Use of Prothrombin Complex Concentrates in Hemophiliacs with Inhibitors: Clinical and Laboratory Studies

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PEDIATRICS Vol. 62 No. 5 November 1978 767

Use of Prothrombin

Complex

Concentrates

in

Hemophiliacs

With

Inhibitors:

Clinical

and Laboratory

Studies

George R. Buchanan, M.D., and Sherwin V. Kevy, M.D.

I’rOlll tIl(’ Diuision of Hematology-Oncology 011(1 tue Transfusion Service, Department of%fedicine, Children s

!lo.spital \h’dical Center, an(1 tIc Department of Pediatrics, Hart-ard Medical School, Boston

ABSTRACT. Nine patients with severe classic hemophilia and inhibitors against factor VIII were treated for 156 bleeding episodes with 503 infusions of Proplex, Konyne, or

Auto-Factor IX, three preparations of prothrombin complex concentrates (PCCs). Approximately two thirds of the bleeding episodes were managed successfully. Although the prothrombin time (PT) and partial thromboplastin time

(PiT) were shortened after most PCC infusions, there was no evidence of disseminated intravascular coagulation. The degree of shortening of PT or PTT was not related to the particular PCC preparation used, dose, or cessation of hemorrhage. All PCC preparations contained activated clotting factors, as manifested by their ability to shorten the

PT’F of normal plasma, factor-Vill-deficient plasma, and factor-IX-deficient plasma. Shortening, which was greater with Auto-Factor IX than with the other products, was inhibited partially by a factor IX antibody and blocked

completely by prolonged incubation with plasma. Although the nature of the procoagulant material in PCCs is uncertain, these products are of proven benefit to hemophilic patients with high-titer inhibitors. Side effects have been minimal and inhibitor titers have not risen. Pediatrics 62:767-774, 1978, hemophilia, inhibitors, bleeding, activated factors.

Approximately 10% of children with severe

hemophilia develop inhibitors, which are anti-bodies directed against the clot-promoting site on the factor VIII mo1eciile.’ These children cannot

be treated successfully with substances containing

factor VIII and are always at risk for uncontrolla-ble hemorrhage. Most develop progressive

an-thropathy secondary to multiple episodes of

untreated joint bleeding. Immunosuppressive

therapy and other modes of treatment, such as

exchange transfusion and infusion of large

amounts of factor

VIII,

have usually been unsuc-cessful.’

Prothrombin complex concentrates (PCCs),

which contain the vitamin-K-dependent factors

prothrombin, factor VII, factor IX, and factor X,

have recently been used as therapy for these

patients despite the fact that PCCs contain no

detectable factor VIII. These concentrates were

initially developed in the early and mid-1960s for

management of hemorrhage in patients with

Christmas disease, vitamin K deficiency, and liver

disease. Infusion of such preparations is

occasion-ally followed by localized or generalized

throm-bosis.5h A clot-promoting effect of PCC in

patients with classic hemophilia was first noted

by Breen and Tullis in 1969. Soon thereafter, it

was proposed that PCCs might be particularly

useful in the treatment of patients with inhibitors, since PCCs have the ability to induce hemostasis

in the absence of factor VIII because of the

presumed presence of activated clotting factors.M

Two groups of investigators have tested this

hypothesis and reported successful use of several

different PCC preparations in children and adults

with factor VIII inhibitors.1

This article reports the Children’s Hospital

Medical Center experience with PCCs in

hemo-philiac patients with inhibitors during the past 3#{189}

years. In particular, clinical and laboratory data

are provided about the use of Auto-Factor

IX,

a

newly developed “activated” PCC product,

which has recently become available for clinical trials. The use of laboratory tests for in vivo and in

vitro monitoring of PCC procoagulant activity

and for prediction of clinical response is

summa-rized.

Received October 24, 1977; revision accepted for publica-lion February 10, 1978.

ADDRESS FOR REPRINTS: (G.R.B.) Department of Pedi-atrics, University of Texas Health Science Center, 5323 Harry Hines Boulevard, Dallas, TX 75235.

at Viet Nam:AAP Sponsored on September 7, 2020

www.aappublications.org/news

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MATERIALS AND METHODS

Patients

Nine patients, 7 to 29 years of age, with severe

classic hemophilia (factor VIII less than 1% of

normal) received PCCs on one or more occasions.

All patients had high-titer inhibitors directed

against the coagulant site of the factor VIII

molecule and most previously demonstrated an

anamnestic rise in inhibitor level after infusion of

factor VIII. All patients were refractory to factor

VIII transfusions and most had progressive

an-thropathy. Informed consent was obtained

according to the guidelines of the Committee on

Clinical Investigation of the Children’s Hospital

Medical Center.

PCC Preparations Tested

Three products were evaluated clinically and

by a number of laboratory parameters: Proplex

and Auto-Factor IX (Hyland Laboratories, Costa

Mesa, Calif.) and Konyne (Cutter Laboratories,

Berkeley, Calif.). Proplex and Konyne are

licensed commercial PCC preparations that

contain factors II (prothrombin), VII,

IX,

and X.

They were not developed for patients with

inhi-bitors and any substances present in Pnoplex on

Konyne that are capable of promoting excessive

blood clotting have been regarded as

contami-nants or impurities. Auto-Factor IX is an

investi-gational PCC preparation developed specifically

for use in patients with inhibitors. It is

manufac-tuned so that it maximizes the amount of

acti-vated clotting factors on other procoagulant

substances. All PCC preparations were infused by

slow intravenous push after reconstitution

according to the manufacturers’ directions.

Laboratory

Studies

Inhibitor levels were measured according to

the method of Kasper and coworkers.I2 Briefly,

normal pooled plasma is incubated at 37#{176}Cfor

two hours with an equal amount of inhibitor

plasma or dilutions of inhibitor plasma, and the

residual amount of factor VIII is measured. One

“Bethesda unit” of inhibitor is that amount which

inhibits 50% of the factor VIII present in the

pooled plasma after the two-hour incubation

period. Prothrombin time (PT) and activated

partial thromboplastin time (PTT) using

Acti-vated Thrombofax (Ortho Diagnostics, Raritan,

N.J.) were determined and one-stage assays for

clotting factors were performed according to

standard published methods, before and after

PCC

infusions.11 Laboratory monitoring for

disseminated intravascular coagulation was done

after many infusions by measuring platelet count,

fibninogen concentration, fibnin degradation

products, and antithnombin III levels (the latter

quantitated by immunoelectrophonesis). The in

vitro effects of Auto-Factor IX, Proplex, and

Konyne on the unactivated PTT were monitored

by a slight modification of an assay described by

Kingdon and colleagues’ for measurement of

activated clotting factors. Serial dilutions of 0.1

ml of Auto-Factor IX, Konyne, on Pnoplex were

incubated in 9 X 70-mm glass tubes for one

minute at 37#{176}Cwith 0.1 ml of Thrombofax and

0.1 ml of normal on congenitally deficient

plate-let-poor plasma. An unactivated PTT was

deter-mined by addition of 0.1 ml of 0.025M calcium

chloride and measurement of the time to visible

clot formation.

Assessment of Clinical Responses to

Auto-Factor IX Infusions

Patients who received infusions of Auto-Factor

IX

were monitored carefully for clinical response

using objective parameters (joint circumference

and warmth, joint mobility, external hemorrhage)

when possible. In addition, each patient was

questioned to determine the extent and nature of

pain after infusion and to compare it with that

experienced after prior untreated hemanthroses.

Clinical responses to Auto-Factor IX were judged

as follows: (1) excellent-a dramatic and

imme-diate cessation of bleeding; (2) good-delayed or

incomplete response but definite improvement

over the natural history of previous bleeding

episodes treated only with local therapy; (3) fain

or questionable-unclear whether the natural

history of the bleeding episode was altered; and

(4) poor-cleanly no beneficial effect of the PCC

infusion. All medical treatment in these patients

was supervised personally by one or both of us.

Attempts were made to correlate the clinical

response with the number of vials infused, the PT

and PTT after infusion, the particular lot of

material used, and in vitro evidence of potential

“thrombogenic” activity.

RESULTS

Experience with Proplex and Konyne

Between February 1974 and December 1976

eight patients received 344 infusions of Proplex on

Konyne for 124 separate bleeding episodes (Table

I).

Most hemorrhages (85%) were hemanthroses,

but other types of bleeding episodes included

iliopsoas hemorrhage, oozing after multiple tooth

extractions, life-threatening upper airway

bleeding, and netnopenitoneal hemorrhage.

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TABLE I

ARTICLES 769

USE OF PROPLEX#{176} FOR PATIENTS WITH FACTOR VIII INHIBIToRS (1974-1976)

Patient :\. of

Bleeding Episodes

lrcatc(1

“%O. of

Dasc.s Recciicdt

InhtiI)itor Lctcl (Units/mi)

‘- ‘

Before After

Proplex Prop!ex

Major Bleeding Episodes

Treated & Comnients

Complications of Therapy

1 33 48 13 0.85 Received some infusions at home

by parents

Hepatitis

2 24 67 156 128 Dental surgery

3 44 178 64 32 Received some infusions at home by parents; received prophlaxis for 6 mo; 80 doses were for 2 major bleeding episodes (retro-peritoneal, pseudotumor)

4 12 20 10.4 1.9 Massive upper airway & facial bleeding

5 6 8 460 136 Iliopsoas hemorrhage

6 1 2 4.0 3.0 Iliopsoas hemorrhage

7 3 12 12.4 8.0 Dental surgery Superficial

thronibophlebitis

8 1 9 3.2 ...

Total 124 344

#{176}Konvnewas used instead of Proplex for approximately 20% of the infusions.

tSee text for schedule.

:1:

Representative inhibitor levels at time intervals from two weeks to two years after multiple infusions of Proplex and Konvne.

units/kg was used, 50 to 75 units/kg was

admin-istened in most cases. Infusions were repeated at

6-

to 24-hour intervals (usually 12 hours) when

necessary. One patient was treated

prophylacti-cally on a schedule of every other day for six

months. Hepanin was not added to any of the preparations before infusion.

Responses were extremely variable and unre-lated to the dose, frequency of administration, lot

of PCC, on in vivo or in vitro laboratory tests.

Proplex was used more frequently than Konyne,

but there were no noticeable clinical or

laborato-ry differences between the two products. Overall,

approximately 60% of the bleeding episodes were

considered successfully treated, with a good on

excellent response. Adequate hemostasis was

achieved during surgical procedures (lapanotomy, tooth extractions) and after the episodes of upper

airway and iliopsoas hemorrhage. The patient

receiving prophylactic treatment experienced

fewer bleeding episodes than expected. Side effects included occasional mild allergic reactions and one instance each of hepatitis B surface antigen (HBsAg)-negative hepatitis and superfi-cial thrombophlebitis. The latter occurred in the

right cephalic vein after six on seven daily

infu-sions of Proplex, 50 units/kg, in the right antecu-bital fossa.

During the past year, it has been our distinct

clinical impression that Proplex and Konyne have

been less effective in stopping hemorrhage than

they were before early 1976. This has been

confirmed by the manufacturers and other

hemo-philia treatment centers.

Clinical Experience with Auto-Factor IX

Our earliest experience with Auto-Factor IX

was in patient 3, who developed paraplegia

secondary to a spinal epidural hematoma in

December 1973. Massive infusions of factor VIII

concentrate were unable to control hemorrhage

at the time of emergency laminectomy.

Auto-Factor IX was then administered, initially at the

rate of two vials per hour, and hemostasis was

achieved. During the ensuing two months, the

patient received 1 15 infusions of Auto-Factor IX

(

two vials per infusion). He has since undergone

substantial improvement in neunologic function.

Auto-Factor IX was not used again until newer

lots of the product became available in November

1976. Since that time, Auto-Factor IX has been

the primary treatment for our patients with factor

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RE5ULTS OF AUTO-FACTOR IX INFUSIONS FOR ACUTE

BLEEDING EPISODES

CLINICAL RESPONSES TO DIFFERENT DOSES OF AUTO-FACTOR IX

#{176}Seetext for definition of clinical responses.

tIncludes five doses for a single hemorrhage into the subperiosteum of the tibia.

4

3

PROTHROMBIN TIME (s.c.)

2

II

0

9

8

30 0

0 X

0xx x

x x

ox 0

000

x0 0

xx

00 0

x0

x 00x

xx oxo

x xxxoxoxx

S REDUCTION 20

BELOW PRE- INFUSION

VALUE

0

Ih 2h’.

TIME POST-INFUSION

FIG. 1. Degree and time duration of shortening of PT after infusion of three vials of Auto-Factor IX into five different hemophilic patients with inhibitors. Curves are typical of those obtained after more than 20 infusions of three vials

each.

TABLE II TABLE III

Patient No. of

Bleeding

Episodes Treated#{176}

No. of

Doses

Received

No. of

Definite

Beneficialt Clinical

Responses

1 9 10 9

2 5 9 1

3 6 13 2

4 6 6 6

5 3 4 1

6 1 1 0

9 1 1 1

Total 31 44 20

#{176}Twenty-three bleeding episodes were treated with one dose, five episodes with two doses, two episodes with three doses, and one episode with five doses; multiple doses were administered 12 to 24 hours apart.

tGood or excellent clinical response (see text for

defini-tion).

VIII inhibitors. Seven of these patients (six of

whom had previously received Proplex or

Konyne) have been given 44 Auto-Factor IX

infusions for 31 separate bleeding episodes.

Twen-ty-seven of these episodes were acute

hemar-throses. The other hemorrhagic events were

tongue laceration, biceps hemorrhage, bleeding

into the soft tissues of the neck, and subpeniosteal

hemorrhage. Five different lots of Auto-Factor IX

were used in doses of one to three vials per

infusion. Each vial contained approximately 150

Subjective Clinical Response#{176}

1

No. of Vials Administered

2 3

Excellent 2 2 4

Good 2 2 7

Fair/questionable 1 4 9t

Poor 1 4 3

Unable to evaluate 1 . .. 1

units of factor IX and 2,000 units of activated

factor IX (IXa) in a total volume of 30 ml. Clinical

responses were variable (Table II) and did not

appreciably differ from those following

adminis-tration of Pnoplex or Konyne prior to mid-1976.

Approximately two thirds of all bleeding episodes

were considered successfully treated with

Auto-Factor IX, as indicated by a good or excellent

clinical response. There was no correlation

between the clinical response and the number of

vials infused (Table III) or with the amount of

factor IXa (in units pen kilogram body weight)

that was given. No particular lot of Auto-Factor

IX seemed more effective than others and

responses were inconsistent, although some

patients (patient 1, for example) seemed to

PROTHROMBIN PARTIAL

TIME THROMBOPLASTIPI

TIME

FIG. 2. Percent reduction below preinfusion value of PT and

FTc is indicated one hour after transfusion for more than 25 different infusions of Auto-Factor IX (one to three vials).

Circles indicate that infusion resulted in beneficial (excellent

or good) clinical response; X’s indicate that infusion was unsuccessful in stopping hemorrhage (fair or poor

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60

50

% REDUCTION BELOW BUFFER CONTROL PTT

-. - - : : - -

---- --

--...

---... ...

0

-0

0 50 00 250 500 1,000 s,ooo 0,000

70

ARTICLES 771

40

30

20

RECIPROCAL OF DILUTION OF PROPLEX, KONYNE, OR

AUTO-FACTOR :

Fn;. 3. In vitro effect of Auto-Factor IX, Proplex, and factor VIII concentrate on unactivated PTT of normal plasma is evaluated by measuring percent PTT shortening below buffer control (imidazole-buffered saline, pH 7.40) by various dilutions (1:10 to 1:10,000) of one or more lots of each blood product. X, Auto-Factor IX; triangle, Konyne; circle, lots of Proplex examined in

mid-1976; square, lots of Proplex produced and tested in March 1977.

respond better than others. It is particularly noteworthy that patient 1 had received little

benefit from Proplex during the previous six

months. Side effects of Auto-Factor IX included

one case of non-HBsAg hepatitis and several mild

allergic reactions. No untoward thrombosis was

observed in any patient.

Figure 1 demonstrates that there was usually a moderate shortening of the PT (usually to eight on

nine seconds, or by 20% of the preinfusion value)

for several hours after each dose. The PTT was

unchanged after about one third of the infusions

but decreased variably (usually less than the PT,

however) after most of the others (Fig. 2). The degree of PT and PTT shortening was not related

to the amount of Auto-Factor IX infused.

More than 15 Auto-Factor IX treatments were

monitored carefully for laboratory evidence of

disseminated intravascular coagulation. In no

case was there any significant change from

prein-fusion values in platelet count, fibninogen concen-tration, antithrombin III level, on fibnin degrada-tion products in samples obtained five minutes

and 1, 12, and 24 hours after infusion. Usually

there was a 20% to 40% increase in factor IX and a

widely variable increase (from 50% to 600%) in

circulating factor VII levels after infusion.

In Vitro Studies of PCC

Twelve lots of Proplex, two lots of Konyne, and

six lots of Auto-Factor IX were reconstituted

according to the manufacturers’ directions and

tested for their ability to shorten the unactivated

PTT of normal and congenitally deficient

plas-mas. As shown in Figure 3, the products were

capable of shortening the PTT in dilutions of 1:10

to as high as 1:5,000. Results of this assay were

quite reproducible when the same lot was tested

on multiple occasions. Different lots of

Auto-Factor IX gave similar results and Auto-Factor IX

was always more “active” than Proplex and

Konyne, since it caused a greaten degree of PTT

shortening at all dilutions tested. Lots of Proplex tested within the past six months shortened the PT’1’ in this system less than those examined a

year ago (Fig. 3), which confirms clinical

obsenva-lions that the activated by-products in Proplex

have been attenuated or reduced by alterations in

the manufacturing process.

Attempts were made to identify the nature of

the material in these products which shortened

the PTT. Incubation of Auto-Factor IX at 37#{176}C

with normal plasma for 60 minutes instead of the

usual one minute resulted in complete

disappear-ance of the thrombogenic activity, which suggests

that something in the plasma, probably

anti-thrombin III, neutralized the coagulant activity.

Incubation of Auto-Factor IX with plasma from a

patient with Christmas disease with a high-titer

(112 units/ml) factor IX inhibitor resulted in some

shortening of the PTT of the factor-IX-deficient

plasma, but much less than that noted when

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facton-IX-deficient plasma without inhibitor was used as the substrate. There was only minimal

PTT shortening at a 1:10 dilution and none at

higher dilutions when factor-V-deficient plasma

was incubated with Auto-Factor IX; this suggests

that the active material in the preparation

requires factor V for its clot-promoting effect.

Effect of PCC Infusions on Inhibitor Levels

Factor VIII inhibitor levels were monitored

regularly in all patients receiving PCC (Table I).

In no instance was there evidence of a rise in

inhibitor titer. Inhibitor levels declined or

remained relatively constant in all seven patients

tested before and weeks to months after Proplex,

Konyne, and Auto-Factor IX infusions.

DISCUSSION

Pnothrombin complex concentrates contain one

or more species of activated clotting factors or

other procoagulant substances which can

accelen-ate blood coagulation. Our data confirm other

reports that various PCCs, including Proplex,

Konyne, and Auto-Factor IX, are of benefit to

patients with inhibitors, since their infusion can

result in a hemostatically effective fibnin clot at

sites of hemonnhage.i 10. 1 1.I This is achieved by

bypassing the facton-VIII-nequining reaction,

which generates activated factor X (Xa) in these

patients, whose circulating inhibitor prevents successful use of factor VIII.1 PCCs have been

life-saving in a number of instances,417 and they

have had few side effects in this group of

patients.#{176} II However, PCCs are considered

dangerous for other types of patients, particularly

those with liven disease on disseminated

intravas-cular coagulation, and during the postoperative

period. Infusion of certain PCCs has resulted in

serious thrombosis on thromboembolism in a

number of such patients.3’82#{176} Accordingly, there

have been ongoing attempts by manufacturers of

Proplex, Konyne, and other PCCs to alter the

production process so that fewer

“contaminat-ing” activated by-products are present in the final

reconstituted preparation.’ Hepanin with on

without antithnombin III, the plasma cofactor

necessary for hepanin’s anticoagulant action, has

been added to some preparations to reduce

thnombogenicity.1421 Although these new

proved” products (e.g., Proplex during the past

year) are safer and more effective for patients

who require unactivated factors, they are much

less effective for patients with inhibitors, who have benefited from the contaminating

clot-promoting substances. It is hoped that the

“acti-vated” product, Auto-Factor IX, will soon be

available widely for this latter group of patients,

since our preliminary studies indicate that it is

safe and often effective.

Initial reports suggested that infusions of PCCs

in hemophiliacs with inhibitors were almost

always capable of promoting cessation of

hemor-rhage.9hl However, our experience has shown

that the preparations (even the activated one) are

not always beneficial, and other investigators

have reported mixed responses.’”’222 It has been

the practice in most centers, including ours, to

avoid elective surgery in patients with inhibitors

since a hemostatic response cannot be

guanan-teed. This unpredictability has been attributed to

variable amounts of activated factors in different

lots of product,” but our laboratory studies and

clinical observations were not able to confirm

this.

We examined a number of lots of Proplex,

Konyne, and Auto-Factor IX for activated factors

by measuring the PT and PTT on plasma samples

from patients who received infusions. Although

others have reported transiently reduced PT and PTT after PCC administration,9H2124 no

at-tempts were made to correlate such reductions

with clinical response. Abildgaand and

co-work-ers have, however, noted that bleeding

some-times ceased with doses of PCC that did not affect

PTT. As shown in Figures 1 and 2, there was

nearly always shortening of the PT after

adminis-tnation of Auto-Factor IX, and similar findings

were usually noted after administration of

Proplex and Konyne. The effect on the PTT was

more variable, and after approximately one third

of infusions there was no shortening whatsoever.

Contrary to our expectations, there was, unfontu-nately, no correlation between the number of

vials infused, degree of PT or PTT shortening, in

vitro assay of activated factors, and the clinical

response to infusion. It appears, therefore, that

postinfusion PT on PTT cannot be used to

deter-mine the appropriate dose or to predict response,

which confirms a suggestion made by Pollock and

Lewis13 that correction of abnormal laboratory

tests is not equivalent to hemostasis in the patient.

It is likely that the potentially thrombogenic substances in PCC are activated clotting

factors,323 which are proteolytic enzymes capable

of clotting normal plasma. They have a senine

residue at their active site and include thnombin,

Xa, and a6I4 The most likely sources of the

procoagulant activity in PCCs have been

consid-ered to be thrombin and Xa, since neither of these

enzymes requires factor VIII coagulant activity

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ARTICLES 773

coworkens2I have recently shown that PCCs do

indeed contain activated factors; addition of

heparin and the protease-inhibitor antithrombin

III to PCC markedly attenuated

thrombogen-icity. On the other hand, the potentially

thrombo-genic activity could be enhanced by the addition

of an antibody directed against 21In

vivo and in vitro assay systems have demonstrated

that commercial PCC products that contain 5 to

10 units of hepanin per milliliter are less

thrombo-genic than those that contain little on no

hepan-in.’4 The clot-inducing materials in the PCCs are

inhibited by incubation with soy bean trypsin

inhibitor, an inhibitor of Xa,2#{176}2627 and by

prolonged incubation with normal plasma (see

“Results”). White and colleagues2l have reported

that some of the thrombogenic activity of PCC is

inhibited by an anti-factor IX antibody. We were

able to confirm this finding, but Penner and

Kelly21 reported contrary data. Thus, although

the precise nature of the procoagulant materials

in PCC is uncertain, Xa and IXa do seem to be

present. Sas et al.2M detected thrombin activity in

some of the preparations they tested, but our

studies with factor-V-deficient plasma seem to

confirm earlier observations that there is no

measurable thnombin in Auto-Factor X.21-#{176}

Figure 3 demonstrates that substances capable

of shortening the unactivated PTT of normal

plasma are present in higher concentrations in

Auto-Factor IX than in Pnoplex on Konyne, which

confirms preliminary observations of others.2I

Different lots of each product resulted in similar

degrees of PTT shortening, except that those lots

of Proplex tested in recent months had less

clotting activity than those examined earlier (Fig.

3). There appears to be no definite correlation

between clinical response and the in vitro

proco-agulant activity of any of the three PCC

prepana-tions tested.

We are able to confirm that Proplex, Konyne,

and Auto-Factor IX can induce effective

hemos-tasis in hemophiliacs with inhibitors. Auto-Factor IX appears more “potent” than the currently

manufactured lots of “nonactivated”

prepara-tions, Proplex and Konyne. It remains uncertain

why clinical responses, even with Auto-Factor IX,

are so variable despite uniform evidence of in

vitro clot-promoting activity. Currently efforts

are being made by the manufacturers of

Auto-Factor IX to standardize and improve the efficacy

of the product.

PCC preparations appear to be safe. Clinical

evidence of disseminated intravascular

coagula-tion or excessive thrombosis has, to our knowl-edge, been previously reported in just a single

patient with inhibitons#{176}; only one of the 156

bleeding episodes that we treated with PCC was

accompanied by undesired

thrombosis-superfi-cial thrombophlebitis which rapidly resolved

(patient 8). Since many of these patients have

received limited numbers of transfusions of blood

products prepared from pooled plasma, hepatitis

(usually non-type B) is a complication of PCC

therapy.

Despite some recent reports to the

con-trary,232U32 we and othershl have identified no increase in inhibitor titers after multiple PCC infusions. It is possible, however, that some PCC

preparations do contain minute amounts of factor

VIII antigenic matenial.2512

CONCLUSION

Our results indicate that laboratory assays for

activated factors, as well as in vivo coagulation

tests such as the PT and PTT, do not correlate

with clinical response and are accordingly not

useful in the determination of dose and frequency

of administration. Therefore, therapy remains

empirical and responses must continue to be

evaluated subjectively. We currently use two or

three vials of Auto-Factor IX on 75 factor IX units

of Proplex on Konyne per kilogram for all acute

bleeding episodes that would have been treated

with factor VIII if the patient did not have

inhibitors. Doses are repeated at 12 to 24-hour

intervals when clinical response to the initial

infusion is incomplete, which occurs

appnoxi-mately 50% of the time. Our experience leads us

to continue to use these valuable preparations for

all clinically significant bleeding episodes and not

only for instances of life-threatening

hemon-rhage.

REFERENCES

1. Strauss HS: Acquired circulating anticoagulants in hemophilia A. N Engi I Med 16:866, 1969.

2. Shapiro SS: Acquired inhibitors to the blood coagulation factors. Scm in Th romb Hemostasis 1 :336, 1975. 3. Hultin MB, Shapiro 55, Bowman HS, et al:

Inimunosup-pressive therapy of factor VIII inhibitors. Blood 48:95, 1976.

4. Tullis JL, Melin M, Jurigan P: Clinical use of human prothrombin complexes. N Engl I Med 273:667,

1965.

5. Kasper CK: Thromboembolic complications. Thromb

Thath Haemorrh 33:640, 1975.

6. Blatt PM, Lundblad RL, Kingdon HS, et al: Thrombo-genic materials in prothronibin complex concen-trates. Ann intern Med 81:766, 1974.

7. Breen FA, Tullis JL: Prothrombin concentrates in treat-ment of Christmas disease and allied disorders.

JAMA 208:1848, 1969.

8. Fekete LF, Hoist SL, Peetoom F: “Auto”-factor IX concentrate: A new therapeutic approach to

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ment of hemophilia A patients with inhibitors. Head before the 14th International Congress of Hematol-ogy, Sao Paulo, Brazil, 1972.

9. Kurczynski EM, Penner JA: Activated prothrombin concentrate for patients with factor VIII inhibitors.

N Engl I Med 291:164, 1974.

10. Kelly P. Penner JA: Antihemophilic factor inhibitors: Managelnent with prothrombin complex concen-trates. JAMA 236:2061, 1976.

11. Abildgaard CF, Britton M, Harrison J: Prothrombin complex concentrate (Konyne) in the treatment of hemophilic patients with factor VIII inhibitors. I Pediatr 88:200, 1976.

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- ACKNOWLEDGMENT

This investigation was supported in part by U.S. Public

Health Service grant AM-05581.

\Ve are greatly indebted to Elaine Wilkerson and Sima Atefee for their valuable technical assistance and to Drs. David G. Nathan and Robert I. Handlin for support and advice. These studies could not have been carried out without the assistance and cooperation of the Children’s Hospital Medical Center house staff and hematology fellows and Dr. Aaron Josephson and Mr. John H. Tufekjian of Hyland Laboratories, who provided the Auto-Factor IX

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1978;62;767

Pediatrics

George R. Buchanan and Sherwin V. Kevy

and Laboratory Studies