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 (90μg/ml), while F1+2 remained less than 4 μg/ml. The patient was successfully treated with this alternative method without any clinical or laboratory complications.

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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 μl 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 å- 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 % μg/l μg/l μg/l μg/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, F_1+2,, PAP, Di-D_- It is obvious that the increased dose of rFVIIa (2,4 μg/kgr) on 25/11 activated transiently the coagulation and the fibrinolysis .