Acquired
Inhibitors of Coagulation
PE
Makris, G Gerotziafas, C Christophoridis, Z Foka, E Pithara.
Haem.
& Thromb Unit, A´ Prop Med. Clinic Univ of Thessaloniki-
GREECE.
In Internal Medicine, haemorrhagic manifestations may be due to various origins. The physician needs to be familiarised with these kinds of disorders in order to determine their causes. The problem is more serious when there is no apparent history of haemorrhagic disease. Here we present 14 cases of acquired inhibitors of coagulation. Materiel and methods: We present: 2 inhibitors of factor VIII, (a woman 24 years old developed the inhibitor after delivering her second child, while another, 74 years old, had previously suffered from pernicious anaemia), 1 inhibitor of factor IX (male 60 years old suffering from mild haemophilia B), 1 inhibitor of von Willebrand factor (male 70 years old with cancer of ethmoid sinuses), 1 inhibitor of factor V (female 64 years old in the course of myeloma disease) and 8 inhibitors of von Willebrand factor during myeloproliferative syndromes (5 females and 3 males). We performed all the coagulation assays (clotting times and analytical determination of factors, especially mixture assays) The description of these inhibitors had clinical importance because most of the patients had manifested serious haemorrhagic disorders Results of clinical observation of these patients: The two women with factor VIII inhibitor died, the first of haemorrhage and the other of chronic hepatitis (consequence of replacement therapy). The other three patients with the inhibitors of factors IX, V, Willebrand have been better (the one with the ethmoid cancer for 13 years, the other with fIX inhibitor for 3 years and the woman with myeloma for 5 years). Only three of the rest have died of haemorrhagic cerebral episode (2 women and 1 man). Conclusion: Acquired inhibitors are a serious clinical entity which often can lead to death because of uncontrollable haemorrhagic manifestations. The physician needs to be familiar with this entity so as to suspect the presence of inhibitors and to perform a suitable and complete laboratory control. Usually, management of the underlying disease leads to the recovery from the inhibitor.
DDAVP
Treatment - Our experience for the past 12 years
PE Makris, G Gerotziafas, Z Foka, C Semoglu, E Sophianos, E Pithara, G Bischiniotis, K Deligiannis, A Anagnostopulos, N Liolios.
Haem. & Thromb. Unit A’ PRP, A’ & C’ Surgical Department, PaedoSurgical Clinic of University of Thessaloniki, Intensive Care Unit of AHEPA University Hospital of Thessaloniki, GREECE.
The aim of this presentation is to show the advantages of the alternative treatment with DDAVP versus the classical administration of antihaemophilic factors to the great majority of haemorrhagic patients. Material. We have used DDAVP systematically for the past 12 years. During all this time 114 haemorrhagic patients have undergone 810 dental extractions, while another 12 patients have been subjected to surgical operations (4 patients were submitted to surgical correction of inguinal hernia, 2 to apppendectomy, 1 to nail extraction, 1 to removal of extensive corns of the sole, 1 to surgical correction of phimosis, 1 to orchidectomy, 1 to opening of a coccyx cyst and 1 to surgical correction of acromial exarticulation. All the patients were led to surgical operation after a confirmed positive response to the experimental administration of DDAVP, which augmented 3-6 times the levels of the pre-existing factor. None of these patients had problems due to an abnormal triggering of fibrinolytic pathway, a fact that had been previously screened with measurement of d-dimmers during the experimental administration of DDAVP. In the table we demonstrate the changes observed in factors before and after the operation. The use of this treatment to the majority of Haemorrhagic patients undergoing surgical operation, has been shown to be safer, more effective and less costly in comparison with the classical method.
FVIII:C |
|
vWF |
|
vWF:Ag |
|
before |
after |
before |
after |
before |
after |
% |
% |
% |
% |
% |
% |
10 |
60 |
12 |
66 |
32 |
89 |
16 |
74 |
128 |
210 |
135 |
350 |
8 |
50 |
20 |
120 |
25 |
130 |
34 |
170 |
50 |
190 |
45 |
210 |
15 |
80 |
23 |
90 |
30 |
150 |
7 |
40 |
5 |
80 |
18 |
90 |
13 |
60 |
19 |
95 |
22 |
99 |
6 |
30 |
120 |
255 |
121 |
350 |
11 |
55 |
150 |
365 |
118 |
440 |
35 |
150 |
144 |
198 |
155 |
500 |
20 |
120 |
35 |
210 |
40 |
200 |
6 |
30 |
13 |
67 |
15 |
79 |
Isotopic
synovektomy in haemophilic arthropathies
PE
Makris, L Settas, Z Foka, G Gerotziafas, E.Pithara, K
Konstantinidis, Ph Grammatikos.
Haem. & Thromb. Unit A’ PRP, & A’ Pathological Department, of University of Thessaloniki, Nuclear Unit of AHEPA University Hospital Thessaloniki, GREECE.
Haemophilic arthropathy is a serious complication of haemophilic syndromes, since the progressive destruction of articular surfaces result in the eventual deformity and crippling of joints. Furthermore, chronic haemartrosis is an additional factor of the impairment of the joints. The management of chronic haemarthrosis is not only difficult and costly, but it is also very discouraging for the patient, since it demands long term replacement therapy. The cause of these haemorrhagic episodes is synovitis. Isotopic synovectomy has been used as an alternative treatment of different kinds of arthropathy, included haemophilic arthropathy. We applied this method to selected patients in order to improve the clinical manifestations of the chronic liquid haemarthrosis and to prevent an eventual crippling. Materiel and methods: We applied isotopic synove-ctomy to 4 scoolboys suffering from haemophilia A and chronic liquid haemarthrosis of knee joints (One of them had both his knees affected). We administered the colloid isotope 90Y (Yttrium) by intraarticular infusion in aseptic conditions. Following the infusion, the affected limb remained immobilised for 48h. Results: The four pupils had been followed for 10 months after the intra articular infusion of the isotope. Three of them had had complete remission of the haemarthrosis for 10 months and all of them for a total period of 10 months. The psychological situation of the boys has been ameliorated. They have started to swim, and, as a result, the supportive property of the muscles about the joint has been improved. Conclusion: Isotopic synovectomy's results are equal, if not better, than that of surgical synovectomy in the treatment of haemophilic arthropathy.
Coronary artery by-pass surgery in an haemophiliac patient
-continuous infusion of FVIII:C.
PE Makris, Oikonomidis A, Diarmisakis E, Pithara E, Papadopulos K, GT Gerotziafas, Z Foka, Spirou P.
Haem & Thromb Unis AHEPA University Hospital, CardioSurgery Clinic “G Papanikolaou” Hospital Thessaloniki Greece.
The elevated factor VIII levels are related with coronary artery
disease. Furthermore, bolus administration of concentrated
factors is associated with atherogenic effect due to its high
peak levels. Continuous infusion is a method which can minimise
these side-effects. Materiel and methods: Man 62 years
old, weighing 104 kg, had suffered from severe haemophilia A,
mitroid valve stenosis with atrial fibrillation and developed
atheromatic coronary disease. As a consequence, he underwent
surgical opening of the valve and coronary artery
"by-pass" surgery of one vesicle. We administered
highly purified FVIII (Monoclate -P) according to the following
protocol: a) 6000 iu bolus in the beginning of the operation,
b)12000 iu continuous infusion using a pump, during the
operation (which had lasted for 4 h) and c) during the first 24
h 48000 iu. Rate of administration: 2000 iu FVIII:C plus 20 iu
of heparin (5 ml/h). Every 4h we were renewing the solution. On
the second day the dosage was reduced to 18000 iu, on the third
day to 6000 iu, from the fourth till the tenth day to 3000 iu and
on the tenth till the fourteenth day to 500 iu/24h. Results
-comments: Levels of FVIII:C varied between 95-31%, TAT
increased the third day (90ìg/ml), while F1+2 remained less than
4 ìg/ml. The patient was successfully treated with this
alternative method without any clinical or laboratory
complications.
.
Stability
of concentrated factors of coagulation
E Pithara, G Gerotziafas, K Konstantinidis, Pe Makris
Haem. & Thr.. Unit, Ahepa Hospital, Thessaloniki, Greece.
In
order to accept the clinical use of continuous infusion of
concentrated factors of coagulation as a replacement therapy of
haemophilic syndromes, we checked the stability of these
compounds after their reconstitution. We took 500 ìl of each
compound, which had already been ready for administration, and
we checked its activity at the beginning, and after 30 min 4h and
24 h respectively. We checked the following commercial
preparations: Monoclate-P, Mononine, Coate-H and Kogenate.
Results:
preparation |
0
min |
30
min |
4h |
24h |
|
|
|
|
|
Koate-H |
88% |
79% |
53% |
27% |
Monoclate-P |
162% |
140% |
128% |
59% |
Kogenate |
100% |
79% |
54% |
54% |
Mononine |
105% |
89% |
79% |
70% |
The changes in factor activity observed during the above four time periods didn’t establish the stability of these compounds. Therefore, we decided to use a new solution every 4 h for the case of replacement therapy by continuous infusion. The experiment took place in very hot conditions (in July). In September we repeated the experiment and realised that all the preparations had remained stable for 24 h. Nevertheless, for security reasons, we recommend to change the dilution every 4 h in the case of continuous infusion .
Hematuria
and renal colics in haemophilic patients.
GT
Gerotziafas, K. Konstantinidis, G.Kaiafa, E.Pithara, PE Makris.
Haem. & Throm. Unit, AHEPA Univ. Hospital Thessaloniki Greece.
In the past, hematuria in haemophilic patients used to be treated by replacement therapy or by a- aminocaproic acid (EAKA). As a result, patients could develop transient anuria, calculi formation and gradual deterioration of renal function, complications associated with the formation of haemoglobin crystalls inside the kidney. Later, conservative management of these episodes, which included fluid replacement and administration of soda, was recommended. These measures not only shortened, but they prolonged the duration of hematuria for 25-30 days, a fact that leads to excessive blood loss and provokes anxiety to the patient. Furthermore, hematuria is often accompanied by renal colics after the administration of EAKA, factors or without any treatment at all. (1 patient in 3). In addition, because of the often infection of haemophiliacs with HIV virus, it is imperative that the duration of hematuria be short, for the safety of the persons related to the patient. Materiel and methods: We studied 65 episodes of hematuria in 50 patients (46 suffering from haemophilia A and 4 from haemophilia B).
Table. Comparison among the different treatment procedures.
kind
of treatment |
number
of episodes |
number
of colics |
duration
of therapy |
without treatment | 15 | 6 | 8-10 days |
FVIII/FIX | 12 | 4 | 4-8 days |
Transamin | 25 | 8 | 5-10 days |
All of them | 13 | 0 | 1-2 days |
We propose the following treatment procedure: 1. Conservative measures. 2. administration of 5-20 iu/Kgr of high purity concentrated factors. 3. tranexamic acid, 500 mg 3 times a day. In this way the duration of hematuria is only 1-2 days.
rFVIIa
treatment of a haemophiliac
with
a very high responder inhibitor
PE
Makris, G Gerotziafas, E Pithara, Th Papageorgiu, F Athanasiadu,
D Katriu.
Haem
& Thromb Unit, AHEPA Univ. Hospital, Thessaloniki-Greece.
A
boy 2,5 years old, (haemophiliac A, FVIII:C <1%) had
received 2000 units of Monoclate-P for a gastrointestinal
bleeding. 40 days later he had had an hemarthrosis in the left
knee and was treated with 1000 units Kogenate. In the same time
we decided to implant a infuse-a port. On the day of operation (6
days later) he received 1000 units of Kogenate without any
haemorragic problem. After 2h, the child started to bleed and
another administration of 1000 units didn’t give any result.
There was no apparent surgical reason of bleeding. The general
situation of the boy had been aggravated and he received two
units of red blood cells and another 2.000 units of Kogenate. On
the 2nd day an overdose of 3000 units of Kogenate was without any
real haemostatic effect. The laboratory control revealed a
strong inhibitor of FVIII:C (256 Bethesda units). Waiting for
Novo Seven (kindly offered from Novo Nordisk), we treated with
cyclophosphamide and Kogenate, but the results were poor.
Furthermore, the surgical field had been infected by
Pseydomonas and Timentin was administered. Treatment (22/11)
with NovoSeven at 1,2 mg every 4 h had poor results. The child
was re-operated (25/11) for the removal of the infuse-a-port for
it was considered as the possible cause of infection During this
operation the patient was covered with 2,4 mg every 3h and only
after this dosage the bleeding definitively stopped.
date FI Inhib A2-APL TAT F1+2 PAP Di-D Hct
g/l B/u % ìg/l ìg/l ìg/l ìg/l %
19/10 3.9 - 10 1.2 300 0.5 33
22/11 6.9 256 122 17 2.2 1200 1.0
25/11 4.4 256 99 70 2.3 950 4.0 30
4/12 2.3 256 108 5.5 1.7 470 1.0 36
In
this table we present some laboratory parametrs indicating the
activation of haemostasis after the Novo Seven administration,
like fI, A2-APL, TAT, F1+2,, PAP, Di-D-
It is obvious that the increased dose of rFVIIa (2,4 ìg/kgr) on
25/11 activated transiently the coagulation and the fibrinolysis
.