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The Subcutaneous Use of Heparin

A Summary of ObservationsBy GEZA DE TAKATS, M.D.

The present use of anticoagulants is hampered by the necessity of giving a number of injections ofheparin each day, or of using an oral anticoagulant which acts by throttling prothrombin deliveryfrom the liver and does not seem to be a safe anticoagulant, since its laboratory control is notstandardized. Because of this an attempt is made in this paper to show the effectiveness of admin-istering heparin subcutaneously and of giving only enough to restore the clotting mechanism to itsnormal level but not necessarily prolonging the clotting time. With this principle a single injectionof heparin a day or every second day seems sufficient, and the danger of hemorrhage is greatly min-ized.

B ECAUSE there is a definite need for ananticoagulant which need not be in-jected intravenously, and because of

our conviction that dicumarol prophylaxis andtherapy are at present unsafe and unpre-dictable,' an investigation of various heparinsolutions and suspensions w-as undertaken withregard to their injectability and efficacythrough a deep subcutaneous route. When thesite of so-called intramuscular injections asgiven by the nursing staff is examined bybiopsy, it is often found to be the deep sub-cutaneous tissue. The samples tested were 200mg. of heparin in gelatin,* with and withoutvasoconstrictors, 400 mg. of heparin in gelatinwith and without vasoconstrictors, 200 mg. ofheparin in gelatin with, and 200 mg. of depo-heparin without vasoconstrictors and 10 percent heparin in aqueous solution in doses of100 and 200 mg.

GENERAL CONSIDERATIONS

While in the case of penicillin the infectingorganism is the dominating factor determiningpenicillin resistance or penicillin sensitivity, inthe case of heparin, there is a multiplicity of

From the Fourth Surgical Service, St. Luke's Hos-pital, Chicago, aided by a grant from the UpjohnCompany, Kalamazoo, Michigan.

*This cartridge of Depo-heparin sodium, 200 mg..with vasoconstrictors contains: heparin sodium(20,000 units), 200 mg.; epinephrine hydrochloride1 mg.; ephedrine hydrochloride, 10 mg.; gelatin, 180mg.; dextrose, 80 mg. Preserved with sodium ethylmercuri thiosalicylate 1:10,000.

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factors influencing its action. These have beensummarized in table 1. In addition, there maybe a daily change in heparin requirement, andthere also seems to be a cumulative action, orpossibly a phenomenon of storage.2 All thisindicates the difficulty in prescribing set dos-ages, and the necessity of utilizing a test doseof heparin (10 mg. in 1 cc. solution given intra-vrenously) before heparin therapy is started.3The effect of this dose on the individual istested by capillary coagulation times, deter-mined before and 10 minutes after the injection.Such tests reveal nonreactors, hyporeactors,mean reactors and hyperreactors. Of 97 normalindividuals tested a few years ago, 40 werehyporeactors, 31 were hyperreactors and 20were mean reactors.' In 250 patients there wasa much higher percentage of hyporeactors, andnonreactors appeared. The guiding influence ofsuch a test dose on prophylactic and therapeuticdosage is obvious.

Heparin activity can l)e controlled by co-agulation times, and for years we have em-ployed capillary coagulation times for this pur-pose because (1) this is a simple bedside test,and can be performed by technicians, internes,nurses and even patients; (2) repeated veni-punctures in patients under heparin therapyproduce hematomata; (3) coagulation timeswith the one tube Lee-White method may beprolonged from 40 to 60 minutes during therapywith heparin, producing a time consuming pro-cedure; (4) three and five tube Lee-White co-agulation times may start with a 25 to 30

Circulation, Volume II, December, 1950

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SUBCUTANEOUS USE OF HEPARIN

minute normal coagulation time4 and silicone-coate(l tubes may exhibit a 60 to 70 minutenormal coagulation time,5 indicating that allthese methods are pure artefacts and that theblood surrounded by a nonwettable endotheliallining does not clot anyway.For these reasons, capillary coagulation times

are a(lvocated, not with the idea of studyingthe patient's clotting mechanism, but merelyto follow and control the administration ofheparin. Heparin can of course be titrated inwhole blood and in plasma with protaminesulfate, but in our opinion this can never be-come a satisfactory bedside test for the controlof heparin administration. Heparin tolerancecan also be tested in vitro,4 although as pointedout by Best and Jaques5 the clotting time pro-(lucei with moderate doses of heparin in vivo

TABLE 1.-Response to Heparin

agulation time so that small amounts of addi-tional heparin as used in subcutaneous ther-apy may be detected by lengthening of theclotting time. Our experience with the recentlypublished method of Rosenthals has been mostsatisfactory, and has gradually led us to adoptthe principle that, for prophylactic purposes,the maintenance of a sensitized clotting timeat the upper limit of normal is protective. Thismeans the use of far smaller quantities of hepa-rin than have been advocated in the past,amounting for the adult of average weight to200 mg. of heparin every 48 hours in a retard-ing medium such as gelatin. The normal sen-sitized clotting time varies between 20 and 30minutes, using 4 gamma as a sensitizer. Fig-ures below or above these indicate hypocoagul-ability or hypercoagulability of the blood. Else-where we have reported on the clinical valueof such a sensitized clotting time.9

Decreased Response

AgeAcute ThrombosisPostoperative StateDehydrationHemoconcentrationPolycythemiaHyperlipemiaCarcinomatosisDigitalisEpinephrine

Increased Response

YouthTraumatic or Hemor-

rhagic ShockHepatic DamageNeostigmineSodium TetrathionateDicumarolCarinamide

is considerably greater than that obtained on

mixing the same quantity of heparin withthe blood in the test tube. The heparin tolerancein the circulating blood measures the state ofthe clotting mechanism, a dynamic equilib-rium of coagulant and anticoagulant factors,and in addition is influenced by excretion, stor-age and enzymic degradation.' This is the rea-

son why single large intravenous doses are

wasteful, and a moderately elevated plateau-type of clotting curve is desirable.The addition of minute amounts of heparin

(1 to 4 gamma) to a cubic centimeter of bloodin vitro reacts with a number of enzymes, co-

factors, profactors and accelerators,7 the sum

total of which inhibit or facilitate the actionof heparin, but it is most useful in sensitizingthe ordinary Lee-White method of venous co-

-METHODS OF STUDY

The patient's age, sex, diagnosis and otherconditions known to influence the response toheparin were noted. A heparin tolerance testwas run on each individual before the admin-istration of heparin. A coagulation time wasdetermined before and every two hours afterthe administration of heparin until the pre-injection level of coagulation time was reached.Often capillary coagulation times were deter-mined more frequently until the peak wasreached. Untoward effects, such as pain orhematoma at the site of injection, or bleedingelsewhere, were noted.

OBSERVATIONS

(1) 200 Mg. of Depo-Heparin without Vaso-constrictors. Figure 1 shows a control of thisdrug by venous coagulation times. Note thatthe effect is over in about 12 hours and thatthe peaks are so high as to make the venouscoagulation times impractical. Figure 2 showsthe control by capillary coagulation times.Thus, case 6 in figure 2 shows a poor response.This patient, Esther 0., a heavy set womanwith chronic thrombophlebitic edema, showedmarked heparin resistance following operation.In contrast, case 3, a young boy who had justrecovered from a massive acute thromb)ophle-

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GEZA DE TAKATS

bitis, showed a good response. The same hepa-rin sensitivity is exhibited by case 4, figure 1,a patient with Buerger's disease in a state ofremission.

(2) 200 MAIg. of Depo-Heparin with Vaso-constrictors. Figure 3 shows the control withvenous coagulation times, whereas figure 4 il-lustrates the control by capillary coagulation

of 56, with extensive arterial and venous throm-bosis who showed little therapeutic effect; evenless did case 6, Charlotte K., who exhibited apostoperative infection. The average durationof effect, which varied from 9 hours to 30 hours,was 22 hours.

27'

40' 40'

20

18

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0

to

10

en(L)

mc

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W

0

_

0'a0

0

0U

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2 4 6 8 10 12Time in hours

FIG. 1. The effect of 200 nig. of heparin-gelatinwithout vasoconistrictors on venious coagulation time.Note the high peaks, the steel) curves, and the rela-tivelv short duration.

times. The highest response in figure 3 is shownby case 10, Bernice 0' 1., a 30 year old womanWith a postphlebitic syndrome. The peak andduration of effect is quite variable. Case 1 offigure 4 is Mary S., a young girl with a con-genital vascular anomaly but no thromboem-bolic disease, who showed a peak of 11 minutesand duration of effect to 30 hours. Case 4 onthe other hand is an arteriosclerotic individual

2 4 6 8 10 12 14 16 18 20Time in hours

FI(G. 2. The effect of 200 mg. of heparin-gelatinwithout vasoconstrictors on capillary coagulationtime. Note the marked variation in resI)onse. Case3 exhibits an exaggerated response in a young boyduring the stage of recovery from an acute thrombo-phlehitis. Case 6 is in a stage of postoperative hepa-rin-resistance.

(3) 400 M[g. of Depo-Heparin without Vaso-constrictors. Figure 5 illustrates the effect ofthis dose, measured by capillary coagulationtime, and indicates again extreme variability.The high curve with a peak of 32 minutes anda duration of effect up to 38 hours belongs to

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Wm. P., a thin, undernourished individual whoreceived with this dose (3.5 mg. of heparin perpound of body weight) an overdose resultingin a large hematoma at the site of injection.On the other hand, curve 3 belongs to Esther

27'

(4) 400 Mg. of Depo-Heparin, 200 Mg. with,and 200 Mg. without, Vasoconstrictors. Figure6 illustrates the control with capillary coagu-lation times. These curves are more of a pla-teau type, show fewer peaks and last from16 to 32 hours, with an average of 25 hours.Note the almost complete lack of response of

32'

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aI

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12 14 16 18 20 22 24 26TIME IN HOURS

I I l AI i l I

0 2 4 6 8 10 12 14 16 18 20TIME IN HOURS

FIG. 3. The effect of 200 mg. of heparin in gelatinwith vasoconstrictors, controlled by venous coagula-tion times. Peak and 'duration of effect vary

markedly.

0 24 -

n 22 _

za 20 _

- 18

_ 16 _

z 14 -

2#- 12

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44

48

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32

TIME IN HOURS

FIG. 4. The effect of 200 mg. of heparin in gelatinwith vasoconstrictors on capillary coagulation time.Resistance and sensitivity are demonstrable, but thecontrol is easier because of the shorter clotting times.

0., the same individual who showed poor re-

sponse to heparin in Figure 3 to 200 mg. ofdepo-heparin with vasoconstrictors. Her curve

dropped to the preinjection level in 12 hours.The duration of effect varied from 19 to 35hours, with an average of 31 hours.

FIG. 5. The effect of 400 mg. of heparin in gelatinwithout vasoconstricbrs on capillary coagulationtime. The highest curve (case 5) is the result of anoverdose (3.5 mg. of heparin per pound of bodyweight). The effect lasted 48 hours. In case 3 the effectwas not measurable with capillary coagulation timesafter 12 hours.

12

to

E

0 2 4 6 8 10 12 1416 18 ED2224 262830Time in hourIs

FIG. 6. The effect of 400 mg. of heparin in gelatinwith half dose of vasoconstrictors on capillary coagu-lation time. Case 8 shows minimal response. He wasan obese individual, with active arterial and venousthrombosis.

case 8, Henry H., an obese individual withmultiple, massive venous and arterial throm-boses.

(5) 400 Mg. of Depo-Heparin with Vasocon-strictors. Figure 7 shows the capillary control.The duration of effect varied from 13 to 48hours, an average of 27 hours. Noteworthyamong the poor responses in the individual

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GEZA DE TAKATS

z 12 _

10

0 236 2rs.)'-

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32TIME IN HOURS

FIG. 7. The effect of 400 mg. of heparin in gelatinwith full dose of vasoconstrictors. Capillary coagula-tion times were used. These are flat curves. Notethat in case 2 the effect lasted for 36 hours; in case 5for 19 hours. Both patients weighed the same, butcase 5 had an acute, case 2 a chronic thrombophle-bitic edema.

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graphs is that of case 5, Peter G., with an acutethrombophlebitis, who exhibited a poor re-sponse, lasting 19 hours.

(6) 150 Mg. of Depo-Heparin with and 150Mg. of Depo-Heparin without Vasoconstrictors.Because of our experience with hemorrhagiccomplications when the 400 mg. dose was ad-

EFFECT OF PROTAMINE ON HEPARIN RESPONSE

O- Heporin a/one

Heporinl pro/amine at~pek (i)

*-_ Heporin protomine simul/toneouslyat 0 lime

F L.

S.W

75 mgu proinmne

50,popery WOma0s

HOP,,

X

2 3 0 2 3Time in hours

2 4 6 8 10 12 14 16 18 20Time in hours

FIG. 8. The effect of 200 mg. of heparin in 10 percent aqueous solution, given intramuscularly. Capil-lary coagulation times were used. Note the differencein response between case 2 and case 6. The formerreceived protamine for a severe hemorrhage in an

abdominal incision. Case 3 had a subsiding deepthrombophlebitis, with a capillary coagulation timeof 38 minutes, at 6 hours, but showed no bleeding.

0 2 3

FIG. 9. The effect of intravenous protamine sulfateon the action of heparin. In the left row of curves

(V.S.) 50 mg. of heparin were given intravenously,alone; a second time at the peak of response prota-mine was given; a third time heparin and protaminewere given simultaneously. The dose of protaminewas one half that of heparin. Note a dampening, butnot a neutralizing effect. In the middle row and inthe third row, a 1.5 to 1 ratio of protamine to heparinwas used. Note that in patients F. L. and S. W.,protamine, given at the peak, promptly restored theclotting time to normal; given simultaneously, it com-pletely neutralized the effect of heparin, whichshowed a good effect in both patients when givenalone.

ministered to patients weighing around 120pounds, this dosage was administered to a fewpatients. Even this dose resulted in a largepostoperative hematoma in Vesta W., who re-

ceived 1.71 mg. of heparin per pound of bodyweight. This case will be discussed under theheading of untoward reactions.

(7) 200 Mg. of Heparin in 10 Per Cent Aque-

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oats Solittion. There is again a tremendous vaii-ation in the effect of this injection. Figure 8shows the capillary control with high peaksand a duration varying from 7 to 19.5 hours.One case in this group developed a severehemorrhage. This patient, case 2 of Figure 8,will be discussed in detail. Note the poor re-sponse of case 6, J. B., a 44 year old vascularsclerotic, whose capillary coagulation timeshardly show a rise.

T'he N\eutralization of Hepasint by I'rotatnincSulfJate

Various doses of protamine sulfate were givenintravrenously to neutralize the action of hepa-rin (fig. 9). While a 1 :1 ratio of protamine toheparin definitely dampens the effect of hepa-tin, a complete suppression of the heparin ef-fect on capillary coagulation time is obtainedby a 1.5:1 ratio. Thus 75 mg. of protaminesulfate given simultaneously (but not in thesame syringe) with 50 mg. of heparin, has ledto the flattening of clotting curves.When protamine sulfate is given at the height

of the clotting curve, within 10 minutes thereis a steep fall of the clotting time to a lowerlevel.Here again a 1.5:1 ratio (i.e. 75 mg. of pro-

tamine to 50 mg. of heparin) seems the mosteffective, but smaller (loses, such as a 0.5: 1ratio, are partially effective. (fig. 9).So far, there havre been no untoward reactions

following the intravenous use of protamine;when given into muscle there is severe burningfor 24 hours, but a noticeable antiheparin ef-fect. We do not advise the latter method ofaclministration unless it can be made morepainless, possibly with procaine ais in the caseof aminophylline.The duration of the effect of intrav enous

protamine is approximately four hours. Hepa-rin response up to four hours is abolished ordampened. In case of continuing hemorrhageafter administration of heparin, protamine in-jections must be repeate(l.

DI)iscvussIoNxWith increasing experience we have (level-

oped certain guiding principles which of coursemay have to be modified in the light of further

observations. In addition to the factors enum-erated in table 1, weight is an important fac-tor in determining heparin response. This isillustrated by patient Wm. P., who receivedpreoperatively 400 mg. of Depo-heparin with-out vasoconstrictors, resulting in a capillarycoagulation time of 32 minutes with a durationof effect to 38 hours, and a large hematoma atthe site of injection. The amount he received wasequivalent to 3.5 mg. per pound of body weight;in our opinion 2 mg. per pound is sufficient asa preoperative or therapeutic dose. 1Postopera-tivrely, even the 2 mg. per pound weight dosemay be too much, as shown by the case ofVesta MW., who received 300 mg. of Depo-hepa-rin (1.71 mg. per pound of body wveight) anddeveloped a huge hematoma in the incision ofa lumbar sympathectomy. This patient hadno thrombosis at the time, but had had thiscondition in the past. In postoperative pro-phylaxis 1 mg. of heparin per poun(l of bodyweight is a safer daily dose.

This matter raises the question of the ad-v:isability of giving large doses of heparin intra-muscularly the absorption of which is not underany further control than that given by thegelatin-dextrose menstruum and the vasocon-strictor. However, even with 200 mg. givenin 10 per cent aqueous solution, we have ob-served a severe hemorrhage from an unstus-pected cervical erosion in Viola AI., who re-quired several transfusions to restore her bloodcount.

In addition, heparin seems to have a cumu-lative effect, because a patient whose coagula-tion time has returned to normal may respondthe second and third time with a far longercoagulation time or even with hemorrhage.There are several possible explanations for thiswhich we plan to investigate in the future.Suffice it to say here that, once the patienthas received a large dose of heparin, the hepa-rin requirement diminishes, and the return ofthe capillary coagulation time to a normallevel does not mirror the increased sensitivity.Increased heparin sensitivity may be due toseveral factors, some of which are listed intable 1. From the standpoint of avoiding hemor-rhages after heparin administration the fol-lowing points need emphasis: (1) Small amounts

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of heparin remain in the blood stream, al-though only a single dose of heparin is givenfor a longer time than venous or capillarycoagulation times can detect them. They aredemonstrable, however, with a heparin clottingtime or heparin titration.* (2) After certainshocklike states, including coronary thrombosis,pulmonary embolism and massive peripheralthrombosis, anticoagulant substances appearin the blood,10 and they may manifest them-selves by increased reactivity to heparin (case10 of figure 3, and cases 3 and 9 of figure 2).We have again and again seen astonishing re-sponses to heparin after the 10 mg. test dose inpatients who were recovering from or had justsuffered an acute thrombosis. In such patients

This brings us to the important question:what is the desirable range of capillary coagula-tion time, a range which is both safe and pro-tective against thrombosis or extension ofthrombosis? Our experience, extending over 12years, indicates that for therapeutic purposesa range between 8 and 12 minutes is effective.There is no need to reach peaks of 20 to 30minutes. This is uneconomical because so muchmore of the drug will be excreted through thekidney. Therefore, the plateau type of curveis preferable. The heparin-gelatin emulsion issometimes painful. While it is a definite im-provement over the Pitkin menstruum, our rec-ords indicate a 15 per cent incidence of painof which patients spontaneously complain, someof course more bitterly than others.

POSTOPERATIVE CLOTTING CURVE I

CONCLUSIONS

2 OATS AFTER OPERATION *

FIG. 10. Prolongation of sensitized clotting timesfollowing operations. Straight line represents average

curve of 7 patients. This is a frequent response.

the prothrombin level may also drop as we

have observed after coronary occlusion; theheparin-retarded clotting time lengthens fol-lowing operations, suggesting the appearance

of antithrombic substances (fig. 10).The site of injection may show hematomata,

which is very infrequent, but it is to be notedthat, if any other hypodermic or other formof injection is given, large hematomata may

occur even when coagulation times are notexcessively prolonged. It is known that massivehemorrhages may be produced by paraverte-bral sympathetic blocks under dicumaroll' andthis seems to be true when too much heparin isadministered.

* Unpublished Data.

A study of the graphs presented indicatesthat the variability of the patient's responseto heparin is great. The value of mass sta-tistics, transferred to punch cards and analyzedfor statistical significance, is not questioned;but they will not substitute for a close clinicalobservation of each patient receiving antico-agulants. The balance of coagulant and anti-coagulant factors is delicate and seems to swingspontaneously; the administration of an anti-coagulant markedly influences this balance.

Regarding dosage schedules, the followingtentative schedule has been followed: a prim-ing dose of intravenous heparin (30 to 50 mg.)is followed by the deep subcutaneous injec-tion of heparin in gelatin. The initial primingdose will raise the capillary coagulation time to8 to 12 minutes and this should be maintainedwith the average daily dose of 2 mg., with vaso-constrictors, per pound of body weight. Thisdose refers to the treatment of acute throm-botic episodes and must be kept up for 14 days.Shorter periods of administration will give riseto the recurrence or flare-up of the thrombosis,when heparin is discontinued. This statementrefers to surgical patients; after coronarythrombosis, four weeks seems to be a saferperiod.One mg. per pound of body weight is a good

average prophylactic daily dose. In the presence

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of an open lesion, or of a recent surgical in-cision, this dose must never be exceeded, butmay even be split by giving it every second day.

Control of the clotting mechanism is suffi-ciently safe if a capillary coagulation time isdetermined once a day, usually in the morning,with the heparin administered at noon-time.When a sensitized clotting time is used, thistoo can be run once a day and should be keptat the upper limit of normal. Such a controlleads to smaller prophylactic doses than havebeen employed in the past.9

Aside from occasional sensitization to hep-arin, the only complication of heparin admin-istration is hemorrhage. The following pre-cautions are useful in minimizing this untowardreaction: (1) heparin should be administeredaccording to body weight; (2) following trauma,operation or acute vascular accidents, naturalanticoagulants may potentiate the effect ofheparin; (3) protamine sulfate should alwaysbe on hand and its injection repeated everyfour hours until hemorrhage stops; (4) hemor-rhage continuing in spite of administration ofprotamine is a rare self-perpetuating mecha-nism uninfluenced by neutralization of heparinwhich must be combated by blood transfusions.

SUMMARY

An emulsion of heparin in gelatin, given witha daily control of capillary coagulation times,is a simple efficient anticoagulant therapy. Thegreat variability of response to heparin makesset schedules of dosage impossible. The thera-peutic dose should always be double the pro-phylactic dose; in the case of an acutethromboembolic episode, the administration ofheparin should be maintained for two weeks.The determination of heparin tolerance gix es a

good insight into the state of the clotting mech-anism; it can be done in vivo or in vitro.

ACKNOWLEDGMENT

The technical assistance of Mrs. Jeannette Pear-son Leavens is hereby gratefully acknowledged.

REFERENCES

1 DE TAKATS, G.: Anticoagulant therapy in sur-gery. J. A. MI. A. 142: 8, 1950.

2 ASPLUND, J., BORELL, W., AND HOLMGREN, H.:Untersuchungen uber die Speicherung des Hep-arins im Tierorganismus, sowie flber seineResoiptionsmbglichkeiten imi Darm und Pla-zenta. Ztschr. f. mikr. anat. Forsch. 46: 161939.

3 DE TAKATS, G.: Heparin tolerance. A test of clot-ting mechanism. Surg., Gy-nec. & Obst. 77:31, 1943.

4 AAUGH, T. R., AND RUDDICK, D. AV.: A test forincreased coagulability of the blood. Canad.\I.A.J. 50: 574; Studies on increased coagula-bility of the blood. Canad. M\1.A.J. 51: 11,1944.

5 BEST, C. H., AND JAQUES, L. B.: Heparin inblood clotting and thrombosis. Ann. New YorkAcad. Se. 49: 501, 1948.

6 JAQUES, L. B.: Heparinase. J. Biol. Chein. 133:445, 1940.

7Blood Clotting and Allied Problems. Transalc-tions of the First and Second Conferences.Josiah _Macy, Jr., Foundation. New York, 1948and 1949.

8 ROSENTHAL, R. L.: Blood coagulation in leu-kemia and polycythemia; value of heparin clot-ting time and clot retraction. J. Lab. & Clin.Med. 34: 10, 1949.

9 DE TAKATS, G.: A sensitized clotting time. Angi-ology 1: 317, 1950.

10 SCHILLING, F. J., AND DE NATALE, A.: Naturallyoccurring anticoagulants and accelerator sub-stances in human blood. Am. J. _M. Sc. 218:70, 1949.

1LILLY, G. D., AND LEE, R. AM.: Complications ofanticoagulant therapy-. Surgery 26: 6, 1949.

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GEZA DE TAKATSThe Subcutaneous Use of Heparin: A Summary of Observations

Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 1950 American Heart Association, Inc. All rights reserved.

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