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A new case of high-molecular-weight kininogen inherited deficiency.

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American Journal of Hematology 22:415-419 (1986)
A New Case of High-Molecular-Weight
Kininogen Inherited Deficiency
Jean-Jacques Lefrere, Marie-Helene Horellou, Daniele Gozin,
Jacqueline Conard, Jean-Yves Muller, Michael Clark, Jean-Pierre Soulier,
and Meyer Samama
Laboratoire Central d’Hematologie, H6tel-Dieu (J.J.L., M.-H.H., J.C., M.S.), Centre National
de Transfusion Sanguine (D.G., J.-Y M., J.-P.S.), and Service d’Hematologie Pediatrique,
H6pital Saint-Louis (M.C.), Paris, France
A preoperative hemostasis study discovered a prolonged activated partial thromboplastin time in a 23-year-old Portuguese Caucasian woman without personal or past
family history of hemorrhage or thrombosis. This was corrected by pooled plasma
that excluded circulating anticoagulant. Activated partial thromboplastin time was
prolonged whatever the activator, particularly ellagic acid, and was not corrected by
prolonged kaolin incubation. Levels of factors VIII and XI1 were normal; factor XI
and prekallikrein levels were either moderately low or normal according to activators
and defective reagents used. High-molecular-weight kininogen (HMWK) level assessed by coagulation and immunological method was virtually nil. Fibrinolysis
activity was normal before and after veinous occlusion. The programmed operation
was performed without any particular preparation and no complication arose. Family
investigation found heterozygous HMWK deficiency in the proposita’s father and
three of her siblings.
Key words: prekallikrein, contact coagulation system
Between 1974 and 1976, a small number of publications reported cases of a
congenital deficiency of a then unknown coagulation factor, the high-molecularweight kininogen (HMWK). It was named after one of the patients suffering from
this deficit and factors Fitzgerald [1-31, Williams [4], Flaujeac [5-71, Reid [8], and
Fujiwara [9] were described in succession. HMWK takes part in the contact system,
the earliest phase of the intrinsic coagulation pathway.
In view of its great rarity, we describe here another case of a congenital deficit
of HMWK in a 23-year-old woman.
Coagulation assays were performed according to classical techniques [lo]. The
study of the contact system was made according to previously described techniques
[ll]. The dosage of the complement was performed in Pr. Kazatchkine’s laboratory.
Received for publication September 12, 1985; accepted February 6 , 1986.
Address reprint requests to Dr J.J. Lefrtre, Centre National de Transfusion Sanguine, 6, Rue A.
Cabanel, 75015, Paris, France.
0 1986 Alan R. Liss, Inc.
Case Report: Lefrkre et al
The immunological dosage of HMWK was realized in Mrs. Steinbuch’s laboratory
(C.N. T.S. Orsay).
A 23-year-old white Caucasian (Portuguese) woman, without past surgical or
obstetrical history, or of hemorrhage or thrombosis, was referred for ovarian hysterectomy. There was no known family history of hemorrhage or consanguinity. Preoperative hemostasis check-up showed (Table I) a normal bleeding time, a normal
platelet count, a normal Quick test, a prolonged APTT, a normal thrombin clotting
time, and a normal fibrinogen level. After 1 hr incubation at 37°C of normal plasma
with the patient’s plasma, APTT was normalized, thus eliminating the hypothesis of
a circulating anticoagulant. There was no difference in APTT with the various
reagents used (Table 11) and prolonged incubation with celite did not correct APTT
(patient: 48 sec; normal plasma: 32 sec; patient after 15 min incubation: 56 sec;
normal plasma after 15 min incubation: 32 sec). The study of the intrinsic coagulation
phase factors showed the following: factor VIII 70%, factors IX and XI1 100%, and
discordant results for prekallikrein and factor XI activity: APTT studied with platelin
activator reagent (General Diagnostics) and Merz Dade XI defective plasma
showed 42% factor XI, but studied with C.N.T.S. XI defective plasma, it showed
95% after activation by a cephalin 1/400 and kaolin mixture. APTT studied with
Fletcher Trait Immuno defective plasma and APTT reagent after 1 min incubation
showed 35% prekallikrein level, but it was estimated at 100% with Fletcher Trait
King defective plasma after 30 sec incubation with a cephalin 11400 and kaolin
mixture. Immunological assay of prekallikrein was 5 p g / d and chromogenic dosage
of prekallikrein with activation by celite was estimated at 70%. Global contact
measured by the amydolytic (chromo-kallicrein, Diagnostica Stago) method after
activation by dextran sulfate was below 10%.Factor XII activation capacity measured
by the amydolytic method (dextran sulfate + exogenous prekallikrein) was 80%.
TABLE I. Patient’s Preowrative Hemostasis Check-Ur,
Bleeding time (Ivy’s method)
Platelet count
Quick test
Thrombin clotting time
Fibrinogen level
6 min
250. 109/L
47 sec
20 sec
2.5 g/L
< 8 min
150. 109/L
28 sec
19 sec
2-4 g/L
TABLE 11. Patient’s APTT With the Various ThromboplastinUsed
Platelin + activator (General Diagnostics)
Automated APTT (General Diagnostics)
CK prest (Diagnostica Stago)
Cephamat (Biomerieux)
78/31 sec
48/33 sec
52/33 sec
49/30 sec
Case Report: High-Molecular-Weight Kininogen Deficiency
Functional dosage of HMWK by the coagulation method showed very low
levels with different defective reagents used: 0.65% with Flaujeac plasma, 1.7% with
Fitzgerald (King), less than 5 % with Fitzgerald (Immuno). Immunological assay of
HMWK antigen by Laurel1 technique with Behring anti-HMWK antiserum was nil
(no detectable precipitate). Full correction of patient plasma APTT was obtained by
addition of 30% normal plasma. For added normal plasma concentrations exceeding
l o % , we obtained a dose-related linear response. Fibrinolysis study results were
almost normal: Euglobulin lysis time before anoxia was 11 hr (normal: 3-10 hr), and
was 2 hr after 10 min anoxia by venous occlusion (normal
90 min); FearnleyGallimore test lasted 2 hr before anoxia (normal: 3-10 hr) and 1 hr after 10 min
90 min). We found no abnormality in component factors: CHS0 =
anoxia (normal
106%, C3 = 116%, C4 = 87%, B = 107% (normal values = 100 f 20%,results
expressed in percentage of a reference pool).
A study of the proposita’s family discovered four heterozygous HMWK defect
trait carriers (Table 111, Fig. 1); levels were near to 50% of normal values with
comparable results between functional and immunological dosages. These patients
did not have an impaired global contact activity through their HMWK defect; prekallikrein and factor XI were normal.
TABLE 111. APTT, Global, Contact Measured by Amydolytic Method After Activation by
Dextran Sulfate Functional and Immunological HMWK Dosages in the Proposita’s Family
112 (proposita)
Global contact
activity (dextran
sulfate) (%)
< 10
> 100
dosage (%)
dosage (%)
Fig. 1. Proposita’s family (proposita denoted by arrow).
Case Report: Lefrere et al
The scheduled surgical operation was performed without any particular preparation and was not complicated by any hemorrhage.
HMWK is a one-chain a-globulin with a 110,000-dalton molecular weight [ 121.
It is transported in plasma complexed with prekallikrein and factor XI, allowing the
latter’s binding to negative-charged surfaces [3,13,14]. The patient had no tendency
to hemorrhage as seen in factor XI1 defect [ 151, in prekallikrein defect [ 16,171, or in
congenital HMWK defects previously described [1,4,6,8,9]. The hereditary transmission of the trait appears to be recessive autosomal since both sexes are affected.
Unlike the prekallikrein deficit, prolonged preincubation of patient’s plasma with
celite does not normalize APTT. Yet, unlike the prekallikrein deficit, the use of ellagic
acid does not correct APTT: It is known that contact phase activation by ellagic acid
is possible in cases of the prekallikrein deficit but not of the HMWK deficit.
In Fitzgerald [l], Williams [4], and Fujiwara [9] plasmas were reported to
associate HMWK deficit with low prekallikrein levels. In these patients, decreased
prekallikrein level (20 to 40 %) is underestimated. Prekallikrein also appears abnormal
under immunological assay since it does not migrate without its binding protein,
This new case of HMWK congenital deficit (there are fewer than ten mentioned
in the world’s publications) was clinically entirely nonsymptomatic, which is the
usual case in congenital deficits of contact factors. The biological study pinpointed
the close relationship between HMWK and prekallikrein.
Prekallikrein, even when present at normal levels, is poorly absorbed by
surfaces when its binding protein is absent; on the other hand, heterozygous subjects
show normal prekallikrein activation, proving that in congenital deficiencies such as
the one reported, the defect only concerns HMWK. The variable impairment of
prekallikrein activation is not related to the level of this protein, but to HMWK,
which is necessary for its optimal activation.
We thank Mrs J. Lerable for her valuable technical cooperation.
Waldmann R, Abraham JP, Rebuck JW, Caldwell J, Saito H, Ratnoff OD: Fitzgerald factor: A
hitherto unrecognized coagulation factor. Lancet i:949-95 1, 1975.
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trait: A role of high molecular weight kininogen in clotting and fibrinolysis. J Lab Clin Med 87:327337, 1976.
Donaldson VH, Kleniewski J, Saito H, Sayed JK: Prekallicrein deficiency in a kindred with
kininogen deficiency with Fitzgerald trait clotting defect. Evidence that high molecular weight
kininogen and prekallicrein exist as a complex in normal human plasma. J Clin Invest 60:571-583,
Colman RW, Bagdasarian A, Talamo RC, Scott CF, Seavey M, Guimaraes JA, Pierce JV, Kaplan
AP: Williams trait. Human kininogen deficiency with diminished levels of plasminogen proactivator
and prekallicrein associated with abnormalities of the Hageman factor-dependent pathways. J. Clin.
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Case Report: High-Molecular- Weight-Kininogen Deficiency
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deficiency. Clin Res (abstract) 24:47, 1976.
9. Hayashi H, Koya H, Kitajima K, Kimura I, Oh-Ishi S, Ueno A, Uchida Y, Katori M: Fujiwara
trait: The first case of a possible kininogen deficiency in Japan. Acta Haematol Jap, 41:243, 1978.
10. Caen JP, Larrieu MJ, Samama M: L’htmostase. Methodes d’exploration et diagnostic pratique.
L’expansion scientifique, Paris, 1975, p 383.
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