title: Procoagulant and prothrombotic effects of the herbal medicine, Dipsacus asper and its active ingredient, dipsacus saponin C, on human platelets.
abstract: BACKGROUND
  In spite of the growing popularity of herbal medicines and natural food supplements, their effects on cardiovascular homeostasis remain largely unknown, especially regarding pro-thrombotic risks.
  
  
  OBJECTIVE
  In the present study, 21 herbal tea extracts were screened for the procoagulant activities on platelets, an important promoter of thrombosis to examine if herbal medicines or natural products may have prothrombotic risks. We discovered that Dipsacus asper (DA), known to have analgesic and anti-inflammatory effects, potently induced procoagulant activities in platelets. We tried to identify the active ingredient and elucidate the underlying mechanism.
  
  
  RESULTS
  Among 10 major ingredients of DA, dipsacus saponin C (DSC) was identified as a key active ingredient in DA-induced procoagulant activities. DSC-induced procoagulant activities were achieved by the exposure of phosphatidylserine (PS) and PS-bearing microparticle generation that were caused by the alteration in the activities of phospholipid translocases: scramblase and flippase. These events were initiated by increased intracellular calcium and ATP depletion. Notably, DSC induced a series of apoptotic events including the disruption of mitochondrial membrane potential, translocation of Bax and Bak, cytochrome c release and caspase-3 activation. The key roles of apoptotic pathway and caspase activation were demonstrated by the reversal of DSC-induced PS exposure and procoagulant activities with the pretreatment of caspase inhibitors. Interestingly, EGTA reversed DSC-induced procoagulant activities and apoptotic events suggesting that an intracellular calcium increase may play a central role. These results were also confirmed in vivo where platelets of the rats exposed to DSC or DA exhibited PS exposure. Most importantly, DSC or DA administration led to increased thrombus formation.
  
  
  CONCLUSIONS
  These results demonstrate that herbal medicines or natural products such as DA or DSC might have prothrombotic risks through procoagulant activation of platelets.
authors.affiliation: College of Pharmacy, Seoul National University, Seoul, Korea.
authors.forename: J-S
authors.initials: JS
authors.lastname: Song
authors.forename: K-M
authors.initials: KM
authors.lastname: Lim
authors.forename: S
authors.initials: S
authors.lastname: Kang
authors.forename: J-Y
authors.initials: JY
authors.lastname: Noh
authors.forename: K
authors.initials: K
authors.lastname: Kim
authors.forename: O-N
authors.initials: ON
authors.lastname: Bae
authors.forename: J-H
authors.initials: JH
authors.lastname: Chung
mesh_terms: D000255:Adenosine Triphosphate / Q000097:blood; D000293:Adolescent; D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001777:Blood Coagulation / Q000187:drug effects*; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000097:blood; D053148:Caspase 3 / Q000097:blood; D055252:Cell-Derived Microparticles / Q000187:drug effects / Q000378:metabolism; D002614:Chelating Agents / Q000494:pharmacology; D003029:Coagulants / Q000302:isolation & purification / Q000633:toxicity*; D045304:Cytochromes c / Q000097:blood; D049917:Dipsacaceae / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004533:Egtazic Acid / Q000494:pharmacology; D006801:Humans; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000302:isolation & purification / Q000633:toxicity; D010314:Partial Thromboplastin Time; D010718:Phosphatidylserines / Q000097:blood; D049294:Phospholipid Transfer Proteins / Q000097:blood; D028321:Plant Preparations / Q000302:isolation & purification / Q000633:toxicity*; D018517:Plant Roots; D015539:Platelet Activation / Q000187:drug effects; D011517:Prothrombin Time; D051381:Rats; D017207:Rats, Sprague-Dawley; D018570:Risk Assessment; D012307:Risk Factors; D012503:Saponins / Q000302:isolation & purification / Q000633:toxicity*; D013927:Thrombosis / Q000097:blood / Q000139:chemically induced* / Q000473:pathology; D013997:Time Factors; D055815:Young Adult; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000097:blood; D051028:bcl-2-Associated X Protein / Q000097:blood
chemical_list: C494772:BAK1 protein, human; C494826:BAX protein, human; D002614:Chelating Agents; D003029:Coagulants; D010718:Phosphatidylserines; D049294:Phospholipid Transfer Proteins; D028321:Plant Preparations; D012503:Saponins; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; C085394:dipsacus saponin C; D004533:Egtazic Acid; D009828:Oleanolic Acid; D000255:Adenosine Triphosphate; D045304:Cytochromes c; C505407:CASP3 protein, human; D053148:Caspase 3; D002118:Calcium