Evaluation of the Safety, Recovery, Half-Life, and Clinical Efficacy
of Antithrombin I11 (Human) in Patients With
Hereditary Antithrombin I11 Deficiency
By D. Menache, J.P. O’Malley, J.B. Schorr, B. Wagner, C. Williams, and the Cooperative Study Group: B.M. Alving,
J.O. Ballard, S.H. Goodnight, W.E. Hathaway, M.B. Hultin, C.S. Kitchens, H.E. Lessner, A.Z. Makary,
M. Manco-Johnson, W.G. McGehee, J.A. Penner, and J.E. Sanders
Antithrombin 111 (Human) (AT 111) was administered to 18
patients with documented hereditary AT 111 deficiency. In
eight patients with no ongoing clinical symptoms of thrombosis, the percent increase per unit AT 111 infused per
kilogram of body weight ranged from 1.56% to 2.74%. and
the half-life from 43.3 to 77.0 hours. No significant difference was noted between patients receiving and those not
receiving coumarin therapy. In clinically ill patients, the in
vivo recovery was significantly lower and ranged from
0.64%to 1.90% increase per unit AT 111 infused/kg. Efficacy
of AT 111 was evaluated in 13 patients for the prevention or
treatment of thrombosis. AT 111 was efficaciousas assessed
by the absence of thrombotic complications after surgery
and/or parturition, and the nonextension and nonrecurrence of thrombosis in patients exhibiting an acute thrombotic episode. No side effects were noted. Follow-up
studies indicated no hepatitis B seroconversion and no
alanine aminotransferase elevations in patients who were
not transfused with other blood products.
0 1990 by The American Society of Hematology.
H
to 65%, and antigen levels from 20% to 60%. Two patients (two
kindreds) had low activity levels but normal antigen levels. One
patient had an AT 111 activity level significantly higher than the
antigen level. Antigen levels were not provided for two patients.
EREDITARY antithrombin 111 (AT 111) deficiency is
a rare autosomal-dominant disorder characterized by
recurrent deep vein thrombosis and pulmonary embolism.’.*
In patients with a history of deep vein thrombosis or
pulmonary embolism of unknown etiology, the prevalence of
Heterozygous patients have
A T I11 deficiency is 2% to 3%.3q4
AT I11 activity levels between 25% and 60% of normal; the
antigen levels vary with the type of the d i ~ e a s e More
.~
than
half of the affected individuals, between 10 and 35 years old,
experience at least one thrombotic episode. AT I11 concentrate, with or without the concurrent administration of
heparin, has been used successfully in Europe in patients
with hereditary AT I11 deficiency for the prevention or
treatment of thrombosis.
In 1982, the American Red Cross (ARC) convened an
Advisory Board to determine the criteria that would demonstrate the efficacy of A T 111. It concluded: (1) The study
should be conducted in patients with documented hereditary
AT 111 deficiency. (2) AT Ill in vivo recovery and half-life
(phase I study) should be evaluated in patients with no
ongoing clinical symptoms of thrombosis. (3) Efficacy of A T
111(phase I1 study) would be established by (a) prevention of
thrombosis in high-risk situations, such as trauma, surgery,
or parturition, or (b) nonextension of an existing thrombus
for 1 week, and prevention of a new thrombotic event during
the treatment period. (4) Because of the rarity and severity of
the disease, the study should be uncontrolled.
MATERIALS AND METHODS
Patients
Twenty-eight patients entered the study after institutional review
board approvals, and were assigned sequential identification numbers. All patients were advised of procedures and attendant risks in
accordance with institutional guidelines and gave written informed
consent. Eighteen of these patients (1 3 kindreds), aged 5 to 85 years,
with hereditary AT I11 deficiency, are the subject of this report. Five
patients were enrolled in phase I study, 10 in phase 11, and three
participated in both.
Patients’ characteristics are provided in Table 1. Eleven patients
were female; six had no clinical history of thrombosis. Age of onset
for the first thrombotic episode ranged between 14 and 46 years.
Thirteen patients had a concomitant and parallel decrease in AT I11
functional and antigen levels, with activity levels ranging from 29%
Blood, Vol 75,No 1 (January 11, 1990:pp 33-39
Phase I Study (Pharmacokinetic Study)
In vivo recovery and half-life were evaluated after the intravenous
(IV) administration of a single dose of AT I11 calculated to raise the
AT 111 activity level to 120% of normal, assuming a 60% recovery.
AT 111 determinations were performed on citrated blood samples
collected before infusion and within 30 minutes, and at 1, 2, 4, 12,
24,32,48,72, and 96 hours postinfusion. In vivo recovery (expressed
as percent increase/unit administered/kg body weight) was calculated by subtracting the base level from the postinfusion level and
From the American Red Cross, National Headquarters, Washington DC; Plasma Derivatives Laboratory, American Red Cross,
Rockville, MD; Department of Hematology, Walter Reed Army
Institute of Research, Washington, DC; Milton S. Hershey Medical
Center, Pennsylvania State University, Hershey. PA; Department of
Hematology/Oncology, Oregon Health Sciences University, Portland;
Section of Pediatrics, Hematology/Oncology, Health Sciences Center, University of Colorado, Denver; Divison of Hematology, Health
Sciences Center, State University of New York at Stoney Brook,
Long Island; Division of Hematology, College of Medicine, University of Florida, Gainesville: Baptist Hospital, Miami, FL: Department of Hematology, Geisinger Medical Center, Danville, PA;
School of Medicine. University of Southern California, Los Angeles;
Department of Medicine, Michigan State University, East Lansing;
and the Fred Hutchinson Cancer Research Center. Seattle, WA.
Submitted March 30.1989: accepted September 6,1989,
Supported in part by Grant No. CA 18029 from the Public House
Sciences and Grant No. HL 24944 from the National Institutes of
Health.
Presented in part at the annual meeting of the American Society
of Hematology. San Francisco, CA. December 1986.
Address reprint request to Doris Menache, MD, Blood Services,
American Red Cross, National Headquarters, I730 E Street, NW,
Washington, DC 20006.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
“advertisement” in accordance with 18 U.S.C. section I734 solely to
indicate this fact.
8 1990 by The American Society of Hematology.
0006-4971/90/7501-0005$3.OO/0
33
34
MENACHE ET AL
Table 1. Patient Characteristics
Patient Sex/
ID No. Age
1
AT Ill Level
(Act/Ag %)
MI33 43/36'
First Thrombotic Episode:
Age/Type
Other Thrombotic Episode
Family History of
Thrombosisor Known
Study
AT Ill Deficiency
Phase
Father: patient no. 9
Son: AT 111 deficient
Cousin: AT 111 deficient, thrombosis
N/A
None
Mother and sister: AT 111 deficient and
PE during pregnancy
II
None
Father: DVT and 5 PE, died age 38
with massive PE
Sister: AT 111 deficient
II
Mother: patient no. 7
F/22 3 8 / 2 0 t
4
MI29 22/25$
6
F/24 52/50'
N/A
None
7
F/49 44/39'
39/Thrombophlebitis
10- 15 episodes. Thrombophlebitis Daughter: patient no. 6
associated with oral contracep- Son: died age 19 at first thrombotic
episode
tives, DVT.PE
Family: 19 known affected members
9
MI68 57/51'
10
F/18 54/92f
14
MI22 (65/60'§)
F/30
70/26$
+
Multiple DVT, mesenteric vein
thrombosis with resection of
small bowel
3
15
I
21/DVT
29/DVT
46/DVT
+ PE on heparin
+
PE
15/DVT associated with oral
contraceptives
22/DVT
+
PE
Multiple DVT, PE (2). vena cava
ligation
I (twice)
Son: patient no. 1
I
II
I1
Mother: AT 111 deficient, 2 episodes of
DVT
Aunt: thrombophlebitis
Other relatives: thrombophlebitisand
PE
DVT. DVT during pregnancy
21/DVT
I (twice)
DVT during pregnancy on low-dose Father and Brother: AT 111 deficient/
NL Ag
heparin
None
+ PE
Mother: thrombosis
Father: patient no. 17
One son died age 32 with PE
Two other sons AT 111 deficient
II
II
I
+
I1
16
MI62 50/106*§ 14/DVT associated with surgery
DVT (at least 3 episodes)
17
MI85 52/NDt
None
Son: patient no. 16
19
F/O6 51/50f
None
Sister: patient no. 2 1
II (twice)
Father, 3 uncles and 2 cousins: AT 111
deficient
Grandmother: died age 30 with MI
Great uncle: AT 111 deficient, PE
Great aunt: AT 111 deficient, DVT
Great grandmother: DVT. died age 56
with MI
21
F/O5 62/56$
None
Sister: patient no. 19
II
22
MI17 45/45$
DVT (2 episodes)
Mother: AT Ill deficient postpartum
DVT
Sister: AT 111 deficient
II
25
F/29 60/50'§
24/DVT
PE associated with oral None
contraceptives
Sister: patient no. 26
Father and uncle: DVT
I
26
F/24 52146.5
N/A
None
Sister: patient no. 25
I1
I
+
27
F/33 49/ND'
33/DVT during pregnancy
Postpartum vena cava and pelvic
thrombosis
One brother: died age 31 with vena
cava thrombosis
Another brother: multiple thrombosis
28
F/35
24/DVT associated with oral
contraceptives
DVT (3 episodes)
One brother: at least 3 DVT
One sister: DVT during pregnancy
58151'5
Abbreviations: N/A, nonapplicable; Act/Ag, activity antigen; DVT, deep vein thrombosis; PE, pulmonary embolism; NL, normal.
'Preinfusion level determined at ARC.
tPreinfusion level determined by investigator.
$Level at diagnosis provided by investigator.
§Level determined while on coumarin therapy.
II
I
+
II
35
ANTITHROMBIN 111 (HUMAN) IN AT HI DEFICIENCY
dividing this result by the units administered/kg body weight.
Half-life was calculated using a two compartment model: Curve
fitting was done using RS/ 1 software on a VAX 8350 minicomputer
(Digital Equipment Corp, Concord,MA).
AT 111 activity assays' and antigen (Laurel1 rocket technique)
were performed at the ARC. The standard used was calibrated
against the First International Reference Preparation.'
Phase II Study (Eficacy Study)
Patients were treated with an initial dose of AT I11 calculated to
raise the AT 111 level to 120% of normal, and with repeat doses to
maintain a minimum level of 80% for at least 5 days. Heparin
administration was used according to each investigator's judgement.
AT 111 determinations were performed by the investigators
according to methods in place in the various laboratories.
Safety of A T III (Human)
After administration of the product, patients were monitored for
side effects. Follow-up studies for hepatitis were performed on serum
samples collected before infusion, and at 2, 4, 6, and 9 months
postinfusion. Testing for antibody to human immunodeficiencyvirus
type 1 (anti-HIV-1) was performed on a limited number of samples.
All samples collected were tested by the ARC for HBsAg, anti-HBs,
and anti-HBc. Alanine aminotransferase (ALT) and anti-HIV-1
tests were performed at the investigator's institution.
A T IZZ (Human)
AT I11 was prepared for the ARC according to the method of
Wickerhauser and Williams' by the Michigan Department of Public
Health (MDPH), Lansing, and by Baxter Healthcare Corporation,
Hyland Division, Glendale, CA. The method of manufacture included heating the product for 10 hours at 60°C in a solution
containing 0.5 mol/L sodium citrate. Ten AT 111 lots manufactured
by MDPH and two by Hyland were used. AT 111 specific activity of
the final container product ranged from 4.3 to 7.6 IU/mg of protein.
Statistics
Student's t test was used to compare mean values of unpaired
samples drawn from normal populations with equal variances. All P
Fig. 1. Disappearance curves of AT 111 activity
and AT 111 antigen (-+I.
AT 111 (Human) at
58.8 IU activitylkg (73.2 IU antigen/kg) was administered to patient no. 6. Blood samples drawn at
regular intervals were tested for AT 111 activity and
antigen. The results less the patient's AT 111 base
level (0.52 activity IUlmL; 0.60 antigen IUlmL),
were entered on a semilogarithmicplot. Data were
fitted to a two-compartment model. Half-life calculated from the slope of the regression line (-----I
for the beta component was 58.7 hours for AT 111
activity and 48.7 hours for AT 111 antigen.
values are two-tailed unless otherwise specified. The acceptable type
1 error rate was taken to be .05."
RESULTS
A T III Zn Vivo Recovery and HalfLife (Phase Z Study)
AT I11 in vivo recovery and half-life were determined on
10 occasions in eight patients (five kindreds) using three lots.
Two patients were studied twice, first with and then without
the concurrent administration of coumarin." Four patients
were under chronic coumarin therapy and two had no
medication. The dose administered ranged from 27.7 to
117.8 IU/kg.
The percent activity increase/unit A T 111infused/kg body
weight, determined 15 to 30 minutes after administration
of the product, ranged from 1.56% to 2.74% (mean,
2.05 +_ 0.36). AT 111 antigen increase ranged from 1.66% to
2.59% (mean, 2.09% 0.34%).
A T I11 half-life (T 1/2), calculated for eight patients,
from the second component of the curve beginning a t 24
hours postinfusion, ranged from 43.3 to 77.0 hours (mean,
61.3 + 12.5 hours) and the antigen half-life from 43.3 to 76.1
hours (mean, 53.3
10.3 hours). Disappearance curves
observed for one patient are illustrated in Fig 1.
There were no significant differences (data not shown) in
AT I11 recovery and half-life whether patients were receiving
coumarin therapy or not, nor was there a significant difference between products (MDPH v Hyland).
+_
+_
AT III Clinical Eficacy (Phase II study)
Zn vivo recovery. Results of A T I11 assays, performed on
samples obtained within 30 minutes after the first administration of A T 111, were provided by the investigators for 11
patients. With the exception of the bone marrow donor, the
percent A T 111activity increase/unit infused/kg body weight
ranged from 0.64% to 1.90% (mean, 1.28% + 0.36%) and
(=-I,
0.1
0
20
40
60
Time Postinfusion (hours)
-
80
100
36
MENACHE ET
AL
Table 2. Clinical U s e of A T 111 in Surgical Patients
%AT 111
Recovery
per IUIkg
lnfusedt
Range AT 111.
During
Treatment
No. Days AT 111
InfusedINo. Days
Treatment Course
Total IU
Infused
Heparin
(no. days)
Product
Ureteral lithotomy
Ileum resection
Colectomy
Transurethral prostatectomy
Resection retroperitoneal neuroblastoma
Bone marrow transplant
0.64
1.51
1.02
1.41
1.17
68-120
40-1 3 4
37-7 1
72-132
64-173
13/13
711 1
213
314
10114
23,298
27.168
5,780
8,265
6,528
7
15
NO
NO
3
FFP (500 mL)
PRC ( 2 U)
FFP ( 4 U)
NO
NO
ND
82-126
518
3,809
NO
Platelets ( 7 4 U)
PRC (6 U)
Bone marrow aspirations
2.59
72-131
518
4,474
NO
NO
Patient
No.
1
4
16
17
19
21
Procedure
Other
Blood
Abbreviations: PRC. packed red cell: ND, not determined: FFP, fresh frozen plasma.
*AT 111 activity levels in percent of normal.
tWithin 3 0 minutes after first infusion with AT 111.
was significantly lower than that observed in the phase I
study (2.05 f 0.36) ( P < .0001) (one-tailed Pvalue).
Surgical procedures. AT 111 was administered prophylactically, with or without heparin, to six patients (Table 2)
who received 3 to 11 infusions for 3 to 14 days, in doses
ranging from 13 to 52 IU/kg. With one exception (no. 16),
AT I11 activity levels were increased to between 95% and
164% before surgery. Maximum levels maintained during
the treatment course ranged between 71% and 173%. Minimum levels observed before the infusion of a dose of AT 111
ranged from 37% to 82%. None of the patients developed
clinical symptoms of thrombosis. Patient no. 19 received a
bone marrow transplant with no replacement therapy 2.5
months after resection of a retroperitoneal neuroblastoma.
One week after transplant, while thrombocytopenic (platelets <10,000/mm3), clots developed in her Hickman catheter
(Davol Corp, Cranston, RI). Because of repetitive clotting in
the catheter (two episodes cleared with urokinase), treatment with A T I11 was started 10 days posttransplant. All
clotting ceased within 48 hours of treatment and no subsequent episode occurred. No heparin was administered.
Pregnancy and parturition. Past obstetrical history and
management of the current pregnancy for the five patients
entering the study are summarized in Table 3. AT I11 was
administered prophylactically, with or without heparin, to
four patients (Table 4) during labor and/or for 5 to 6 days
after delivery. Each patient received 5 to 6 infusions; the first
dose ranged from 30.4 to 93.0 IU/kg. Maximum levels
maintained during the treatment course ranged between
137% and 208%. Minimum levels observed before infusion of
a dose of AT 111ranged from 52% to 102%. Each patient had
a normal vaginal delivery resulting in a viable infant. None of
these patients developed clinical symptoms of thrombosis in
the postpartum period.
The fifth patient was not treated prophylactically and
developed vena cava and pelvic vein thrombosis a t 4.5 weeks
postpartum. AT 111 (33 IU/kg/d) was administered with
heparin for 7 days. Maximum AT 111 levels maintained
during the treatment course ranged between 135% and
175%. Minimum levels observed before infusion of a dose of
AT 111 ranged from 84% to 116%. Symptoms resolved and
the patient was discharged.
Deep vein thrombosis andpulmonary embolism. Patient
no. 14, with the angiogram diagnosis of pulmonary embolism, developed extensive venous obstruction while treated
with heparin. Despite an increased heparin dose and the
concomitant administration of coumarin, a repeat Doppler
test suggested extension of the leg vein thrombosis with
possible vena cava involvement. AT 111was administered for
2 consecutive days (27 IU/kg/d) with heparin, and A T 111
levels were maintained close to 100%. The patient improved
and was discharged.
Severe acute systemic lupus erythematosus. A 17-yearold boy (no. 22) treated with coumarin was admitted to the
Table 3. Pregnancy and Thrombosis
~~
Current Pregnancy
Obstetric Histwy
Patient ID
(no./age) Gravida Para
3/22
10118
15/30
I
111
IV
N/A
0
1
26/26
27/33
II
II
1
0
Theraov
..
DVT During
Previous
Pregnancy
Heparin
Beginning at
DVT
Labor/Delivery
AT 111
No/No
No
No
YesJYes
Yes, at 10 weeks Yes/Yes
N/A
No
Yes on heparin Yes, 3 weeks, 15,000 b.i.d.
Yes. 1 0 weeks, post-DVT,
Yes
30,000 t.i.d.
No
Yes, at pregnancy, 6,000 daily No
Yes/Yes
No
Yes, 14 weeks, post-DVT,
Yes, at 1 4 weeks No/No
16,000 t.i.d.
Abbreviations: N/A, nonapplicable; DVT, deep vein thrombosis; b i d . , twice per day; t.i.d., three times per day.
Postpartum
AT 111
Heparin
Yes
Yes
Yes
No
Yes (tubal ligation) Yes
Yes
Yes, post-DVT
Yes
Yes, post-DVT
37
ANTITHROMBIN 111 (HUMAN) IN AT 111 DEFICIENCY
Table 4. Clinical Use of AT 111 During Parturition or Postpartum
Patient
No.
3
10
15
26
27
Clinical
Indication
Parturition
Parturition
Parturition
Parturition
Postpartum vena cava
and pelvic thrombosis
% A T 111
Increase per
lU/kg Infusedt
Range AT Ill*
During
Treatment
No. Days AT 111
Infused/No Days
Treatment Course
Total AT Ill
(IU infused)
Heparin Units
(no. days)
1.16
1.24
1.11
1.68
1.90
52-137
102-208
77-135
80- 192
84- 175
616
518
518
515
717
16,553
15,324
14,563
10,950
17,355
5,000 b.i.d., day 1-6
No
2 1,000, day 1
12,000, day 1
10,000-32,000, daily,
day 1-7
Abbreviation: b.i.d.. twice per day.
*AT 111 activity levels in percent of normal.
tDetermined within 30 minutes after first infusion of AT 111.
hospital for rectal bleeding, facial rash, and a pulmonary
infiltrate. Evidence of acute severe lupus erythematosus with
lupus pneumonitis was documented. He was treated with
high-dose corticosteroids and A T 111. Thereafter, he developed acute respiratory failure, pneumothorax, pneumocystis
pneumonia, autoimmune thrombocytopenia, and hemolytic
anemia. He was treated aggressively with immunosuppressive therapy, plasmapheresis, IV immune globulin, multiple
blood components, and antibiotics. Ultimately, all symptoms
resolved and the patient was discharged. A total of 144,700
IU A T 111 (50 infusions) was administered during a 52-day
hospitalization. AT 111levels were maintained between 100%
and 180%. No thrombotic complications were noted during
or after hospitalization.
Side Effects and Adverse Reactions
A T 111 was well-tolerated by all patients; no adverse
reactions were noted. One patient complained (12 hours
postpartum) of light headedness that resolved rapidly, and
the infusion was not interrupted.
Hepatitis B markers. Of 18 patients who received AT
111, four were treated on two separate occasions and six were
transfused with other blood components. No hepatitis B
seroconversion was noted for 15 patients followed for a period
of 6 months or more, nor for one patient (no. 17) followed for
a period of 3 months. Two patients showed evidence of
hepatitis B markers. Patient no. 19 became positive for
anti-HBs a t 9 months after the second treatment with A T 111
(1 1 months after first treatment). Patient no. 22 became
transiently anti-HBs and anti-HBc positive.
ALTfoZZow-up testing. Test results were provided by the
investigators for 10 patients. ALT or serum glutamicoxaloacetic transaminase (SCOT) elevations were noted for
two patients (no. 1 and 19). With the exception of two
patients tested a t 2-week intervals, all other patients were
tested every 2 months.
Anti-HIV-I follow-up testing. Results in four patients
were negative at 9 weeks, 6 months, and 8 months postinfusion.
DISCUSSION
The phase I and phase I1 studies were designed to evaluate
the safety, recovery, half-life, and clinical efficacy of A T 111
in patients with documented hereditary A T 111deficiency.
Among 18 patients studied, six had no history of thrombosis; the clinical history of the remaining 12 patients was
remarkable for a high incidence of pulmonary embolism
(six), multiple thrombosis associated with the use of oral
contraceptives (four), pregnancy (two), delivery (one), or
surgery (one). Thirteen patients (10 kindreds) were type I,
one type 11," and one patient with activity levels consistently
higher than the antigen remains unclassified. Twelve of 13
kindreds had a positive family history of thrombosis. There
was no family history of thrombosis for the type I1 patient.
In patients with no ongoing clinical symptoms of thrombosis, administration of one A T 111 IU/kg body weight resulted
in an increase of AT I11 activity ranging from 1.56% to
2.74% and a half-life of 61.3 f 2.5 hours (range 43.3 to 77
hours). These results are consistent with those previously
p ~ b l i s h e d . ' ~The
- ' ~ mean antigen half-life of 53.3 hours was
shorter than that of the biologic activity.
There was no significant difference in A T I11 recovery and
half-life whether patients were on coumarin treatment or not,
confirming previous observations,I6 nor was there a significant difference between products.
In contrast, AT 111 in vivo recovery was significantly lower
( P <.0001) in patients who were ill (phase I1 study).
Differences obtained between the two groups of patients may
be due to the fact that all A T 111assays for the phase I study
were performed in the A R C laboratory, whereas for the
phase I1 study, assays were performed by other laboratories
that did not use the same reference as a standard or the same
assay method. Differences obtained for these two groups of
patients need further investigation.
Administration of A T I11 to patients with hereditary A T
111 deficiency has been reported to be successful for the
prevention of thrombosis after
and for the control
of recurrent thrombosis refractory to heparin
There were no thrombotic complications after surgery in any
of the six patients treated. Of three of these patients also
undergoing surgery without replacement therapy, two developed thrombosis (one fatal, no. 17), whereas one had no
thrombotic complication^.^^ A T 111-deficient patients undergoing surgery without replacement therapy have a high
incidence of thrombosis. To our knowledge, there is no
reported case of thrombotic complication after surgery in
patients under replacement therapy. Control of thrombotic
events also occurred subsequent to the administration of A T
MENACHE ET AL
38
I11 in all three patients treated for acute and recurrent
thrombosis.
Thromboembolic complications occur in 68% of AT IIIdeficient pregnant women.24 Prophylactic management of
these patients is difficult. While coumarin drugs cross the
placenta and have a teratogenic effect, heparin has the
potential of further reducing the level of A T III.2sSuccessful
prophylaxis with low-dose heparin has been reported in some
instance^,^^^^^-^^ but not in other^.^^,^' In our series, low-dose
heparin did not prevent thrombosis during one pregnancy,
but was efficacious at 15,000 units twice per day during
another pregnancy (no. 10).
During the current pregnancy, heparin was administered
prophylactically to two patients and to two other patients
after a thrombotic episode.
To prevent thrombotic complications during labor, delivery, or termination of pregnancy, replacement therapy using
either plasma26329
or AT II124.30-34
appeared to be successful.
In our series of five patients, the only one who developed
thrombosis in the postpartum period had not been treated
prophylactically with A T 111.
One minor side effect (light-headedness) was noted after
administration of 14 lots of AT I11 to 18 patients who
received a total of 128 infusions (344,280 IU) for 24
treatment courses.
Heat treatment used in the manufacturing process has
been shown to inactivate intentionally added viruses35336
in
this product. Patient follow-up studies indicate that the only
two patients in whom antibodies to hepatitis B virus were
detected were among those who received multiple transfusions with other blood components. For one of these patients
(no. 22), the sequence of events (appearance of antibodies at
2 weeks and disappearance at 10 weeks postinfusion) is in
favor of passive transmission by the multiple transfusions.
For patient no. 19, it is difficult to assess whether the late
seroconversion a t 9 months was related to the transfusion of
the many other blood products administered or to another
cause. The two lots of AT Ill infused to this patient did not
induce seroconversion in three other patients. ALT or SGOT
elevations were noted for two patients; both had a disease
involving the liver: cirrhosis of the liver (no. 1) and neuroblastoma with liver involvement (no. 19). There were no ALT
elevations in the remaining 10 patients tested. However, it
should be noted that only two patients were followed a t short
time intervals (every 2 weeks), while the others were followed
at 2-month intervals. At the time the study was initiated
(1982), AIDS was just emerging and testing for anti-HIV-1
was not begun until 1985. Therefore, follow-up studies were
limited to four patients, none of whom indicated seroconversion to HIV.
In summary, AT 111 manufactured for the ARC has a
normal in vivo recovery and half-life. Use of this product for
the prevention and treatment of thrombosis in patients with
hereditary AT I11 deficiency fulfilled the criteria establishing
safety and efficacy.
ACKNOWLEDGMENT
We thank the members of the Advisory Board for advice and the
help provided in developing the protocols: J.O. Ballard, MD, Milton
S. Hershey Medical Center, Hershey, PA, M. Bern, MD, New
England Deaconess Hospital, Boston, MA, S.H. Goodnight, MD,
Oregon Health Sciences University, Portland; E.B. Reeve, MD,
University of Colorado Health Science Center, Denver; H.R. Roberts, MD, University of North Carolina, Chapel Hill; and S.S.
Shapiro, MD, Jefferson Medical College, Philadelphia, PA. We are
indebted to the many physicians and nursing staff of the collaborative institutions. We also thank J. Nardolillo. Transmissible Diseases
Laboratory, American Red Cross, Rockville, MD, for statistical
analysis and D.B. Clark, PhD, Plasma Derivatives Laboratory,
American Red Cross, Rockville, MD, for pharmacokinetic analyses.
The patience and accuracy of S. Rossi, secretary, for all the data
entry, is gratefully acknowledged.
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