From bloodjournal.hematologylibrary.org by guest on September 20, 2012. For personal use only.

1949 4: 1290-1297

THE CHAIN REACTION OF THE BLOOD CLOTTING MECHANISM IN RELATION TO THE THEORY OF HEMOSTASIS AND THROMBOSIS
J. H. MILSTONE

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more product may reactions rapidly of is and products the a lag thereafter accelerates reaction period. to include mechanisms a simple reactions. Glasstone 1946. (Glasstone. by serve. which P. M. creasingly combinations when with faster. layer to to by the layer. clot. Thereby and and next. was originally It over and introduced has been When. blood This was would tested flowed probably with through larger the work cuts.From bloodjournal.. the lag action BIOCHEMICAL MECHANISM Whatever of blood. School The of Medicine. reaction. on hemorrhage the cut of surface. accretion. of to the of connection applied thereaction the series velocity photochemical of D. reaction’S various i. of the work concept which by Co. might of freshly as appear. break. difficulty the juice However. slow the goes but later in- But. BLOOD CLOTTING AND MECHANISM THROMBOSIS IN RELATION HEMOSTASIS H.it might yet promptly be arranged congeal when mixed with punctures. a chain result Hence. chain nonstationary. New Brown in Haven. The as one tissue which.hematologylibrary.: the possible a special Textbook is said Here. chlorine. other as terms besides nonstationary ‘cJi chain “autocatalytic reaction. S. Other would resemble conjecture. plug arrived begin depicted at some by function chemical Tocantins. one start the formed with are period. addition.org by guest on September 20. type and York. process only a hemostatic it a chain would be to exert plug incite reaction the effect might neighboring from on would one the be introduced.2 occur in Once during was the the transmitted process coagulation through had process a series From This sity * samples of Pathology. Fund of the Yale Univer- aided of chain Memorial with to Chemistry. would and be deposited hinder Therefore. this cut As the tissue. mechanism. Then. THE CHAIN REACTION TO THE OF THEORY ByJ. in was a chain which described Yale from the University James reaction the clotting by Gratia School Hudson does 1911. well an a for unexpected small mechanism coagulated film tissue clotted. . respect.* the or reaction that chain as enzymatic. teleologic reaction be they Ordinary stoichiometric down. be It is this autocatalytic the are present regarded discussion. group I 2. apt to but proceed ensures explosively. this difficulty was needed clotting. functions can the we be natural have imagined. could propagated its which layer initial mechanism grow in might this Thus. THE THE OF MILSTONE. 2012. by a grant reaction and themselves of Medicine. For personal use only. Conn.D. over then broadly in Physical again. rapid THE This when offers the opportunity lag has been for passed control or during overcome. REQUIREMENT I PHYSIOLOGIC F OCCASION for the blood arose to to remain invent fluid a blood in the clotting vessels.t a chain reactions. throughout used in order reactions its An plasma Laboratory was prime experiment function.90 New ed. is involved. consecutive Van is imeffect” and autoreincreases combination actions as plied are catalytic Nostrand described of hydrogen repeat Inc. tissue would This juice continue layer with would that through seal portion a over of the blood wounded not lined the admixture yet by passageway freshly To layer the juice could clotted overcome of blood be achieve coagulation would then blood.. 1083).

respectively. blood This clots is illustrated in figure . . obtained simple beginning with two-stage show there must repeated which followed the intimations coagulation by a in period a glass of autocatalysis.hematologylibrary. w w z I U U- 0 I- z 0 FIG. reactions along the results which line and calcium. 1. does as more than in may to plug. In similar Gratia 1935. occur has when never been Actually. tube. the propagation wrote of (a) of these the blood coagulation as an endlessly transmissible were nineteenth not chain the century. each tube of fluid plasma was caused to serial clot passage by with with a few drops Gratia’s of serum previous from in the discussion. thrombus.-SOME EVENTS OCCURRING WHEN BLooD CLOTS IN A GLASS The TUBE. impressed unaware differences technic by Fischer the formal of resemblance the clotting demonstrations autocatalytic between process were effect. before representing The Hemberger.) and modifications changes and probably on become observations obtained. accelerated appear. chain and the limit help illustrate reaction the the is the kind The of process decreases which in and or synoptic could cause the growth activity. infirst two complementary nism: Separation approaches of have coagulation been made factors. Although dications spectacular. By 1904. 2012. had developed In the far enough presence of into separated And to engender the classic two- stage i. J. the with propagation repeated new they in the separation of bacteriophage formation and thrombin. i. preceding reported and results. theory: Prothrombin Fibrinogen -* -s of thrombin. platelet historical based continous experimental background is outlined prepared Mr. for (Figure to the and reactions have The three plug fibrin propagation growth of a thrombus. before separated concept 1904. Many A studies frequent the complete have finding events been has of experiment made been a that chain of the a lag re- rate period at production-characteristics which such outlines a action. of a thrombokinase fibrinolytic of a diagram necessary less pertinent antithrombin hemostatic This will is effects. been seeding apparently experiments initiated it H.91 in the of minor first tube.From bloodjournal. For personal use only. Beginning reaction. products of tube. to (h) the analysis of of coagulation individual mechareactions. was of Fischer. have been that have the been In the and factors presence continuing and be modified. this twin approach Thrombin. the all thrombokinase present. But. Fibrin. MILSTONE 12. of a hemostatic thrombin Such appear are case text.org by guest on September 20. type of not data is the the been broken attempted line by Armin curves. antithrombokinase.

on the spent stages. three succesive I9I2. 1191 CHAIN REACTION OF BLOOD CLOTTING MECHANISM done. amount last only enzyme Aftera effect a partial is kept manipulation.org by guest on September 20. fibrin production clot As is accordingly than half the of fibrin Then. hours. of is the routine rough test that summary for very clotting little of data time. ways. several investigators9 The chain however. and Then. to liquefy is the is haif-houror of the due for fact its rarely. coagulation reaction of are virtually conclusions: activation prothrombin. up until that time. of enzymes.hematologylibrary. is the Carrying to thrombin sufficient experiments a large dwindles-the one step thrombokinase on part antithrombin the activity blood. of As the a result potential understood. For personal use only. During is and the the the diagram performance impression is a tentative. gained a solid physical This gross change until viscosity the end rapidly pint finer is increases imminent. confirmed by methods. a surpris- It is a remarkable potential for but the thrombin further Soon main to noted amount reason for its late clot the fibrinogen. to enough fibrinolytic represented fibrinogen continues. At the time to polymerized and the the solid fibrin. accelerate not as shown in a There figure chain was suggested another isolated recent (a) (b) the literature.6 thrombin just delay must Collingwood time they into to period an by different the a prompt work technical unanimous comprises in these the production basic mechanism is involved that show and and of was called three that the rapid Collingwood approaches. on standing by blood. activity. clotting which process been possible latent noted The reaction. fibrinolytic explanation fibrinolytic represents the or artificial activity Normally. the retracts. thrombin first be and in formation developed. period in before the is not who clot enough appeared. and have The ‘thromboplastin” been diversity introduced. stems More ‘thrombokinase” . the the accelerated of start is that. there was reported 1901 inby Arthus. A interpretation corroborated further foreshadowed Using result findings. as can or more inactive be developed contains only to the may full. and disease ing the The degree. These pretations ing distinct that can Contemporary broad develops still experiments. be complex partially potential state. in the diagram. activity celeration seeding kinase MacMahon. less this production more. diminishes action of most be determined development fibrinolytic clot. clot in a comparatively of fibrin brief impression interval. shows findings elaborated partly are used from in with the different greater fact ways that diversity terms and that than like several might new be terms supposed.From bloodjournal. the This appears. effect. been converted clotbecomes many weighing. has the been forms. has i. are of reactions. theclor somewhat. 2012. thrombokinase separating sets of test tubes. shape to the the that own if of ever. in detail. that from an inactive the precursor coagulation it prothrombokinase. This delay production of further. MacMahon developing carried in of by loss of and the followat least of three a factor can be interthromboout ac- discussion that simple due Reasoning the from fact in by whole ofthe concluded thrombokinase Recently. of the part activity blood one in normally For developed fibrin curve reasons an can fibrinolytic has the firmer. obtained and when in the takes various blood place normal.

elucidation (Lenggenhager intact prothrombokinase is the the essential and question cited contribution a three-stage whether in prothrombokinase of the 8). of important be complex conversion This of prothrombin.* with rather entirely process As a consequence. and Thus can process. blood reactions. J. off to the a good biochemical blood. production although of x accelerates x). evidence only ordinary prothrombokinase precautions. reflected that them.93 important is the uncertainty concerning which and really how many factors participate in as the direct now activation thought to of prothrombin. and his of associates” in favor have of brought a more forth complicated impressive. main the would development thrombokinase the of in the activity.org by guest on September 20. three thence this discussion and inthe does the not principal of deal with locus the of the possibility autocatalytic This blood decision MacMahon. unclotted detailed within start a small accelerate in evidence and which the amount the first fresh of can of coagulating three of reaction the portion a chain propagate blood. This the - thrombin.. of ities I . which situation in turn so as accelerates to emphasize the production the similar- x). Any and 1936. been stages theory. by neglecting including thrombokinase to tion participate For the present directly discussion in the activation there are may It blood the part effect blood.. plasma Whether that one effect or might not more be reactions in one enumerated. of differences: Complex. the presence thrombokinase 3. It is possible summarize present of individual viewpoints Complex rather -s than chain this presence of their reaction conversion. H.g. 1940. when get the old these two-stage three The complex. chain evidence ( e. of such which factors. details..7 question forth with contain the left argument. An autocatalytic Prothrombokinase Thrombokinase or of 2. which clotting To avoid precede of undue the and for future plasma leave for a complexity. * coagulation blood. complex attained all factors.’9 is found plasma platelets . calcium.From bloodjournal. In the In plex. has that it Moreover. is prothrombokinase uncertain. different by grouping may this necessary and form signifito clot in a from to the be in found formulasubobtainable oversimplification. results the active in the acceleration corn- Prothrombin Fibrinogen is an -s Thrombin. and which between that are is demonstrably from conversion time concerned required with the present inactive is of for the of the further blood development the in. evidence autocatalytic reaction this do is many been the question else. the active cance glass can.or in both. differences emphasized and for the form in tube. Fibrin. reactions against something accelerate occur? the not the To occurrence development date of no a simple of convincing How has different presented x accelerates chain either the for or (e. reference mechanism this who brought Collingwood 1912. For personal use only. activate prothrombin. MILSTONE 12. would is in on is obtained the change Also platelets. thrombokinase followed experimentally. of and a large the autocatalytic prothrombokinase stances from. Beyond thrombokinase.g.8 consumes the is of thrombokinase mixed the we take place clotting have activity.. 2012. When euglobulins. quite Scegers conclusive. the to production the y.hematologylibrary.

the other the a heat-labile the may this the indirectly serum Brinkhous. 2012. review cause to alter. blood. of to they be known. transformed this fibrinogen . necessitate do not metamorphosis. as it yet. The suggest of chain that fresh and plasma. platelets. whole in so on. will or on that platelets. intensity of the or precise whether or “critical mode it is always It in progress is still is likely and a mystery. are a pronounced could thrombus and in platelets Condevelopment effects platelets as well are the the plug. renewed flowing platelets Thus where nidus the related. thrombocytes. the further chain might but Exactly complexity stationary much independent ignored.’8 be is serum related globulins. the can exerts same to change serum basis and factors platelets. proceed in although On the the absence not of yet whole consolidated. .’’ between of platelets. what How or whereby thrombocytolysin. stagnant along probably suggestions need ‘congenital than is with differ blood. 12. some a useful appreciably The fibrin that former from have it (sometimes. sticky. fibrin of with have component Various constituent. .94 CHAIN REACTION OF BLOOD CLOTTING MECHANISM THE ROLE OF THE THROMBOCYTES This the will advance. the high is absolutely even by in that curious red formed thrombus content Although the of the necessary.” in blood but on are brought about require particularly The the factor. tube formed platelets. gives the means material of shuttling metamorphosis and to be there reaction eddying a is how is cannot not directly thrombin. . the known. In patients their absence alterations are less “21 incapacited Phylogenetic represent formation are And platelet used. postulate even different mechanism. white clot. the test a disproporapparently. is appears This already that does reaching the not chain prove out that to reaction include material experimental derived when impression will lead from they are that platelets present.org by guest on September 20. .” the platelets Tocantins’6 plasma. are states which not concerned the in general turn changes and neighboring not the was The platelet simply by presence demonstrated lysis contact of by name but it platelet and fusion with glass factor and Wright has ‘ observed in the found Minot in coagulating presence of calcium. in flowing in is fibrin. in 1917. on reaction considerations. chain result might accelerain be would be of intihelp as or the con- production series. has comparisons a primitive been not facts the does suggested of Be that two compel the as it entirely us to thrombocytes which materials to chain apply reaction them. is not In they platelets his involved. THE PROBLEM OF REGULATION How to We be are the brought likewise chain to reaction an effective ignorant starts. plasma a white metamorphosed concerned the and two whether hemostatic continuously this related. mately hinder A in not turn.” of control. blood. side it platelets. for fibrin hemostatic may.From bloodjournal. is absence abnormality to usually that be corroborated. with of if two a separate the upon adhesive of the case is not certain may platelets connection. the the recognized . mechanisms superimposed. For personal use only. that needs the only control concentration. of factor has different suggested is In tion A tinuously formed supplied ceivably thrombokinase. tionately very that be it it thrombus or little). .hematologylibrary.

indihas slowly to removed been maintain fast and coagulant relations. develop- thrombokinase RELATION Undoubtedly. fibrinogen circulation. in the In all the blood of coagulant tube in the the cardioclotting products rapid loss Several reactions by an retardation of the test disposal circulation dispersion may be the of is thrombokinase If. why but would can not also dampen the process plug or a a hemostatic fresh vascular thrombus system? phenomena or active continue are of to grow known their until which products. of outline these significant extensively prospects to which the future heparin has is of the the investigator. H. must They on it when was Althoughis still it normal circulating other shock and anticoagulant blood. for its further investigation. MILSTONE 12.From bloodjournal. in significant quantity been in of platelets. critical But TO juncture detailed THROMBOSIS of study the entire of this system has just is the begun. These questions For from blood. usual or level after suggestions to every anaphylactic that changes few days. extent . under plug action to the enough inferred the proceeding total secretions body are these are to reach irradiation. Ware. of It is quite ment of possible that the activity. Nevertheless if we it and state are guides For to there it to is clearly understand theoretical of of thrombosis. of great it incorporated result Mere importance. and Murphy here then the and both way Seegers’4 the is open believe. the balance. coagulation what prophylaxis to estimate the makes continue a detailed the being are therapy in based in the propagates prognosis. as link an important activity Quick’2 in the is and striking. requirements might contribute kind Such which of that they of prothrombin and reactions.8 thrombin chain antithrombokinase and antithrombin may accomplish effect. inhibition. 23 the tests Modern view present. renewed blood a degree converted in this clotting the The propagation failure. balance be in discharged data on factors consumed response the It Suggestive cate that in to the prevent fluidity antithrornbin products this way. the chain. the limit clotting of dynamic factors figure i. could could could physiologic the illustrated antithrombokinase inactivate quantitative already hemostatic such a overpowering. only some of state prevailing thrombosis. The fibrinolytic the in anti enzyme(s) thrombin Heparin augments ways delays the heparin occurs activation of prothrombin. reaction. a highlyanticoagulant There have steadily the are in This blood. 2012. fundamental few how efforts attempt factors it to are to prophylaxis of the tests remain analysis to of and be disclosed. For personal use only. and uncertain blood. a static Otherwise. turnover completely the implies for As take slow help excessive already the part been up to necessity.hematologylibrary. which likelihood the hypercoagulable therapy system used that the beckon chain is as a anticoagulant that and and noted the question the coagulation dicumarol. J. Depending process growth or of a thrombus.org by guest on September 20. circulating gross effects have action action of to coagulation. made a and coagulation are the detect stop. it effects more in some whether appears offer than means is now for breaking appreciated. 22.95 mechanism when it is exerts already not under merely way. of in formed. thrombosis patient’s on the factor in administration this Among are many necessary why who a thrombus hope to are that starts.

Insur. maintain thrombokinase activity. It forms. conditions some where case. of Consequently. be of at least The one chain of reaction platelets effect occurs and may Both to metamorphosis autocatalytic the offers that plays an serve advantages the some The adequate long thrombin a function the chain part chain since in making physiologic occurs propagation. and R. July by removing raised the intwo products articles of which by smoldering appeared clotting since the present paper A.From bloodjournal. the these reaction whenever would to be relative remains subject data In pathology of from is so usually importance be evaluated.96 CHAIN REACTION OF BLOOD CLOTTING MECHANISM reaction furnishes the and biochemical basis for the propagation of a thrombus.” thrombosis is very as the heparinization emphasized system singleit out SUMMARY: A WORKING HYPOTHESIS Detailed during development evidence the coagulation of in reaction in its reaction countermechanism. been and has thrombokinase been of accumulating blood. reaction? Nassim have tissue platelets Anticipation and covered will The by important. Alexander. it thrombi There were may no be chain some reaction. may derived reduce reactions inactivate the have fluidity of demonstrated liquefy fibrin. mentioned of the its same B. 12.hematologylibrary. see deVries by J. Of the latter of the left ventricle growing hardly by repeated surface be called diffusion formation could sustained on the from extension of be an example. or nothing pioneer anew include mural is to the Best21: seems “It little of reasonable agglutinating underlying of the mural growth cardiac clotting yet injured their may cardiac damage thrombus. independently It was idea For and a step briefly toward was submitted : 739-746. . and it deposition the substances thrombus? through he found or in the suppose nature with ments that reaction. play contribution of the unless some coagulation the part in in the individual’s the genesis mechanism extension of in various that is likely it is the types circumstances unusual. 1949. Med. page reactions. Goldstein: Blood The 1949. of its a thrombus classic intimately One disciplines together a part forms. 5-7. is a possible control in most the growth the of a hemostatic clotting where a mechanism. a discussion implications ere w idea. degree suppressing state but of does the not subsequent of statement once of the the chain of Solandt. tissue fresh a thrombus propagation would a mural myocardium. operation in that. appear that the involved. These reactions the * circulating This question for 4: blood has been publication. thrombus plug. H. 2012. presented reference i. the Is injured the factor coagulant continued through thrombus and the of at the far ventricular platelets Or free to the to experithe thromchain do does surface. propagate might even impossible if there into the without chamber Here blood fibrin depend the one. has long has will The to been been be occur The as chain in evidence. which It also is likely and demands instances explosive materials potentially With which can phenomenon from help to blood. sine qua non success This of an have of this question region. In studdifferent biochemical the formation 24 experiments propagation speculate brought might are the chain of what reaction a thrombus the and blood of outcome extended. might is far of of stagnant. thrombus. 74. bosis. For personal use only. Milstone: J.org by guest on September 20.

Lectures 709-711. and B.2.: Studies on the enigma and of the the hemostatic three W. i: New coagulability 1948. possible to to delimit correlate the in growth this way of the a hemostatic data on blood plug. 1946. factor : The sur 102. defect 2. G. I7 platelets. fibrin factor Proc. R.: K. G.: A. Med. 395409. and abnormal of study MANN. normal fibrinolysis. mechanism. J. bacteriophage unbegrenzt human of Ann.: stages The dysfunction of of blood hemophilia. patients 24 ASCHOFF. Pathology.-2. Clotting Soc. Physiol.60. W. J. M. Platelet formation 1948. for Blood in increased : 147-154. MACFARLANE. Path. : Discussion A. T. H.78. C. L. Med.2. L. COLLINGWOOD. 3 FISCHER.: A N. H.0. Szeged ofblood coagulation. L. and for Exper.80. H. G. platelets extracts. J. Investigations a clotting Acta Med.5-2. MILSTONE. : The A. Hoeber. GRATIA. Gen. R. ‘ Biol.Jr.. 11 OWREN. 23 HURN. coagulation analysis formation blood of 3: 5-15. the AND postoperative M. J. -I MILSTONE. dans le sang Biochem. Chem. H. factor. Am.. In prothrombin 1947. WRIGHT. 279. Pp. Three-stage autocatalytic Med. For personal use only. of AND metamorphosis J. MILSTONE. S.4. A review.1: Med. M. of T. LAKI. hemophilic blood. 1938. 1947. 68: by H. J. Science io6: in Sc. 2. . D. 2.8. thrombin Acta the Scandinav.2.1. rend.-3I0.org by guest on September 20. Exper. participates chloroform. SEEGERS. 546-547.. blood 140-147.: AND 1917. and 1943. Kettenreaktion. Biochemistry Univ. and disease. J. Y. Deficiency 1947.’ M. ofhemostatis. Brit. in hemophilia: 66: 117-12.From bloodjournal. I 6 109i16. P. and G. H. ARTHUS. H. AND BEST. A. of the in blood.: The defect Exper. TOCANTINS. AND WARE. in Physiol. M. Am. coagulation: test cases. AND SEEGERS. 2012. critical gaps in our under- REFERENCES I 2 TOCANTINS.: Am. K.Clin. of utilization. its application BARKER. : Blutgerinnung 1935. J. interaction purified II prothrombin R. “ Allied mammalian MaCy. coagulation. Immunol. A. Studies I A5TRUP.: The anti-coagulants in blood and serum. G. SEEGERS. in plus a plasma globulin. York.. 2. J. 192..’ 1947. & prothrombin W. 26. MILSTONE 1197 Such effects it is could of now help a thrombus.. J. of 1944. 1948. blood viscous equilibrium Josiah platelet clotting In 17 Blood and The MINOT.: The Instit. MURPHY. Physiol. 2. 1912.’ io8- “4.: Protein Problems.: FAHEY.: Proc.. mechanism on the als in 1941. : The 1947.: W. IV. M. Clotting L. 192.53- with thrombosing Thrombosis.: B. 45: de biol..92. H.J. H. of J. 125. Lancet NASSIM. or coagulation to end the propagation While with standing present still knowledge remain. function reactions Science 1 6i8. C. J. 1947. Compt. required Soc.595.47. 119’145. 25 SOLANDT. antithrombin Inc. Gen. J.: 194. of in Ac-globulin the blood 1948. modification to the F. Activation 1948.72. Physiol. i. io6: Prothrombokinase R. 2. of blood. J.4. blood clotting. and Normal thromboplastin. on Waugh-Ruddick D. H. activation la production 1901. A. Scandinav. 2. CHRISTENSEN. tendencies. of hemostasis and thrombosis. : A 42. AND MACMAHON. clotting 3l 301-32.hematologylibrary.. coagulation. 1948. #{176}WARE. Soc. L. & platelet Biol..96. Path. extrait des Ztschr. the blood Medicine 155-2. M. ‘947. J. (bacteriolysin) ubertragbare blood which by Surg. B.. new on 7: Suppl. R. 2. 1939. ‘ WARE. M. i3 MILSTONE.: Production and prevention of cardiac mural thrombosis in dogs. 592. Paul 2. BRINKHOUS.. plasminogen de fibrinferment : Etude 53: vaisseaux. I: 113-143. 15. J. 22 SILVERMAN. streptococcal 30 149-157. Physiol.: Variations Clin. Suppl: 12 QUICK. 214. J. in health of Foundation 64-84. A.