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血栓形成后增加内皮功能 Vikram S. Kashyap, M.D., F.A.C.S. Associate Professor of Surgery Department of Vascular Surgery The Cleveland Clinic. New Horizons in Cardiovascular Treatment (Angiogenesis and other) December 11, 2008. 病 例. 53 岁、女性、右下肢急性疼痛 4 天

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血栓形成后增加内皮功能Vikram S. Kashyap, M.D., F.A.C.S. Associate Professor of Surgery Department of Vascular SurgeryThe Cleveland Clinic

New Horizons in Cardiovascular Treatment

(Angiogenesis and other)

December 11, 2008


病 例

  • 53 岁、女性、右下肢急性疼痛4天

  • 右下肢无波动,股动脉无明显Doppler 信号 (Rutherford 缺血分级 IIA)

  • 既往史—90年代早期行主动脉重建,2002年右髂动脉植入支架

  • 1998年因缺血/感染行左侧髋关节离断术

  • 肝素过敏—本病例使用比伐卢定抗凝


主动脉造影

  • 左肱动脉途径

  • 主动脉造影


  • 使用Angiojet行脉冲式溶栓治疗

20 cm输注导管, tPA at 0.5 mg/hr


每隔12小时行动脉造影, 反复 PMT

10 cm 输注导管, 持续 tPA


本病例技术—24小时检查示血栓消退

  • 血栓溶解后暴露病变

  • 使用7mm球囊行PTA

  • 动脉造影




溶栓治疗的益处

  • 能够显示引起急性闭塞的潜在“病变”

  • 降低再灌注损伤

  • 可选择更多治疗手段

    - 腔内治疗: 血管成形+/- 支架植入

    - 有限的外科手术 (补片成形,动脉内膜切除)

    - 在完善检查后行新的旁路手术 (心功能,静脉检查, 等.)



尽管初见成效,但有时

  • 临床上急性动脉血栓形成仍然是一个棘手的疾病

  • 临床常见血栓切除或溶栓后继发血管痉挛或再发血栓形成

  • 近20%病例发生再发血栓形成 (易于血栓形成内膜表面—考虑可引起血小板聚集形成凝血)

  • 内皮血栓形成效应还没有完全阐明


血栓-内皮相互作用的临床关联

在成功除去左肱动脉内急性栓子后的动脉造影


血管痉挛= 栓子引起的内皮功能异常?

  • 血管痉挛可通过NO供体来缓解

  • 如果有持续血凝块,血管痉挛难以处理

  • 在多个动物模型中,血栓形成可引起内皮功能异常

  • NO水平减低可导致内皮功能异常






VIII因子免疫组化

正 常 血栓形成后



p=0.007

*

p=0.003

*


L edr no
L-精氨酸对EDR和NO的影响

Kashyap et al., JVS 2001



内皮依赖性舒张(EDR)

**

**

**

**

*

在鼠肾下腹主动脉(IRA),血栓形成对EDR的影响。 对照组EDR(无血栓形成IRA n=5) 与实验组EDR比较(血栓形成后IRA n=4). *P<0.05, **P<0.001 by two way ANOVA.


使用特异性精氨酸抑制酶后 EDR

**

**

**

##

##

**

##

#

血栓形成IRA使用特异性精氨酸酶抑制剂对EDR的影响.在血栓形成前以精氨酸酶抑制剂预处理可以恢复EDR



EDR 测量

N >3



血栓怎样引起内皮功能异常 ?机制

  • 造成内皮细胞的丢失-No

  • 清除 NO--Perhaps

  • 降低NO的分泌或弥散-No

  • 通过影响eNOS减低 NO 的产量 --No

  • 通过Y+ 通道影响L-精氨酸运输- No

  • 增加内源性血管收缩剂—No

  • 降低L-精氨酸的可用性—Yes

    • 凝血酶增加精氨酸酶活力


L-精氨酸代谢途径


未来研究方向

  • 体外试验 (内皮细胞)

    • 凝血酶、纤维蛋白暴露于精氨酸酶阻断剂

    • 活化中性粒细胞效应

  • 体外试验 (啮齿动物模型)

    • 在血栓形成的肾下腹主动脉使用精氨酸酶阻断剂

    • 基因敲除鼠模型

  • 人体试验

    • 人动脉标本—内皮细胞功能

    • 使用溶栓治疗与L-精氨酸行RCT研究


结 论

  • 暴露于凝血酶的内皮细胞增加了精氨酸酶的活性

  • NO 产生能力不受影响

  • 局部使用L-精氨酸和精氨酸酶阻断剂可以调整内皮细胞异常功能

  • 目的性增加NO可能是一个有前途的治疗方法



New horizons in cardiovascular treatment angiogenesis and other december 11 2008

Enhancing Endothelial Function After ThrombosisVikram S. Kashyap, M.D., F.A.C.S. Associate Professor of Surgery Department of Vascular SurgeryThe Cleveland Clinic

New Horizons in Cardiovascular Treatment

(Angiogenesis and other)

December 11, 2008


Case

53 y.o. female with acute R leg pain for 4 days.

No R leg pulses, faint femoral Doppler signal (Rutherford Class IIA ischemia)

PMH—Aortic reconstruction in the early 1990s, R iliac stent 2002

Previous L hip disarticulation secondary to ischemia/infection in the 1998

Heparin allergy—bivalirudin (Angiomax) used for this case


Aortogram
Aortogram

L brachial approach

Aortography


20 cm infusion catheter, tPA at 0.5 mg/hr


Lysis check angiogram at 12 hours, repeat PMT

10 cm infusion catheter, Continue tPA


Technique in this case lysis check 24 hours
Technique in this case—lysis check 24 hours

Thrombolysis uncovers the culprit lesion

PTA with a 7 mm balloon

Completion arteriography




Benefits of thrombolytic therapy
Benefits of Thrombolytic Therapy

A “culprit lesion” can be identified—the underlying reason for the acute occlusion

Reperfusion injury may be attenuated

More options are available

- endovascular only: angioplasty+/- stenting

- a limited surgical operation (patch angioplasty, endarterectomy)

- elective placement of a new bypass can be performed after full work-up (cardiac, vein mapping, etc.)



Despite initial success sometimes1
Despite initial success, sometimes…

Acute arterial thrombosis remains a vexing clinical entity

Clinical outcomes following thrombectomy or thrombolysis are occasionally suboptimal secondary to vasospasm or rethrombosis

Rethrombosis occurs in up to 20% of patients (thrombogenic intimal surface—thought to cause platelet dependent clot)

The effects of thrombus on endothelium have not been completely elucidated


Clinical correlation of thrombus endothelial interaction
Clinical correlation of thrombus-endothelial interaction

Digital subtraction angiogram of the R brachial artery after successful removal of an acute embolus.


Vasospasm thrombus induced endothelial dysfunction
Vasospasm = Thrombus-induced Endothelial Dysfunction?

Vasospasm relieved by NO donors

Vasospasm is hard to treat if there is persistent clot

Thrombosis causes endothelial dysfunction in multiple animal models

Depressed Nitric oxide (NO) levels are implicated as the source of the endothelial dysfunction






Factor viii immunohistochemistry
Factor VIII Immunohistochemistry

Normal Post-thrombosis



p=0.007

*

p=0.003

*


Effect of l arginine supplementation on edr and no production
Effect of L-arginine supplementation on EDR and NO Production

Kashyap et al., JVS 2001


Western blot1
Western Blot Production


Endothelial Dependent Relaxation (EDR) Production

**

**

**

**

*

Effect of thrombosis on EDR of rat infrarenal aortic ring segments (IRA). EDR of control (nonthrombosed) rat IRA (n=5) is compared with IRA’s after 1 hr of thrombosis (n=4). *P<0.05, **P<0.001 by two way ANOVA.


EDR after specific arginase inhibition Production

**

**

**

##

##

**

##

#

Effect of specific arginase inhibition on EDR of thrombosed IRA. Pretreatment with arginase inhibitor restores the EDR in thrombosed IRA. n=3 in all the three groups. **P<0.001 BEC vs thrombosed IRA analysis of variance. #P<0.01, ##P<0.001control vs thrombosed IRA by two way ANOVA.


Human studies

Human Studies Production


Edr measurement
EDR measurement Production

N >3


Arginase ii
Arginase II Production


How does thrombus cause endothelial dysfunction mechanistic insights
How does thrombus cause endothelial dysfunction? ProductionMechanistic insights

Causes endothelial cell loss--No

Scavenges NO--Perhaps

Decreases NO secretion or diffusion--No

Decreases NO production by affecting eNOS--No

Affects L-arginine transport via the Y+ channel-- No

Increases endogenous vasoconstrictor—No

Decreases L-arginine availability—Yes

Thrombin increases arginase activity



Future studies
Future Studies Production

In vitro studies (endothelial cells)

Thrombin, fibrin exposure with arginase blockade

Activated neutrophil effects

In vivo studies (rodent models)

Arginase blockade in thrombosed infrarenal arterial segments

Mouse model, knockouts

Human studies

Explanted human arteries—endothelial function

RCT using thrombolysis and L-arginine supplementation


Conclusions
Conclusions Production

Endothelial cells exposed to thrombin have increased arginase enzymatic activity

NO generation capability is unaffected

Local administration of L-Arginine or arginase blockade may ameliorate endothelial dysfunction

Targeted NO augmentation may prove to be an attractive therapeutic alternative


Questions? Production


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