CONGENITAL AFIBRINOGENEMIA

(1)

By

PAUL G. FRIcK, M.D., AND IRVINE McQuARr1u, M.D.

Minneapolis

44

C

ONGENITAL afibrinogenemia is a rare

disturbance of protein metabolism manifested by its profound effect on the blood clotting mechanism. Since its original

description by Rabe and Salomon,’ 15

re-ports including 16 cases appeared in the literature’” 13-16 and three cases were

pre-sented by Diamond’2 at the International

Congress of Hematology in Buffalo in 1948. A review of these reports is given in table 1 with the addition of a new case presented

in detail in this paper.

CASE REPORT

The patient was a 7 yr. old white boy known

to be a bleeder since birth. He received the

first transfusion on his fifth day of life because

of persistent bleeding from the umbilical cord. Later he had several episodes of external hemorrhages due to injuries which responded

promptly to tranfusions. For this purpose he

was hospitalized 16 times by his private physi-cian. The admission to the University of Mm-nesota Hospitals on April 3, 1952 was prompted

by an episode of hematemesis and melena.

Be-cause of severe shock a blood transfusion was

immediately started; while the blood was run-fling a clotting time done with the technic of the glass capillary was reported to be “longer than 15 mm.” (normal up to 6 mm.), the

bleed-ing time was 5 mm. (Duke method) and the platelets were 222,000/cmm. The first impres-sion was that of a hemophilic patient with an

acute gastrointestinal hemorrhage. An abnormal thrombin titration17 and the small size of the

clot a few days after admission led to the suspicion of a defect in the last phase of

co-agulation. About 2 wk. after discontinuing plasma transfusions the patient’s blood was found mncoagulable because of the absence of

From the Departments of Internal Medicine and

Pediatrics,University of Minnesota Hospitals, Mm-neapolis.

(Received for publication July 5, 1953.)

Portion of a thesis to be submitted in partial

fulfillment of requirements for the Ph.D. degree, by Dr. Frick, University of Minnesota.

fibrinogen; this fact strongly suggested the di-agnosis of congenital afibrinogenemia which was assessed by other tests presented below.

In addition radiologic studies revealed a

du-odenal ulcer which healed over a 2 mo. period

under dietary regimen and repeated trans-fusions of blood and plasma. The

administra-tion of fibrinogen was not only indicated for

hemostasis, but also because it was essential for scar formation and healing of a peptic ulcer.

The family history did not reveal any other bleeders, but it was disclosed that the patient’s

parents were first cousins.

Laboratory Data : In order to avoid the

dis-turbing effect of transfused fibrinogen, all tests

were done at a time when the patient did not

receive any therapy. Urinalysis negative. Hgb

14.2 gm./100 cc. WBC count 7.1 thousand/ cmm. with a normal differential count. Sedi-mentation rate 1.5 mm. after 1 hr.

(Wester-gren). Hematocrit 44%. Serum bilirubin direct

0.1 mg./100 cc., total 0.7 mg./100 cc. Cephalin-cholesterol flocculation negative. Thymol tur-bidity 4 units. Zinc turbidity 11 units. Serum cholesterol 190 mg./100 cc. with 74% esters. Total serum proteins 7.9%, albumin 3.3 gm.,/ 100 cc., globulin 4.6 gm./100 cc., a cflobulin 1.7 gm./100 cc., globulin 1.5 gm./100 cc., -I,globulin 1.4 gm./l00 cc. (method of Milne’t). Bromsulphalein retention 0% after 45 mm. Serum cholinesterase 1.41 pH/hr. (normal

range 0.52-1.08 pH//hr.). Urine urobilmnogen 0.2 mg./day, urine coproporphyrin 144 ,ig./

day.

The extremely low sedimentation rate has been described previously in

afibrinoge-nemia;8 this clearly illustrates the influence of the concentration of fibrinogen on this widely-used test. The sedimentation rate re-mained unchanged during two acute infec-tions (infectious mononucleosis and

(2)

en-CONGENITAL AFIBRINOGENEMIA 45

countered with parenchymal liver damage,

while an elevated value is usually found with excessive losses of albumin (e.g.,

nephrosis) which presumably calls for an

increased rate of albumin production. In this case there was no trace of albumin in the urine on repeated analysis. Not having

any explanation for this abnormally high cholinesterase activity, the authors will limit

themselves to record it as an isolated

devia-tion from normality of a single liver

func-tion test.

Determination of the Concentration of Single Clotting Factors: A systematic study

was undertaken in an attempt to determine

the concentration of all clotting factors

known at the present time.

Fibrinogen : Different methods were ap-1)lied 111 a vain attempt to demonstrate the

presence of fibrinogen:

1. Coagulation. It was not possible to

obtain any fibrin clot from the patient’s plasma with equal volumes of any of the following reagents:

(a) CaCl, (conc. 1%1/8() NI).

(b) CaCl2 (cone. 1%..1/8o M) + rabbit

brain thromboplastin.

(c) bovine thrombin (cone. 1-5000 U./

ccm.)

2. Heating. Upon heating the patient’s

plasma there was no turbidity nor

floccula-tion between 53#{176}and 56#{176}C., which is the temperature zone where fibrmnogen

floe-culates out. The first sign of increased viscosity followed by turbidity and heat

coagulation became manifest at 71#{176}C.as a

result of physical changes of serum albumin. 3. Electrophoresis. There was no

fibrino-gen peak in the electrophoretic pattern of

the patient’s plasma (chart 6).

The patient’s plasma and serum were as-sayed repeatedly for fibrinogenolytic and

fibrinolytic activity. At no time was it pos-sible to detect any lytic effect on normal fibrinogen or fibrin.

Prothrombin: The 2-stage method was

applied to determine the concentration of

prothrombin.’#{176} The patient’s plasma con-tained 360 U/cc. prothrombin, a value

which is within normal range.

Platelets : Repeated platelet

determina-tions gave consistently normal values rang-ing between 222,000 and 410,000/cmm.

Antihemophilic Globulin (AHG): The

concentration of AHG was found to be nor-mal. AHG was estimated by comparing the effects of the patient’s plasma with normal plasma on the clotting time and the

pro-thrombin consumption of hemophilic blood (table 3, chart 1). For both assays the

plas-mas were prepared with 1/10 vol. of 0.1 M

Na oxalate sol. The tests were carried out with fresh plasma within three hours after

venipuncture.

Simultaneously with the 2-stage

deter-ruination of prothrombin consumption a 1-stage test was performed2l which gave

comparable results. The data of these assays demonstrate that the patient’s plasma was similar to normal plasma in its

antihemo-philic activity.

Plasma Thromboplastin Component

(

PTC): The authors were fortunate enough

to have a patient available who had a de-ficiency of PTC identical to the case re-ported by White et al.22 The PTC activity of afibrinogenemic plasma was tested on this patient’s blood with the same technics used

for the assay of AHG (table 4, chart 2). The afibrmnogenemic plasma had a rectify-ing effect on the abnormalities of

PTC-defi-cient blood which was comparable to the effect of normal plasma.

Prothrombin Conversion Factors : Recent studies have shown that the rate of conver-sion of prothrombin to thrombin is influ-enced by two factors which for the sake of

simplicity will be called Labile Factor (L.F.) and Stable Factor (S.F.).23 A deficiency of

either factor causes a delay in the rate of prothrombin conversion which is best il-lustrated by the prothrombin conversion

rate curve obtained with the modified 2-stage method for prothrombin determina-tion reported previously.24 The curve

(3)

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(5)

r-TABLE 2 TABLE 3

EFFErT OF AFImHN0GENEMIc PLASMA VS. NORMAL

PLASMA ON CLOTTING FIME OF IIEMOPIIILIC BLOOL) Hemophilic blood (cc.)

NaC1 0.9% sot. (cc.) Afibrinogenemic plasma (cc.) Normal plasma (cc.)

1.0 1.0 1.0

0.1

0.1 0.1

Clotting time (inin. 66 17 ii

‘Fechnic: Modified Lee-White clotting time rising 2

glass tubes (8X 75 11)111.) for each clotting tiiiit deter-ruination. 1 .0cc. heniophilic 1)100(1 S placed in each I ube containing either 0. 1 cc. of nornial Saline or 0. 1 (c. of

the plasmas to he tested. All tubes are inhIne(liately

tilted twice for adequate fluxing of the heiiiophilic 1)100(1 with saline or plasnur. Starting 10 iiii,r. lIfter col-lection of the heniophilic 1)100(1, the first of each couple of tubes is tilted every minute until it is clotted; the

same is done with thesecond one after the first one is

clotted. ‘I’lieendpoint of the secon(I tube is reII(l as clotting time of venous 1)100(1.

genemic plasma exerts a L.F. activity which

is comparable to normal (chart 3).

Stable Factor: The availability of blood

from a patient with congenital S.F.

de-ficiency24 provided an excellent opportunity

ij 200 U

C

-a E

0

-c

0

a-0 ‘I,

C

D

0 10 20 30 40 50 60 70

Time after venipuncture (minutes)

CHART 1. Effect of afibrinogenemic plasma vs. normal plasma on consumption of prothrombin of henio-philic blood. Technic: 2-stage method described by Langdell et al.’#{176}

48 PAUL G. FRICK AND IRVINE McQUARRIE

Routine tests of hemostasis

Bleeding time (Ivy method): 4 ruin.

Clotting time (Lee-White):

Prothroinbin time (Quick):

Platelets (Reese-licker): 225 .000/ernm.

Capillary fragility (Rumpel-Leede): negative Clot retraction: No clot

tion of adequate concentrations of L.F. or S.F. to a plasma deficient in either of the

respective conversion factors results in a

normalization of their prothrombin

conver-sion curves. The authors assayed the activity

of L.F. and S.F. in afibrinogenemic blood

by comparing its action with the effect of

normal blood on a plasma deficient in one

or the other conversion factor.

Labile Factor: Normal oxalated plasma stored for 6 days at 20#{176}to 24#{176}C.under

sterile conditions was used as a source of

L.F.-deficient plasma.

The delayed rate of prothrombin conver-sion was rectified by BaSO4 plasma

(6)

afibrino-EFFECT OF’ AFIBRINOGENEMIC PLASMA vs. NORMAL

ILASMA ON (‘LOTTING TIME OF PTC-I)EFICIENT BLOOD

PTC-deficient blood (cc.) 1.0 1.0 1 .0

NaCl 0.9% sol. (cc.) 0. 1

Afibrinogenetnic plasma (cc.) 0. 1

Normal plasma (cc.) 0. 1

Clottitig tulle (111111.)

to

assay the afibrinogenemic serum for its S.F. activity. Afibrinogenemic and normal blood were collected under sterile

condi-tions and placed in a waterbath at 37#{176}C.for

48 hours. The sera were drawn off after

centrifugation and assayed on S.F.-deficient plasma. After 48 hours storage neither serum contained any thrombin and only traces of prothrombin and L.F.

There is no appreciable difference

be-tween the corrective effects of afibrino-genemic and normal serum on the retarded

prothrombin conversion rate of S.F.-de-ficient plasma; hence their S.F. activities

were comparable (chart 4).

U

C

E 0

0

a-0

.IJ

C

0 tO 20 30 40 50 60 70

Time after venipuncture (Minutes)

CONGENITAL AFIBRINOGENEMIA 49

CHART 2. Effect of afibrinogenemic plasma vs. normal plasma on prothrombin consumption

of PTC-deficient blood.

TABLE 4 This last assay concluded the group of

tests undertaken to determine the activity

or concentration of all clotting factors known up to date. With the exception of

fibrinogen, all of them were found to be

normal, and it appeared definite that the

absence of this clotting entity was an

iso---

lated coagulation defect.

105 13 19 Prothrombin Consumption Tests: Both

the 1-stage and the 2-stage method were

ap-plied todetermine the patient’s prothrombin

consumption (chart 5, table 5), which was

found to be more rapid than normal. This is

presumably due to the fact that in afibrino-genemia the adsorbing and neutralizing

ef-fect of fibrin on thrombin is missing and the thrombin evolving during the process of clotting remains uninhibited in its

auto-catalytic action on the conversion of

pro-thrombin.5

Electrophoretic Studies (see chart 6): As expected the fibrinogen peak was absent in

the patient’s plasma. An observation of

ma-jor importance is the identity of the patterns

(7)

PAUL G. FRICK AND IRVINE MCQUARRIE 50

80

Stored normal plasma (LF. deficient)

toted normal plasma F normal 80504 plasma

70

Stored normal plasma

C

0

60

.--5

“I C

5) 50

0 .E

40

0

30

5)

E

.-;

C 20

.-0

to

I I I I I

0 I 2 3 4 5 6 7 8 9 0 Il 2 1314

Incubation time (Minutes)

CHART .3.Effect of afibrinogenemic BaSO4 plasma vs. normal BaSO4 plasma on prothrombin conversion

rate of L.F.-deficient plasma. Technic: BaSO plasmas were prepared by adding 700 mg. BaSO (Merck

& Co.) to 10 cc. oxalated plasma. This mixture was gently shaken for 5 mm. and BaSO4 centrifuged out

at 2000 rpm for 10 mm. 0.1 cc. L.F.-deficient plasma was mixed with 0.1 cc. afibrinogenemic or normal

BaSO plasma immediately before 2-stage determination. Final dilution of L.F.-deficient plasma: 1:300.

140 ‘

-130

120 d

5)

Ito

-?

C

2

....l

I

-5U,C₅₎ 90

0 80

.E

- 70

6O

0 50

5)

E

a)

C 30

0 20

to

-0 I 2 3 4 5 i#{235} 9 tO II 12 13 14 15 6

Incubation time (Minutes)

CHART 4. Effect of afibrinogenemic serum vs. normal serum on prothrombin conversion rate of

S.F.-(leficient plasma. Technic: 0.1 cc. S.F-deficient plasma mixed with 0.1 cc. of either afibrinogenemic or

normal serum immediately before 2-stage determination. Final dilution of S.F-deficient plasma: 1:300.

deficient plasma

(8)

Normal blood

--

Afibrinogenemic blood

200

-00

0 lO 20 30

U U

C

E

0

0 0 0

UI 4.,

C

400

r

Time after venipuncture (Minutes)

CHART 5. 2-stage prothrombin consumption of afibrinogenemic blood.

changes occurring during the transformation

from plasma to serum, which in essence are

limited to changes in blotting factors, cannot be detected by routine electrophoretic

analysis. It was demonstrated that the

pa-tient’s plasma contains normal

concentra-tions of prothrombin, AHG, PTC, L.F. and

S.F.; the serum, on the other hand, is

prac-tically free of prothrombin, L.F. and AHG,

and contains appreciable amounts of S.F.

TABLE 5

1-STAGE PROTIIROMBIN CONSUMPTION OF

AFIBRINOGENEMIC BLOOD

1’nne after Serum

venipuncture prothroinhin

(Inin.) time (see.)

0 (plasnia prothrombin time) _15.0

10 14.2

20 _14.2

30 32.1

40 59.6

60 90.0

Technic: 1-stage prothrombin time determination

On 0.1 cc. of each serum sample using 0.1 cc. of

pro-thrornhin-free normal IlaSO4 plasma as fibrinogen

sub-strate.

and PTC but no detectable active thrombin. It is probable that the absolute absence of changes demonstrable by electrophoresis

between afibrmnogenemic plasma and serum, despite the profound conversion, activation and neutralization of plasma components, is

due to the small concentration of these fac-tors when compared with the concentration

of the total serum proteins. Fantl26 gives a value of 15 to 23 mg./100 cc. for human pro-thrombin adsorbed with BaCO3; in the light

of recent investigations this value is

prob-ably too high because it does not reflect pro-thrombin alone but the S.F. as well.

Seeg-ers27 states that human prothrombin 1 mg. has a specific activity of 2000 units; assum-ing a normal value of 300 units/cc. plasma, the calculated concentration of pro-thrombin would be 15.0 mg./100 cc. The concentrations of AHG and PTC are not

known. The concentration of bovine L.F., which is higher than in humans, lies below a value detectable by routine electro-phoretic analysis; according to Ware and Seegers,28 it constitutes less than 0.7% of the

total plasma proteins in bovine plasma. In

(9)

Ascending boundaries Descending boundaries

E

5)

UI

U

E

5) C 5) a)

0

C

CIiAwr 6. Electrophoretic patterns of afibrinogenemic plasma and serum. Method: Standard Tiselitis cell of 3 cc. capacity. Patterns obtained at pH after 2 hr.

Tune after

transfusion

Concentration of fibrinogen in mg./100 cc.

161 111

86

37

26

too low for quantit. det.

none detectable

52 PAUL G. FRICK AND IRVINE \IcQUARRIE

for fibrinogen, no other clotting factor, either before or after coagulation, influences

routine electrophoretic patterns.

Studies on the Turnover Rate of

Fibrino-gen: This patient offered an excellent op-portunity to study the rate of disappearance

of injected fibrinogen in humans. For this purpose a transfusion of the content of 20

TABLE 6

RATE OF DISAPPEARANCE OF FIBRINOGEN AFTER

TRANSFISION OF FRACTION I

4hr.

1 (lay 3 (lays

5 (lays

7(layS

10 days 12 (lays

Method of Fibrinogen Determination:

Precipita-ti()n of fibrin according to the method of Cullen and Van Slyke23 and micro-Kjeldahl nitrogen deter-mination on the fibrin clot obtained from 0.1 cc.

plasma with the method of Ma and Zuazaga.

E

5)

UI

U

E

5) C 5) a)

0

C

ampuls of Fraction I (approx. 200 mg.

fibrinogen each) was given and the

fibrino-gen level determined at intervals up to the day of its disappearance.

The value of 161 mg./100 cc. obtained

3: hour after the infusion corresponds to

approximately half the concentration of fibrinogen in normals. There was a gradual

fall during a period of 12 days at the end of which time no fibrinogen could be detected

with any of the methods listed earlier. On the 10th day a niinute crumble of fibrin could be precipitated with CaC12, but a quantitative determination would not

have been adequate. A comparison of these

data with previous reports on transfusions

111 afibrinogenemia is difficult l)ecause of

differences in the age of the patiellts and in

the volumes of transfused blood. Breckoff,u

who restudied the case of Rabe and

Salo-mon, stated that fibrinogen was still present

10 clays and absent 17 days after transfusing

400 cc. blood in the 13 year old patient.

Diamond32 claimed that once a level of 200

(10)

/

a, E

I.-50

40

I-Stage prothrombin time

--- Thrombin time (thrombin solution I)

-- Thrombin time (thrombin solution 2)

I

N-% Normal plasma

A- % Afibrinogenemic plasma

F - Fibrinogen mg. %

0__

N 100

A 0

F 405

90 80

10 20

364.5 324

Fraction I, the fibrinogen level fails to 50

mg./100 cc. in approximately three weeks.

Sch#{246}nholzer gave 600 cc. blood to a 13 year old patient and reported the presence of

fibrinogen after 13 days, while by 24 days it was not detectable any more. Castex and Pavlovsky7 noted disappearance of fibrino-gen within 96 hours after transfusing their patient with fresh blood up to a plasma

fibrinogen level of 1 gm./1. Madden and

Gould33 reported an average turnover of 8.1

days ill three human subjects by feeding 535

labelled DL-methionine and assaying the fibrin clots for the radioisotope. It is possible

that the preparation used in the present

au-thor’s study underwent some deterioration

during its processing and was not directly comparable to native fibrinogen. However,

some preliminary data obtained after

trans-fusion of citrated plasma substantiate the

values obtained with Fraction I. Therefore

it is reasonal)le to assume that the data are representative of the turnover rate of

fibrin-ogen in this patient.

130

120

110

l00

90

U,

0 C 0

70

U)

c 60

Influence of Fibrinogen Concentration on

the 1-Stage Prothrombin Time and on the Clotting Time with Thrombin : The

availa-bility of fibrinogen-free plasma containing

all the other clotting factors in normal con-centration facilitated the study of the

influ-ence of the fibrinogen concentration on Quick’s prothrombin time and thrombin

time. By mixing normal plasma with the patient’s plasma in various proportions, it was possible to obtain a series of plasmas

with different fibrinogen concentrations without alterations of any other coagulation factor. This simple procedure eliminates the

necessity of defibrination with thrombin or

heat; both these methods are known to alter clotting elements beside fibrinogen, and the results obtained with technically

defibri-nated plasma are not as accurate as the ones obtained with naturally afibrinogenemic plasma.

The data in chart 7 demonstrate that the

concentration of fibrinogen has to fall ap-preciably before it influences coagulation

70 60 50 40 30 20 0 0

30 40 50 60 70 80 90 00

2835 243 2025 62 l2L5 8l 40.5 0

C1IAnT 7. Influence of fibrinogen concentration of 1-stage prothrombin time and on thrombin time.

Technic: Thrombin solution 1 was set to give clotting time of 10 sec. when added to equal volume of

normal plasma. Thrombin solution 2 gave time of 20 sec. by same method. For present study, 0.1 cc.

(11)

tests. Between 400 and 200 mg./100 cc. fibrinogen there are not significant changes in the prothrombin times nor in the clotting

times with thrombin. The prolongation of times is moderate, between 200 and 50 mg./ 100 cc., but rises rapidly thereafter.

CLiIc.i REVIEW OF AFIBRINOCENEMIA

Symptomatology and Diagnosis: As in other congenital hemorrhagic cliatheses the unspecific symptom of hemorrhage occurs

early in life in afibrinogenemia. Frequently the site of bleeding is the umbilical cord. Despite the absolute incoagulability of

blood the symptomatology of afibrino-genemia is not as severe as in hemophilia.

Bleeding occurs only following direct trauma or with internal ulcerations, as in this patient. Hemarthrosis, which is such a conspicuous symptom of hemophilia, where it leads to severe crippling, does not

occur in afibrinogenemia. There is no ade-quate explanation for this paradoxic

situa-tion thus far. Roentgenologic studies of the joints of the patient did not reveal any pathologic changes. MacFarlane,’ Sch#{246}n-holzer4 and Prentice14 studied in part

in-dividuals with afibrinogenemia at a more advanced age than this patient and con-firmed the absence of articular alterations.

Congenital afibrinogenemia is probably more common than is realized since there is

a certain tendency to classify congenital male bleeders with a prolonged coagulation time as hemophiliac patients. The errors of not observing venous clotting times up to the end point or of merely performing a

capillary clotting time as screening tests are the main reasons for this failure. In addition, it is probable that a certain number of

babies suffering from this disease suc-cumbed to umbilical hemorrhage without

ever being diagnosed.

The typical routine laboratory results of

congenital afibrinogenemia consist of an indefinitely prolonged clotting time and

pro-thrombin time in the presence of a normal bleeding time, normal platelet count, nega-tive cuff test and absent clot retraction. It is doubtful that the reported occasional

oc-currence of the temporary thrombocyto-penia is an essential part of this disease.

Considering the propensity of children to develop postinfectious thrombocytopenia, it is possible that such temporary platelet de-ficiencies have induced hemorrhagic epi-sodes which called for medical attention

and study at the time of thrombocytopenia. All these cases repeatedly revealed normal platelet counts when rechecked at a later

date. The rare occurrence of increased capil-lary fragility is probably a reflection of tem-porary thrombocytopenia. Most reported

cases had a negative Rumpel-Leede test.

Another test with variable results is the

bleeding time. This test is not too reliable in children, because it depends on the depth and width of the incision, the support of the surrounding tissue and the relaxation of the

patient. If the cut includes vessels of

rela-tively large size, the bleeding time becomes

complicated by abnormalities in coagula-tion; this is a well known fact in hemophilia. If carefully done the bleeding time in afibrinogenemia is normal. Some of the cases reviewed had a prolonged bleeding

time on one occasion, but all of them were found to have normal values upon retesting.

Therapy and Prophylaxis: During the phase of acute bleeding, the administration

of plasma or whole blood is promptly effec-tive. The results obtained with plasma trans-fusions in afibrinogenem ia are unquestion

-ably more impressive and longer lasting than in hemophilia. This phenomenon is probably related to the slower turnover rate of fibrinogen when compared with AHG,

and to the relatively small amount of fibrino-gen needed for adequate hemostasis. As to prophylaxis it would he ideal to keep the fibrinogen concentration constantly above the critical point of 50 mg./100 cc.32 Con-sidering the rate of disappearance of

fibrino-gen from the blood stream this would mean replacing 3 of the patient’s blood volume with normal plasma at weekly intervals. Diamond suggested the use of Fraction I in

an attempt to supply high concentrations of fibrinogen in a small volume of fluid. This

(12)

Un-#{176}H

EL EL 0

225 63 96 96 215 402 219 246 90

90 0 178348 [j

Male

Female

Flbrinogen above 300 mg. %

Fibrinogen below 250 mg. % Aflbrinogenemic

0

S

o

0 Not tested

Eli #{174}Dead

CHART 8. Genealogy of case reported.

by MacFarlane. Twelve relatives had

fibrinogen determinations and the following other tests of hemostasis : bleeding time,

clotting time, prothrombin time, platelet

count, clot retraction, capillary fragility test, thrombin titration, and prothrombin

con-sumption test.

With the method used in this laboratory

the normal range of variation for fibrinogen is 250 to 400 mg./100 cc. All the values be-low 250 mg./100 cc. are considered

hypo-fibrinogenemic. The patient’s parents and two siblings had values below 200 mg./100

cc., while the third sibling had a concentra-tion of 348 mg./100 cc. It is remarkable that the four children happened to follow

exactly the classical mendelian pattern of a recessive, not sex-linked, character. With only one exception all the aunts and uncles

that could be tested were hypofibrino-genemic. As to the other tests for hemostasis

no abnormalities were detected except for a mild thrombocytopenia in one maternal

uncle.

SUMMARY

A case of congenital afibrinogenemia is described. Despite the absolute

incoagula-bility of afibrinogenemic blood, this type of hemorrhagic diathesis is not accompanied

by hemarthrosis.

Systematic studies of this patient’s blood

revealed that all other known clotting fac-tors are present in normal concentration.

Comparison of the electrophoretic pat-terns of afibrinogenemic plasma and serum confirmed the fact that except for fibrinogen no other clotting factor is detectable by routine electrophoretic analysis. This is due

to the extremely small concentration of these entities when compared with the

value of total serum proteins.

On the basis of family studies the

heredi-tary pattern of congenital afibrinogenemia is assumed to be recessive and not

sex-linked.

The rate of disappearance of fibrinogen from the blood stream after transfusion of Cohn’s Fraction I has been studied. Start-ing from a level of 161 mg./100 cc., the zero

level was reached in 12 days.

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University of Minnesota Medical School

SPANISH ABSTRACT

Afibrinogenemia Cong#{233}nita

Los autores presentan un caso de afibrino-genemia cong#{233}nita, padecimiento raro en el

(l11 se encuentra una alteraci#{243}n del meta-bolismo proteico manifestado por un acentuado

efecto sobre el mecanismo de Ia coagulaci#{243}n

sangumnea. Se trata de un ni#{241}oblanco de 7 a#{241}osde edad, con historia de hemorragias

desde el nacimiento en diversas partes del

organismo, producidas por traumatismos. Al

ingresar al hospital Ia primera impresi#{243}n fu#{233} de hemofilia con hemorragia gastro intestinal; sin embargo una cifra anormal de trombina y

co#{225}gulo pequefio en la prueba de Ia retracci#{243}n, oblig#{243}a pensar en defecto de la iiltima fase de Ia coagulaci#{243}n; dos semanas m#{225}starde de suspendido el tratamiento con plasma, Ia sangre

del niflo era incoagulable por ausencia de fibrin#{243}geno.

El laboratorio mostr#{243} anormalidad iinica-mente en las siguientes pruebas:

sedimenta-ci#{243}nglobular de 1.5 mm. a Ia hora (este dato

de cifra tan baja se ha descrito en Ia afibrino-genemia); protemnas totales 7.9 grs. (3.3 grs. de

alb(imina, 4.6 grs. de globulina, 1.7 grs. de alfa globulina, 1.5 grs. de beta globulina y 1.4 grs. de gamma globulina); colinesterasa del suero elevada. Se analizaron aisladamente todos

los factores de Ia coagulaci#{243}n sangumnea:

fibrin#{243}geno, protrombina, plaquetas, globulina

antihemofmlica, componente trombopl#{225}stico del

plasma, factores de conversion de Ia

protrom-bina, los factores l#{225}bily estable del co#{225}gulo, encontr#{225}ndose todos ellos normales menos el fibrin#{243}geno. Los an#{225}lisiselectrofor#{233}ticos de los

cambios del plasma al suero afibrinogen#{233}micos no revelaron influencia de ningiin factor de Ia

coagulaci#{243}n, excepto el fibrin#{243}geno, sobre los

patrones electrofor#{233}ticos de rutina, lo que se

debe a las concentraciones extremadamente

peque#{241}as de estas entidades en comparaci#{243}n

con los valores de las protemnas totales del

suero. Aprovechando la oportunidad de analizar

en el paciente el destino del fibrin#{243}geno in-yectado, se hicieron los estudios pertinentes a la desaparici#{243}n del fibrin#{243}geno de Ia corriente sangulnea despu#{233}s de Ia transfusion de la fracci#{243}nI de Cohn; partiendo de un nivel de

161 mgrs. por ciento se alcanz#{243} el de 0 en 12

dIas; asmmismo se estudi#{243} le influencia de Ia

concentraci#{243}n del fibrin#{243}geno sobre los tiempos

de Quick de Ia protrombina y coagulaci#{243}n (IC la trombina.

Los autores hacen una revision de Ia cllnica

de la afibrinogenemia; se caracteriza por

smndrome hemorragIparo presente desde muy

temprana edad del paciente, en ocasiones

siendo la primera hernorragia la del cordon

umbilical. Las hemorragias se observan sOlo

despu#{233}sde trauma directo o a partir de

ulcera-ciones internas; en este cuadro no se observan hemartrosis. Consideran los autores que Ia afibrinogenemia es m#{225}sfrecuente de lo que se

piensa, confundi#{233}ndose con hemofilia en los sangradores cong#{233}nitos del sexo masculino. Desde el punto de vista del laboratorio los hallazgos tIpicos de Ia afibrmnogenemia

con-sisten en: tiempo de coagulaci#{243}n y de

pro-trombina indefinidamente prolongados, al lado de normalidad en el tiempo de sangrado y

niimero de plaquetas, ausencia de retracciOn

del co#{225}guloy negatividad del signo de Rumpel Leed.

Desde el punto de vista de la terap#{233}utica, se recomienda la administraci#{243}n de plasma o

sangre total en Ia fase aguda de las hemor-ragias; para Ia profilaxis, naturalmente que Ia conserviOn de una concentraciOn de fi-brmn#{243}genosobre el punto crmtico de 50 mgrs. por

ciento serma lo ideal, lo que significarIa Ia

re-posici#{243}n semanaria de un cuarto del volumen

total de sangre del paciente con plasma nor-mal, o bien la administraciOn de la fracci#{243}nI de Cohn, que todavIa no se puedo adquirir libre del virus de Ia hepatitis homOloga. El

plasma que se usa con fines terap#{233}uticos en Ia

afibrinogenemia no debe ser necesariamente fresco, como lo requiere Ia hemofilia y la para-hemofilia, ya que el fibrmnOgeno es sumamente estable durante la conservaciOn.

El pron#{243}stico es grave. Ninguno de los in-formes de Ia literatura refiere que los pacientes afibrinogen#{233}micos Ilegan a Ia edad adulta,

ex-cepto uno que alcanz#{243}los 22 aflos de edad. Y

es que el fibrinOgeno no sOlo es un factor in-dispensable para Ia hemostasis, sino tambi#{233}n para la defensa contra algunos procesos

infec-cioso y cicatrizaciOn de Olceras diversas.

Los autores est#{225}nde acuerdo que un factor

hereditario interviene en el padecimiento pero

corno Ia afibrinogenemia se presenta en ambos sexos, este factor debe considerarse como

(15)

1954;13;44

Pediatrics

PAUL G. FRICK and IRVINE MCQUARRIE

CONGENITAL AFIBRINOGENEMIA

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