[6] Harger JH, Laifer SA, Bontempo FA. Low-dose aspirin and prednisone treatment of pregnancy loss caused by lupus anticoagulants[J]. J Perinatol. 1995 Nov-Dec; 15(6): 463-9
[7] Fatquharson RG, Quenby S, GreavesM. Antiphospholid syndrome in pregnancy: a controlled treatment trial [J]. Journal of Obstetrics and Gynecology, 2001, 21 (Supplement): 22.
[8] Triolo G, Ferrante A, Ciccia F, et al. Randomized study of subcutaneous low molecular weight heparin plus aspirin versus intravenous immunoglobulin in the treatment of recurrent fetal loss associated with antiphospholipid antibodies[J]. Arthritis and Rheumatism 2003; 48(3): 728—31.
[9] Sipak-Szmigiel O, Ronin-Walknowska E, Miklaszwicz A, et al. Application of intravenous immunoglobulin therapy (IVIG) in pregnant patients with recurrent spontaneous abortions 2003 May; 74(5): 350-5..
[10] Harris EN, Pierangeli SS. Utilization of intravenous immunoglobulin therapy to treat recurrent pregnancy loss in the antiphospholipid syndrome[J]. Scand J Rheumatol Suppl. 1998; 107: 97-102..
[11] Jeremic K, Pervulov M, Gojnic Met al. Comparison of two therapeutic protocols in patients with antiphospholipid antibodies and recurrent miscarriages[J]. Vojnosanit Pregl. 2005Jun; 62(6): 435-9.
[12] Farquharson RG, Quenby S, Greaves M. Antiphospholipid syndrome in pregnancy: a randomized, controlled trial of treatment[J]. Obstetrics and Gynecology 2002; 100(3): 408—3.
[13] Triolo G, Ferrante A, Ciccia F, et al. Randomized study of subcutaneous low molecular weight heparin plus aspirin versus intravenous immunoglobulin in the treatment of recurrent fetal loss associated with antiphospholipid antibodies[J]. Arthritis and Rheumatism 2003; 48(3): 728—31.
[14] Chamley LW. Antiphospholipid antibodies: biological basis and prospects for treatment [J]. J Reprod Immunol, 2002, 57 (1): 185-202.
[15] 谈蕴珏，林其德，赵爱民．复发性流产与抗心磷脂抗体关系探讨[J]．中国生埴免疫学杂志，1999，12(9)：545-547．
[16] Gautam N. Allahbadial S, Swati G. Low Molecular Weight Heparin in Immunological Recurrent Abortion-The Incredible Cure. Journal of Assisted Reproduction and Genetics[J], February 2003 Vol. 20, No. 2: 82-90.
[17] Lash G. E., Warren A. Y., Underwood S., et al. Vascular endothelial growth factor is a chemoattractant for trophoblast cells[J]. Placenta 2003. 24, 549-556..
[18] Gharavi AE, Pierangeli SS, Levy RA, et al. Mechanisms of pregnancy loss in antiphospholipid syndrome[J]. Clin Obstet Gynecol, 2001, 44: 11-19..
[19] Van Horn J. T., Craven C, Ward K. et al. Histologic features of placentas and abortion specimens from women with antiphospholipid and antiphospholipid-like syndromes[J]. Placenta2004. 25, 642-648.
[20] Girardi G., Berman J., Redecha P. et al., Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome.[J]Clin. Invest. 2003(112) 1644-1654.
[21]. Hamatani, T., Daikoku, T., Wang, H. et al. Global gene expression analysis identifies molecular pathways distinguishing blastocyst dormancy and activation[J]. Proc. Natl. Acad. Sci. USA 2004.101, 10326-10331.
[22] Fiedler, K., Wurfel, W. Effectivity of heparin in assisted reproduction. [J]Eur. J. Med. Res. 2004.(9), 207-214..
[23] Stavreus-Evers A, Aghajanova L, Brismar H, etal. Co-existence of heparin-binding epidermal growth factor-like growth factors and pinopodes in human endometrium at the time of implantantion[J]Mol Hum Reprod, 2002, 8(8): 765-769.
[24] Gonzalez-Timon B, Francis J, Cloke N et al.. Heparin prevents programmed cell death in human trophoblast. Mol Hum Reprod[J]. 2006 Mar 23.
[25] Leach, R. E., Kilburn, B., Wang, J., Liu, Z., Romero, R., Armant, D. R., 2004. Heparin-binding EGF-like growth factor regulates human extravillous cytotrophoblast development during conversion to the invasive phenotype[J]. Dev. Biol. 266, 223-237..
[26] Leach, R. E., Kilburn, B., Wang, J., Liu, Z., Romero, R., Armant, D. R., 2004. Heparin-binding EGF-like growth factor regulates human extravillous cytotrophoblast development during conversion to the invasive phenotype[J]. Dev. Biol. 266, 223-237.
[27] Meroni PL, DI Simone N, Testoni C, D'Asta M, Acaia B, Caruso A. Antiphospholipid antibodies as cause of pregnancy loss[J]. Lupus. 2004; 13(9): 649-52.
[28] Ensom MH, Stephenson MD. Pharmacokinetics of low molecular weight heparin and unfractionated heparin in pregnancy[J]. J Soc Gynecol Investig. 2004 Sep; 11 (6): 377-383.
[29] Bats AS, Lejeune V, Cynober E, et al. Antiphospholipid syndrome and secondor third-trimester fetal death: follow-up in the next pregnancy. [J] Eur J Obstet Gynecol Reprod Biol. 2004 Jun 15; 114(2): 125-9.
[30] 丰盛梅，金慰芳，高建军．．破骨细胞RANK激活后的信号通路[J]．中国骨质疏松杂志，2004，10(4)：507-509．
[31] 甘洁民，朱汉民．抗酒石酸酸性磷酸酶测定及应用[J]．上海医学检验杂志，1997；12(1)：31．
[32] 陈航，高燕，王梅．糖皮质激素对骨密度及骨折发生的影响[J]．中国综合临床2006，22(12)：1149-1151．
[33] Folwarczna J, Janiec W, Gawor M. Effects of enoxaparin on histomorphometric parameters of bones in rats[J]. Pol J Pharmacol. 2004 Jul-Aug; 56(4): 451-7.
[34] Handschin AE, Trentz OA, Hoerstrup SP. Effect of low molecular weight heparin (dalteparin) and fondaparinux (Arixtra) on human osteoblasts in vitro. [J] Br J Surg.2005 Feb; 92(2): 177-83.
[35] Agard C, Barrier JH. Complicated Horton's syndrome: therapeutic modalities[J]. Presse Med. 2004 Jan 24; 33(1): 51-9.
[36] 孟迅吾．全方位地关注原发性骨质疏松症的研究[J]中华内分泌代谢杂志，2000，4(16)：201-202．
[1] Akanli LF, Trasi SS, Thuraisamy K, et al. Neonatal middle cerebral artery infarction; association with elevated maternal anticardiolipin antibodies[J]. Am J Perinatol 1998; 15: 399—402.
[2] Pavan L, Tsatsaris V, Hermouet A, et al. Oxidized low-density lipoproteins inhibit trophoblastic cell invasion[J]. J Clin Endocrinol Metab 2004; 89: 1969—72.
[3] Del Papa N, Guidali L, Sala A, et al. Endothelial cells as target for antiphospholipid antibodies. Human polyclonal and monoclonal anti-h2glycoprotein 1 antibodies react in vitro with endothelial cells through adherent h2glycoprotein 1 and induce endothelial activation[J]. Arthritis Rheum 1997; 40: 551—61.
[4] Blank M, Cohen J, Toder V, et al. Induction of antiphospholipiod syndrome in naive mice with mouse lupus monoclonal and human polyclonal anti-cardiolipin antibodies[J]. Proc Natl Acad Sci USA 1991; 88: 3069-73.
[5] di Simone N, Meroni PL, Del Papa N, et al. Antiphospholipid antibodies affect trophoblast gonadotropin secretion and invasiveness by binding directly and through adhered beta2-glycoprotein I[J]. Arthritis Rheum 2000; 43: 140—50.
[6] Giradi G, Berman J, Redecha P, et al. Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome[J]. J Clin Invest 2003; 112: 1644—54.
[7] Del Papa N, Guidali L, Spatola L, Bonara P, Borghi MO, Tincani A, et al. Relationship between anti-phospholipid and anti-EC antibodies; h2glycoprotein 1 mediates the antibody binding to endothelial membranes and induces the expression of adhesion molecules. Clin Exp Rheumatol 1995; 13:179—85.
[8] Horkko S, Miller E, Dudl E, et al. Antiphospholipid antibodies are directed against epitopes of oxidized phospholipids. Recognition of cardiolipin by monoclonal antibodies to epitopes of oxidized low density lipoprotein[J]. J Clin Invest 1996; 98: 815—825.
[9] Dobado-Berrios PM, Lopez-Pedrera C, Velasco F, et al. Increased levels of tissue factor mRNA in mononuclear blood cells of patients with primary antiphospholipid syndrome[J]. Thromb Haemost 1999; 82:1578—82.
[10] Meroni PL, DI Simone N, Testoni C, et al. Antiphospholipid antibodies as cause of pregnancy loss[J]. Lupus. 2004; 13(9): 649-52.
[11] Go rsk i A, W asik M, Nowaczyk M, et al. Immunomodulating activity of heparin. FA SEB J, 1991; 5: 91.
[12] Kupferminc IJ, Fait G, IanyA, et al. Low-molecular-weight heparin for the prevention of obstetric comp lications in women with thrombophilias [J]. Hypertens Pregnancy, 2001, 20: 35-44.
[13] 闰凤亭，李大金，孙晓漠．环孢素A对正常早孕期细胞滋养细胞体外生长的调节作用[J]．中华妇产科杂志2002，37(2)：74-76．
[14] Konova E, Ivanova I, Petrova P, et al. Effect of intravenous gamma-globulin therapy on lymphocyte population in pregnant women with antiphospholipid antibodies[J]. Akush Ginekol (Sofiia). 2004; 43(2): 3-10.
[15] Jeremic K, Pervulov M, Gojnic M, et al. Comparison of two therapeutic protocols in patients with antiphospholipid antibodies and recurrent miscarriages. Vojnosanit Pregl[J]. 2005 Jun; 62(6): 435-9.
[16] Walenga JM, Bick RL. Heparin-induced thrombocytopenia, paradoxical thromboembolism, and other side effects of heparin therapy[J]. Med Clin North Am, 1998, 82, 635-658.
[17] Walton KJ, Duncan JM, Deschamps P, et al. Heparin acts synergistically with interleukin-11 to induce STAT3 activation and in vitro osteoclast formation[J]. Blood, 2002, 100, 2530-2536.
[18] Takahashi N, Udagawa N, Tanaka S, Suda T: Generating murine osteoclasts from bone marrow. In: Methods in Molecular Medicine. Ed. Helfrich MH, Ralston SH, Vol. 80, Bone Research Protocols, Humana Press, Totowa, NJ, 2003, 129-144.
[19] Walton KJ, Duncan JM, Deschamps P, et al. Heparin acts synergistically with interleukin-11 to induce STAT3 activation and in vitro osteoclast formation[J]. Blood, 2002, 100, 2530-2536.
[20] Mutoh S, Takeshita N, Yoshino T, et al. Characterization of heparin-induced osteopenia in rats[J]. Endocrinology, 1993, 133, 2743-2748.
[21] Folwarczna J, Janiec W, Barej M, et al. Effects of nadroparin on bone histomorphometric parameters in rats[J]. Pol J Pharmacol, 2004, 56, 337-343.
[22] Laurent P, Dussarat GV, Bonal J, et al. Low molecular weight hepadns: a guide to their optimum use in pregnancy[J]. Drugs, 2002, 62, 463-477.
[23] Erduran E, Tekelioglu Y, Gedik Y, et al. Apoptotic effects of heparin on lymphoblasts, neutrophils, and mononuclear cells: results of a preliminary in vitro study[J]. Am J Hematol, 1999, 61, 90-93.
[24] Karti SS, Ovali E, Ozgur O, et al. Induction of apoptosis and inhibition of growth of human hepatoma HepG2 cells by heparin[J]. Hepatogastroenterology, 2003, 50, 1864-1866.
[25] Shaughnessy SG, Young E, Deschamps P, et al. The effects of low molecular weight and standard heparin oncalcium loss from fetal rat calvaria[J]. Blood, 1995, 86, 1368-1373.
[26] Muir JM, Andrew M, Hirsh J, et al. Histomorphometric analysis of the effects of standard heparin on trabecular bone in vivo[J]. Blood, 1996, 88, 1314-1320.
[27] Barbour LA, Kick SD, Steiner JF, et al.. A prospective study of heparin-induced osteoporosis in pregnancy using bone densitometry[J]. Am J Obstet Gynecol, 1994, 170, 862-869.
[28] Nishiyama M, Itoh F, Ujiie A. Low-molecular-weightheparin (dalteparin) demonstrated a weaker effect on rat bone metabolism compared with heparin[J]. Jpn J Pharmacol, 1997, 74, 59-68.
[29] Mutoh S, Takeshita N, Yoshino T, et al. Characterization of heparin-induced osteopenia in rats. Endocrinology[J], 1993, 133, 2743-2748.
[30] Muir JM, Andrew M, Hirsh J, et al. Histomorphometric analysis of the effects of standard heparin on trabecular bone in vivo[J]. Blood, 1996, 88, 1314-1320.
[31] Muir JM, Hirsh J, Weitz JI, et al. A histomorphometric comparison of the effects of heparin and low-molecular-weight heparin on cancellous bone in rats[J]. Blood, 1997, 89, 3236-3242.
[32] Murray W J, Lindo VS, Kakkar VV, Melissari E: Longterm administration of heparin and heparin fractions and osteoporosis in experimental animals. Blood Coagul Fibrinolysis, 1995, 6, 113-118.
[33] Bhandari M, Hirsh J, Weitz JI, et al. The effects of standard and low molecular weight heparin on bone nodule formation in vitro[J]. Thromb Haemost, 1998, 80, 413-417..
[34] Eriksen EF,. K Brixen, P Charles. New markers of bone metabolism: clinic use in metabolic bone disease[J]. Eur J Endocrinol, 1995; 132: 251-263.
[35] Gamero P, Delmas PD. Measurement of biochemical markers: methods and limitations. Principles of bone biology[J], 1996, 1277-1291.
[36]. Yaziji H, Jankila AJ, Lear SC, et al. Immunohistochemical detection of tartrate-resissues[J]. AmJ Clin Patho1, 1995, 104: 397-402.
[37] Nakasato YR, Janckila AJ, Halleen JM, et al. Clinical significance of immunoassays for type 5 tartrate2resistant acid phosphatase[J]. Clin Chem, 1999, 445: 2150-2157.
[38] Hallen JM, Alatalo SL, Ivaska KK, et al. Serum tartrate-resistant acid phosphatase 5b is a useful marker for monitoring alendronate therapy. J Bone Miner Res, 2001, 16 (suppl): S534.
[39] Riss B J, Hansen A M, Jensen K, et al. Low bone mass and fast rate of boneloss at menopause: Equal risk factors for future fracture. A 15-years follow-up study[J]. Bone, 1996, 19: 9-17.