Intravascular clotting

Intravascular

Clotting

A Biologic Error* WILLIAM New

T

HE

against

blood

vated

in

clinical tion

blood

from

loss.

conditions

by

lead

and

of blood

detrimental

when

to

that

the

cause

morphosis

of

case reports

The

this undesired

blood

will

CLINICAL

organism. will

is,

clinical

physical

be

meta-

discussed

and

be presented.

DISORDERS M’~TH INTRAVASCULAR CLOTTING

PHLEBOLITHS The

change

solid

state

hemorrhage This

in

health

result

inside and

in

Phleboliths

Having

of calcification

in

the

no

clinical

significance.

of

calcium

represent

veins,

we know

film are

in all

as is easily

of the pelvis noted

as

scattered

veins,

the

trauma.

vessels

them

about

the

as small

we

are

of

small bits

generally

in all persons and are of Although areas

little

to

against

from

disease,

identified

told that they are found

fluid

blood

spots of calcification

pelvis.

the

mechanism

on the x-ray

adult.

white

from

might

occurs

demonstrated any

blood

protective

which

process

persons,

of

is a

more

of

these

spots

thrombosis

about

in

them.

SURGERY All

surgery

vessels. hemostats The

time

are

vessels

duced.

produces

Each

In

* From The New York.

are the

a

placed

thrombosis surgeon on

the

traumatized pelvis

Cornell

large

University

cuts

in

severed

and

Medical

skin,

vessels.

a clot

veins

blood

the

are

is prooften

College

can

phlebitis

occur

from

results. these

Pulclotted

patient:

CASE 1. Pulmonary Embolism from Surgery: A housewife, age sixty-five, was found to have a carcinoma of the endometrium. Operation was performed on January 28, 1957, and consisted of total removal of the uterus, tubes, ovaries and lymph nodes in the iliac and obturator areas. Pathologic diagnosis was found to be adenoacanthoma with slight to moderate endometrial invasion and vascular lymphatic involvement. Postoperative Course: The patient had a calm postoperative course during the first twelve days. Her temperature remained between 37 and 38Oc. She was allowed up to the bathroom, had her meals sitting up and walked about the room. On February 10, eleven days after the operation, she complained of pain in the right lower part of the chest. The pain was made worse by lying on the right side. Deep breathing was impossible. Examination showed splinting of the chest on the right side. Moist rales were present at the posterior base on the right side. Her temperature rose to 39“~. Examination of the legs was completely normal. The white blood count was 7,800 per cu. mm.; the differential count showed 69 mature polymorphonuclear leukocytes, 10 band cells, 12 lymphocytes, 8 monocytes, and 1 eosinophil. Roentgenograms of the chest showed a localized area of infiltration in the right posterior costophrenic sulcus, with a small amount of pleural reaction around it (Figs. 1 and 2). In the d#erential diagnosis, the conditions to be considered were pneumonitis and pulmonary embolus. The time of onset of pleuritic pain and the response to therapy made the diagnosis of pulmonary embolus likely. During any extensive surgery in the pelvis, a great many small veins have to be tied off. These veins thrombose and thus represent potential sources of emboli. Whether or not this is of clinical signifi-

this that

extensive

veins as in the following

means

it is an error;

and emboli

of

deposi-

combating

York

damaged

substances.

an effective

M.D.

monary

is acti-

to platelet

quickly

a

a number

thrombogenic

has not yet devised

completely

clotting

of

to

New

of protection

phenomenon way

that

release

Evolution

states

This

York,

a liquid

method

a non-specific

and

of

of

CHANGE

solid state is nature’s

T. FOLEY,

and the Vascular

456

Clinic,

The New York Hospital,

New York,

THE AMERICAN JOURNAL OF CARDIOLOGY

Intravascular

Fro. 1.

Pulmonary

through

4 from:

embolism from surgery. (Figures FOLEY, \\‘. T. and WRIGHT, I.

1 S.

Colored Atlas and Management of Vascular Disease. NN York, 1959. Appleton-Century-Crofts. Inc. 1 cancc depends on whether or not a clinically detcctable embolus actually does occur. 7 I-entmenl: The only therapy consisted of heparin (conctmtrated to 20,000 units per ml.) which was given subcutaneously every twelve hours; an units was given. Blood initial dose of 15.000 The aim was coagulation tests were carried out daily. to obtain a maximum of three times the control coagulation time in a period of four hours after adCoagulation time ministration of the heparin. should return approximately to normal by the The dose was varied each day, ranging twelfth hour. from a low of 10,000 units to a high of 15,000 units. The l’his was continued for a period of three weeks. fever slowly subsided during this period. Symptoms referable to the chest persisted for about four days Rales persisted for and then gradually regressed. twelve days. The ahdomen was tender, but not more so than would be expected after such a major surgical procedure. The legs were clinically normal Because of the absence of involvement at all times. in the legs, it was not necessary for this patient to lvcar elastic stockings. STASIS

Stagnant blood tends to clot. Civilization has developed many customs which lead to stagnation of blood. Modern clothing is not Men wear circudesigned for proper hygiene. lar garters that act as a tourniquet on the flow The girdles worn of \-enous blood in the legs. t)y women are designed for standing; none are designed for the woman when she sits down and, if shr sits for many hours at a time, phlebitis can follow. AUGUST 1960

Clotting

FIG.

2.

Pulmonary

rmbolism

from

srrr~n-!~

(oblique

view ).

Thrombophlebitis Dur to Stasis: A middleCASE 2. aged woman gave a history of varicose veins being prevalent in both sides of her family. She inherited After years of standing, these weak venous valves. valves ruptured successively until the entire venous system from heart to ankles was devoid of this protection. Under this increased head of pressure. the superficial veins became widely dilated and varicose. In On a long automobile trip she wore a girdle. the sitting position, this girdle bunched up in the groin and acted as a tourniquet to impede blood How. The followThe stagnant blood clotted in the veins. ing day she noticed red, tender. hot cords along her inner thigh. They quickly extended down to the The following day the entire leg was knee and calf. A fever swollen due to blockage of the deep veins developed. On examination, the long saphenous vein was found Large to be thrombosed from mid-thigh 10 calf. Some measured as clots filled the dilated varices. much as one inch in diameter. The foot and ankle 7‘he calf at were swollen with 3 plus pitting edema. its maximum circumference measured two inches On dependrncy, a deep greater than the other calf. cyanosis developed. When standing, collateral v&s probecame prominent over the hip. Weight-bearing duced pain in the foot and leg. Passive flexion of the foot elicited pain in the calf. Therafiy: She was placed at bed rest and the foot Hot of the bed was elevated on six-inch blocks. moist packs were applied. Anticoagulants were administered ; 15,000 units of heparin were given subThe concentrated cutaneously every twelve hours. On the third form was used (10,000 units per m1.j. administration was started. Theraday Dicumarol’8 peutic levels of prothrombin time were reached on the fifth day. Hepa.rin administration was discontinued and Dicumarol was maintained at a dailv

dose that kept the prothrombin time between twentyfive and thirty-five seconds. Pain and tenderness subsided rapidly, but the hard On the tenth day, clots persisted for many weeks. her temperature returned to normal and she was allowed to walk. A well fitted elastic stocking was made. It extended from the toes to one inch below the knee. On the twentieth day she was discharged from the hospital. After Cure: She was instructed to (1) walk about with the stocking on; (2) sleep with the foot of the (3) swim or walk in deep water as often bed elevated; as possible; (4) elevate the feet on a footstool when and (5) avoid tight garments and sitting for sitting; long periods of time, as in a train or plane trip. Dicumarol administration was continued for an additional six weeks. Each week her prothrombin time was checked, and she was cautioned to expect aches and pains in her legs from time to time, especially when there was a sudden fall in barometric After six weeks, the dose of Dicumarol was pressure.

gradually decreased, then stopped two weeks later. One year She returned to her position as a clerk. later, her leg showed the varicose veins as before. but no additional signs of venous insufficiency had developed, as her elastic stocking protected her. She was told that her venous insufficiency could be improved only by surgery but that, if she followed the regimen outlined, she might avoid further difficulty. Stasis with

may

blood time.

or

For

in

bed

without

of

to

apt

long

heart

be

periods

of

often

occur.

is In

of any

illness

Patients

with

sit all

day

Thrombosis

to

to

disease.

develop.

moving.

cellulitis

are

because

patients

is apt

and

for

If such

sluggish

thromboemholism

to bed

prone

have

they

reasons,

or senile

tissues

tions

lie

Patients

disease.

failure

complication is

arthritis chair

to

confined

phlebitis

from

addition,

these

major

patients

the

occur heart

In

flow.

sedentary the

also

congestive

in

Swelling,

in a

in

situ

CASE 3. Arterial Embolism: This fifty-one year old woman, a factory worker, had been well until November 1954, when severe angina pectoris deThis gradually increased and after six weeks veloped. it culminated in an episode of severe substernal pressure, which led to admission in another hospital. A diagnosis of myocardial infarction was established. Anticoagulants were not given. On the fourteenth day, while straining on a bedpan, a sudden pain developed in her left leg. The leg rapidly became cold and blue. She was then transferred to our hospital. hxamination showed cold, pulseless, cyanotic legs. Our diagnosis was Femoral pulses were absent. embolization of the lower abdominal aorta from a mural thrombus secondary to myocardial infarction. Treatment consisted of anticoagulant therapy and The the use of an oscillating bed and reflex heat. legs became warmer, but the left large toe became black and mllmmified. Collateral flow developed down into the foot. All areas became pink and warm except for the black toe. The patient became ambulatory and was discharged. In March (four months after her embolic phenomenon). the necrotic toe \vas gently twisted off with a thumb forceps. The patient was encouraged to walk long distances slowly. Arterial flow continued to improve and perfect healing was obtained. A follow up for three and a half years shows conShe tinuous improvement in collateral circulation. has resumed work at her former job.

ulcera-

after femoral

areas

The

eddy

currents,

when wall

the

such

mitral

of an artery

tion, boli

thrombi are

tient

thrombus by off

mural and

of the heart or

has an aneurysmal

to form.

This

in rheumatic

wall

heart

the

heart

the

dilata-

is why

to the wall

of

in

em-

disease.

of a blood gives

rise

thrombi infarct.

produce

WE: The

to

emboli

as in the following

isform demonstrated over thrombi

in large patient,

and

may

break

important

lower

arteries, to

has

of

such

a recent

considered

a few

aorta,

extremities

serious rhe

an

or

or

the

embolectomy. patient

must

operation.

myocardial

a grave

hours

iliac

consideration

immediate

condition before

disease

in the

a

which

wall

at that

in the following

peculiar

formation.

myocardial vessels

forms

is deformed,

or damage

to the

flow

as in the auricle

that

so common

or

who

usually

Any

blood

valve

tend

Inflammation vessel

the

of the

given

general

considered

clotting

where

arteries be

within the

.\

be

pa-

infarction

surgical

is

risk.

ARTERITIS

follow.

CURRENTS

In

is seen

blocking

subclavian-axillary should

tion EDDY

a patient

embolism

gives

of a vessel site. case

Two

rise to an inflammacan

produce

examples

blood

of this

are

reports.

CASE 4. Ergot Poisoning: A middle-aged building superintendent had suffered from migraine headaches for many years. He had polycythemia. He had taken ergotamine tartrate at frequent intervals which Fcr two weeks had affected his headaches favorably. prior to admission, he had taken unusually large doses. Gangrene developed in the right fourth toe. The foot was cold; the vasospasm was severe. Treatment consisted of withdrawal of the ergotamine, reflex heat applied to the groin, the use of an oscillating bed and walking for increasing distances hourly during the day. Healing took place without difficulty. THE AMERICAN JOURNAL OF CARDIOLOGY

Intravascular

FIG. 3. Ganqrrm~ syncrasy.

of

the

hands

from

tobacco

idio-

CASE 5. Nicotine Idioqncrasy: Before we first saw him, a physician in early middle age had had three attacks of superficial phlebitis. Spasmodic blanching of the fingers and toes after slight chilling of the body then developed. Ulcerations formed on the finger tips. Examination showed sluggish radial and occluded ulnar pulses. He was hospitalized. He had been accustomed to smoking twenty cigarettes daily but stopped this habit completely during the first hospital stay. Treatment: He was given fever therapy in the form of intravenously administered typhoid vaccine. Using a dilution of 100 million organisms per ml., five million bacteria were given the first day. Four hours later he had a slight chill, followed by a temperature of 101’~. We prefer to obtain two to three degrees of fever without a chill, but this is not always possible. The temperature remained elevated for two days. On repetition of the treatment no elevated temperature was produced. The dose was, therefore, increased by three million organisms every fourth day. Healing was well advanced in three weeks, at which time he was discharged. FIe returned to a busy general practice. For six However, months he succeeded in avoiding tobacco. during a period of great stress, he resumed smoking. T’h(L disease promptly became active and new ulcers appeared. Figure 3 shows the gangrenous hands. Th<, radial, ulnar, dorsalis pedis and posterior tibia1 vessels were occluded. Because of the intense pain, he had become addicted to narcotics.

With Iie was again admitted to the hospital. great difficulty he gave up smoking. Narcotic dcses were reduced, then successfully omitted. Again fever therapy was given. Collateral flow developed and good healing was obtained with only minor loss of tissue (Fig. 4). If this patient should resume the use of toI)acco, the disease may be expected to involve other vessels, such as the brachial, iliac, coronary, cerebral or mesenteric arteries.

Clotting

Flc;. 4.

DIABETES

Hralirq

after tobacco

intc~rtliction

MELLITUS

This disease notoriousl>, gives rise tu a rapid Involved in diabetes type of atherosclerosis. are many complex factors which are not understood. There is a vasculitis that sc-ems to I)e independent of the defect in carl)ohydrate metabolism. In patients in whotn the glucose metabolism is well controlled b)- diet and insulin, extensive vasculitis develops nevertheless. Diabetes affects not onl>- the laqe vrssels, t)ut also involves the small vessels, such as the digital arteries. Gangrene of the toes can occur even in the presence of good pulsations in the dorsalis pedis and posterior tibia1 artcrics. CASE 6. Diabetic Gangrene: A fifty-eight year old municipal worker presented with gangrenous toes. His other leg had been amputated one year previously at another clinic. He was able to walk well with his artificial leg but had taken to bed when his toes caused pain. He had an occlusion of his femoral artery in Hunter’s canal. Therapy: He was treated as an ambulant patient and not admitted to the hospital. The diabetes was controlled by administration of tolbutamide and by diet. Each hour he walked for a minimum of five minutes. He gave up the use of tobacco. Furacin The soluble dressing was applied daily to his toes. necrotic toe separated at a line of demarcation. The bone was severed with scissors. He was encouraged to walk and reported for weekly debridemrnt. Complete healing was obtained.

OTHER TYPES

OF THROMBOEMBOLISM

Atherosclerosis, giving rise to thrombosis, will develop in any blood vessel For example, a that has been damaged. congenital lesion such as coarctation of the Syphilitic inaorta leads to atherosclerosis. volvement of the arteries, in turn, leads to Atherosclerosis:

460

Foley

atherosclerosis, omatous the

arterial

that

Blood

and

clotting

hemorrhage

All

types

of

any

mechanism leukemia

disturbance that

at

are

danger

notoriously

so

occur

in

areas.

It produces

can

place

is always

these

Polycythemia

to thrombi.

and

at

there over

Ather-

degree.

develop

will form

Dyscrasias:

rise

the

of a severe

may

system

thrombi

gives in

often

patches

the

thrombi

same

associated

time. with

At autopsy, massive old and recent pulmonary thromboemboli were found. There was extensive sclerosis of the large and small arteries and arterioles in the lungs. The right ventricle of the heart was hypertrophied and dilated. No congenital abnormalities were found in the heart. The changes in the pulmonary vessels apparently were the result of repeated old and recent embolization with subsequent thrombosis. The site of the origin of the emboli was not demonstrated.

thromboembolism. Toxic

Toxicity: pura

and

chemicals

thromboses

give

at the same

rise

to

purThe

CASE 7. Phlebitis and Purpura from Drug Toxicity: This patient is an elderly woman who complained of pains in her joints. A physician prescribed phenylbutazone, 100 mg., to be taken after each meal for a period of seven days. She obtained a great deal of relief from this medication and decided to take it She continued without consulting her physician. taking the drug for a period of six months. Suddenly bleeding in her mouth, legs and thighs developed Examination disclosed that the bone marrow had There was also ceased to produce granulocytic cells. a complete absence of platelets in peripheral blood Phlebitis had developed in the veins of the smears. legs, as well as large hematomas and widespread ecchymoses. Bleeding had also occurred in the lips, in the oral cavity and about the nose.

Most

Malignancy: associated,

sooner

or

travascular

clotting.

some

types

of

ment

in the

blood

to formation

of

types

of

later, It

carcinoma

is

thrombi

carcinoma extensive

well

known a

the

leading

heart,

arteries

and veins. Thromboembolism from Carcinoma of the CASE 8. Breast: The patient was a twenty-six year old housewife who had an adenocarcinoma of the breast. Phlebitis developed which was not controllable by oral anticoagulants, and other areas of thrombosis Pulmonary emboli developed. With the occurred. attacks of migratory phlebitis, she had episodes of At autopsy extensive intravassevere vasospasm. cular clotting was demonstrated. Embolism extensive evidence

of

Unknown

pulmonary of

the

original

Sometimes

Origin: emboli site

occur from

without

which

blood

clotting

phenomenon number

that

of

turbances

biologic may

and

and to

unknown of

to

come

errors

diseases,

cause.

the

in

by

are

by

which

decade when

cause

of

mi-

such

as

;

malignancy are

the

increases

reached,

leading

of

disof

hygiene,

many

Decade

a great

activity

to

clotting

ages

non-specific These

to

garments;

intravascular

geriatric

is a

activated

secondary

tight

other

be

disturbances.

be

;

cro-organisms stasis

process

can

until thrombi

disability

of

threat the beand

death. Evolution combating and

to

means

has not

developed

this

reaction

disease.

Man

of

coagulant his beginning

coping drugs

attempts

errors

must

with and

a mechanism

to

lytic

the

in

devise

artificial

problem. enzymes

to meet

this

for

hygiene Antirepresent

problem.

inthat

derange-

mechanism, in

are

with produce

clotting

CONCLUSION

time.

they

came.

CASE 9. Embolism of Unknown Origin: A fifty-year old housewife had signs of progressively severe pulClinically, she was thought monary hypertension. She did not reto have congenital heart disease. spond to therapy and died.

DISCUSSION

OF PAPER

BY DR.

FOLEY

DR. THEODORE H. SPAET (New York, h’ew York): One of the things that has disturbed coagulationists is the fact that in blood everything necessary for clotting is present in intimate mixture yet the blood stays fluid. This would not be so surprising under normal circumstances but the preservation of fluidity is stubbornly maintained despite the fact that highly coagulant materials can be introduced into the general circulation. There is virtually never, except under the most unusual circumstances, the production of in uiuo clotting. In the past, the explanation for this phenomenon has largely concerned circulating materials which inhibit clot formation and materials which destroy small clots if they do tend to form. However, a vast amount of coagulant material can be introduced into the general circulation with impunity. The degree of “hemostatic homeostasis” appears to exceed the capacity of circulating agents. We can perhaps formulate a law that blood will clot only if it fails to circulate. We have evidence that blood stays fluid when it circulates because coagulant activity which develops or is introduced is cleared by a cellular mechanism. Our most significant data concern fully formed blood thromboplastin. We have some rather compelling evidence that blood thromboTHE AMERICAN JOURNAL OF CARDIOLOGY

Intravascular plastin is particulate in nature and is selectively cleared by the reticulcendotheilal system. Briefly: (1) If blood thromboplastin tagged with 1131 or P3* is given intravenously it distributes itself like (2) If blood thromboplastin is given carbon in the rat. intravenously during the course of a carbon clearance, the clearance is markedly inhibited. (3) If blood thromboplastin is exposed directly to the reticuloendothelial system (for example, by injection into the hepatic circulation), material that is highly thromboplastic and would ordinarily defibrinate and kill an animal will be less toxic and will cause considerably On the basis of this type of findless defibrination. ing it now seems possible that each blood coagulation intermediate is removed by a specific type of clearance mechanism. Perhaps the reticuloendothelial system may prove to be the effective mechanism for all intermediates. However, at the present time we

AUGUST 1960

Clotting

461

can only speak firmly with respect to blood thromboplastin. DR. GEORGE R. FEARNLEY (Gloucestershire, England): I hesitate to criticize any of this presentation, and as one who smokes I can accept the results of what may happen to smokers. But as a rheumatologist. even at a meeting on fibrinolysis, I cannot accept the statement that the arteritis of rheumatoid arthritis In England where steroids is due to steroid therapy. are used less, we see these complications in patients The general who have never received steroids. opinion in England is that the arteritis of rheumatoid arthritis is not caused by steroid therap)-. DR. WILLIAM T. FOLEY (closing): In the specific case of rheumatoid arthritis referred to by Dr. Fearnley, the young man recovered when steroid therapy was discontinued, suggesting that the steroids were involved in the arteritis.