446 C m Rvparts

Our two patients responded to ATK with a temporary iniprovenient in erytliropoiesis. The reasons for the response art’ itticlear snd deserve further study. None of our patients presented r-KAR gene rearrangement (Degos et a!. 1990). ‘I’he transirnce of the response obviously represented the major limitatioii of the ATK treatment in our two patients. I lowever. this aspect also requires further investigation. In fact. the transience might be due to the onset ofresistance (as occurs in the treatment of APL). although a more likely explanation for the phenomenon could be the existence and subsequent exhaustion of a pool of ATR-responding cells. Should the latter hypothesis be true, recruitment of more immature precursors by means of growth factors could restore sensitivity. Indirect evidence of this possibility has been provided by Li & Sartorelli (1991) who have demon- strated in vitro increased activity of ATR when combined with

In conclusion, ATR deserves further evaluation in a larger population of MDS patients in order to assess the percentage of responders and to elucidate the mechanisms and real potential of its therapeutic action.

G-CSF.

British Journal of Haematology, 1992, 81

REFERENCES

Castaigne. S.. Chomienne. C.. Daniel, M.T., Ballerini. P.. Berger. R.. Fenaux, P. & Degos. L. (1990) AU-trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia. I. Clini- cal results. Blood, 76, 1704-1 709.

Chomienne. C.. Ballerini. P.. Balitrand. N.. Daniel. M.T.. Fenaux. P.. Castaigne, S. & Degos. L. (1990) All-trans retinoic acid in acute promyelocytic leukemias. 11. In vitro studies: structure-function relationship. Blood. 76, 1710-1 71 7.

Clark.R.E., Jacobs.A.,Lush,C.J.&Smith.S.A.(1987)EfTectof 13-cis- retinoic acid on the survival of patients with myelodysplastic syndrome. Lancet. i, 763-765.

Degos. L.. Shroot. B.. de The, H.. Chomienne, C.. Wang, Z.Y. & Castaigne, S. (1 990) Retinoic acid in haematopoietic differentia- tion. Nouvelle Revue Franqaise d’Hematologie. 32, 2 5-38.

Gold.E.J., Mertelsmann. R.H., 1tri.L.M.. Gee, T., Arlin. Z., Kempin. S.. Clarkson. B. & Moore. M.A.S. (198 3) Phase I clinical trial of I 3-cis retinoic acid in myelodysplastic syndromes. Cancer Treatment Reports, 67, 981-986.

Li, J. & Sartorelli. A.C. (1 991) Synergistic induction of the differentia- tion of WEHI-3B D+ myelomonocytic leukemia cells by retinoic acid and granulocyte colony stimulating factor. (Abstract). Pro- ceedings oj the American Association /or Cancer Research. 32 , 34.

ACKNOWLEDGMENT

Supported in part by MURST 40%-60%.

Institute oJ’ Huemutology GIUSEPPE VISANI ‘L. G A. Seragnoli’, ANNARITA CENACCHI University Hospital S. Orsola. PATRIZIA TOSI Bologna, Italy CARLO FINELLI

MIRIAM FOCLI BARBARA GAMBERI GIOVANNI MARTINELLI SANTE TURA

DEEP VENOUS THROMBOSIS AND PULMONARY EMBOLISM IN A PATIENT WITH TYPE 111 VON WILLEBRAND’S DISEASE, PROTEIN C AND ANTITHROMBIN 111 DEFICIENCY

The association between thrombosis and Von Willebrand’s disease (vWD) is only rarely reported. Atherosclerosis remains a risk factor for coronary thrombosis in both mild and severe vWD (Dulhoste et al, 1989: Goodnough et al, 1983). Deep venous thrombosis has been observed only in patients with mild vWD. and then in association with other risk factors for thrombosis (Petaja et al. 1989). We report a patient with severe (type 1111 vWD who suffered a deep venous thrombosis and pulmonary embolism.

A 53-year-old retired nurse had been diagnosed with a bleeding diathesis shortly after birth. In 1960 a diagnosis of severe vWD was made with von Willebrand factor antigen by IRMA and ELISA <0.001 u/dl. factor VIIIc <1%, and bleeding time >15 min. She had frequent spontaneous haemarthroses particularly affecting the right ankle. She smoked 10 cigarettes per day. No family history was available as she was adopted, and had in turn adopted a child.

In October 199 1 her General Practitioner arranged admis- sion to the local hospital after 12 h of severe left-sided pleuritic chest pain. This was not associated with breathless- ness, or haemoptysis. There was no history of swelling or pain in either calf. However, she had received one dose of factor VIII therapy (‘Haemate P’ 2500 units) 10 d prior to admission for a haemarthrosis in the right ankle, for which she had also been immobile at home, and had experienced pain and swelling, suggestive of a haemarthrosis of the left ankle, through the 3 d prior to admission, but had not received specific therapy for this. Previous to these recent episodes she had been quite well, with a normal appetite and no weight loss.

On examination, she was apyrexial. and haemodynami- cally stable. Chest examination revealed normal air entry and no pleural rub. There was no clinical evidence of deep venous thrombosis in either calf. On admission, a full blood count

British lourrial qf Haemutology, 1992, 81 Cuse Reports 447

l'a ble I

Assay ( x ) 7/ 1/92 15/1/92 Reference

24/10/91 7/11/91 Pre-vitamin K Post-vitamin K range

A'r Ill 51 74 75 (Chromogenic: 'Dade'. Haxter. Ihdingen)

Protein C 60 54 57 (Chromogenic; 'Coamate'. KabiVitrum. Stockholm)

Protein S (Elisa: Dakopatts. Glostrup)

Total 69 86 73 Free 45 28 3 1

72 xo- 120

55 73-121

74 60- 1 3 0 3 3 27-63

showed the haemoglobin concentration to be 13.9 g/dl, white cell count 8.9 x lO"/l (neutrophils 49%). and platelets 260 x 1 Oy/l . Chest X-ray and electrocardiogram were both normal. A clinical diagnosis of pulmonary embolism was made. A ventilation-perfusion scan showed an unmatched perfusion defect at the base of the left lung, highly suggestive of pulmonary embolism. Transfer to the Haemophilia Kegional Unit was then arranged, where, in order to further substantiate the diagnosis of pulmonary embolism, bilateral venograms of both lower limbs were done. Thrombosis was confirmed in the right calf veins. The left calf and both popliteal and pelvic veins were patent. Heparinization with 10000 units unfractionated heparin per 24 h was com- menced by intravenous infusion. The Kaolin Cephalin Clot- ting Time ratio was not prolonged by this low dose of heparin (2.3 pre-treatment, and 2 .2 post). As the symptoms resolved rapidly, this was stopped after 48 h. and the patient remains off anticoagulants with no adverse effects or recurrence 4 months later.

Bilateral mammograms. abdominal ultrasound, and abdo- minal and pelvic CT scans were negative, thus excluding an obvious underlying malignancy. Liver function tests showed a raised AST at 5 5 KJ/l (long-standing). Hepatitis B and C antibodies were detected but HIV antibody testing was negative. One-stage prothrombin time was 15.8 s with control 14.8 s, and thrombin clotting time 1 3 . 5 s with control 1 3.0 s. Factor VII assay was 9 3%. Kesults of plasma antithrombin Ill. protein C and S assays are shown in Table I. Extensive investigation of the fibrinolytic pathway 2 months after the thrombosis revealed no specific abnormality, except for prolongation of the euglobin clot lysis time (ELT) at 396 min (reference range 120-240 min) with normal concentra- tions of fibrinogen, plasminogen, alpha 2 anti-plasmin, plasminogen activator inhibitor, and t-PA. Baseline throm- botest was 38% which rose to 55% 1 week after vitamin K ( 1 0 mg x 1 dose). 'This may support abnormal liver function as the cause for protein C and antithrombin 111 deficiency, although factor VII assay was normal (9 3%). and no increase in plasma protein C or AT I I I concentrations was observed

following vitamin K administration. We cannot comment on the likelihood of hereditary protein C deticiency in the absence of known family members. Protein C, S and AT 111 levels in two other patients with Type 111 vWD have been normal.

We do not have a clear explanation for deep venous thrombosis in this patient with severe vWD. The low protein C. borderline AT 111 and prolonged ELT are all potentially contributory. but in the only described case of a n abnormal AT 111 in association with severe vWD. the vWD appeared protective against thrombosis compared with family members with only the AT 111 abnormality (Girolami et a / . 1986). Despite the lack of a specific clinical risk factor(s) for thrombosis. our patient represents the first case to our knowledge of proven deep venous thrombosis with pulmo- nary embolism in a subject with severe homozygous vWD.

Department of Huematology. DAVID BOWEN University of Wales College ofMedicine. HASH DASANI

Princess of Wales Hospital, ARTHUR BLOOM Bridgend. Wales

Heath Park, Card$ and BERNARD YUNC

REFERENCES

Ihlhoste. M.N.. Bonnet. J.. Vergnes. C.. Choussat. A. & Bricaud. H. ( 1989) Von Willebrand's disease and coronary atherosclerosis. Apropos of 3 cases. Archives des Muludies du Coeur et des Vuisseunux.

Girolami. A.. Cappellato. M.G.. Vicarioto, M.A.. Casonato. S. & Marafioti. F. (1986) Associated von Willebrand disease as a possible cause of lack of thrombosis in an AT 111 abnormality (AT Ill Trento). Blut . 52, 29-33.

Goodnough. L.T.. Saito. H. & RatnoK O.D. (1983) Thrombosis or myocardial infarction in congenital clotting factor abnormalities and chronic thrombocytopenias: a report of 2 I patients and a review of 50 previously reported cases. Medicine. 6 2 , 248-255.

Petaja, 1.. Rasi. V.. Myllyla. G.. Vahtera. E. & Hallman. H. (1989) Familial hypofibrinolysis and venous thrombosis. British lournul of Huematology. 71, 393-398.

8 2 , 1 8 7 5 - 1 8 8 8 .