0036-9330190IOO3OI1001$2.00 in USA e 1990 SeoUilIb Medical Joumal
Scot Med J 1990;35: 108-113
A SCOTTISH HEBRIDEAN ANTITHROMBIN III DEFICIENT FAMILY - TWELVE YEARS ON
A.S. Douglas, *I.D. Walker, N.B. Bennett Department of Medicine and Therapeutics, University of Aberdeen and "Department of Haematology, Royal Infirmary, Glasgow
Abstract: The members of this family with A TIll deficiency have been followed for at least 12 years (1976-1989). All those with previous venous thrombo-embolism have been free from recurrence when on warfarin. During the halfcentury 1931-1981, all 11 full term pregnancies in four affected patients were associated with venous thromboembolism; one patient was enigmatic having one full term pregnancy, without thrombotic event; between 1982 and 1989 three pregnancies have been actively managed with no clinical thrombosis. Management involved use of monitored, self administered, subcutaneous heparin before or very soon after conception and throughout pregnancy (warfarin having been stopped), planned delivery under cover of intravenous antithrombin Ill, reduction of heparin dosage at delivery and reintroduction of warfarin in the puerperium. The recognised hazards ofheparin therapy in pregnancy did not occur. The involvement of the arterial system is reviewed. Clinical evidence provides tentative suggestions on (a) possible additional risk of cigarette smoking (b) avoidance of venography (c) avoidance of varicose vein surgery. A probe is now available for the defective antithrombin III gene in this famiy, but there has been no occasion yet to apply this in antenatal diagnosis. Key words: Familial antithrombin III deficiency, pregnancy, warfarin, management. Introduction
HIS family was first reported by us in 1978. 1 •2 It was the first affected antithrombin III (A Till) deficient family recorded in the United' Kingdom, is the largest reported kindred and the experience of the affected members has been gathered over 12 years. The history of the family provides a useful guide to the clinician required to manage this condition. This is a single family "case report' with the appropriate limitations on conclusions.
T
Patients and methods
The kindred is shown in Fig. 1. Patients II 7, II 9 and III 3, have died since 1976; there are two new affected members - IV 17 and IV 18. This family is a type 1 ATIII deficiency ie with approximately 50% of normal levels of functional and immunological antithrombin III - and of heparin co-factor activity. Probable efficacy of warfarin in prevention of new events of venous thromboembolism. When first studied in 1976n7, seven living affected
members (aged 22-73years) had suffered previous episodes of venous thrombembolism (II 7, II 13, III 2, 1113, III 5, III 6 and III 9). III 3 was not anticoagulated because of a gastric ulcer and he died in 1986. The other six patients were treated with warfarin. II 7 died in 1983.,The other five patients are alive and well 12 years after diagnosis. To compare the thrombotic history of these patients while receiving no therapy with what occurred whilst on warfarin we studied the events occurrring in the 12 years before diagnosis in patients II 13, III 2,5,6 and 9 with those during the 12 years after diagnosis while they received warfarin. For patient II 7, the events in the six years prior to diagnosis were compared with those in the six years thereafter while she received warfarin up to the time of death. In the 66 patient-years thus examined while the patients were receiving no warfarin therapy there were eight venous thrombotic events while in the 66 years during which warfarin was administered there were none. A further 14 years warfarin experience without occurrence or recurrence has accumulated in three younger Correspondence and reprint requests: A.S. Douglas, Department of Medicine and Therapeutics, Polwarth Building, Foresterhill, Aberdeen AB92ZD.
108
patients. IV 10 and IV 11 now aged 20 and 23 have been asymptomatic since started prophylactically at the age of 18 years. IV 6 has been on warfarin since 1981 when she was started on warfarin followingpulmonary embolism. In affected males prior to diagnosis and warfarin treatment the first thrombotic event occurred mainly in the third decade (between the ages of 18 and 38). In four (II 10, 1114, III 5 and III 6) the first thrombosis occurred with no recognisable precipitating factor. In one, II 3, a precipitating event was identifiable; diabetic ketoacidosis with coma. All those anticoagulated have been free of thrombosis on warfarin therapy. In affected females prior to diagnosis, the first thrombosis was commonly associated with pregnancy. In two subjects, II 7 and III 2, (but not II 13) recurrent thromboembolism occurred after completion of childbearing. In no female did venous thromboembolism occur or recur while on warfarin therapy. All ten affected patients who developed venous thrombosis suffered pulmonary embolism at that time or later. During warfarin anticoagulation no patient has suffered pulmonary embolism. The risks of stopping warfarin are clear. Patient III 9 stopped warfarin because she was pregnant and had recurrence (see below). Patient III 6 (the propositus) had been free of thrombotic disease for 12 years; in 1989 warfarin was stopped for three weeks in order to have an
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Fig. 1. Family tree 1940-1990.
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A Scottish Hebridean antithrombin m deficient family
Douglas, Walker, Bennett
ENT operation and further venous thromboembolism developed. Pregnancy Betwe~n 1931 and 1981 pregnancy was inevitably associated with venous thromboembolism in affected women with the ~xception of p~tient II 9. This enigmatic patient requires to be descnbed separately - see below. In this half .centur~ there were 11 full term pregnancies all associated With venous thromboembolism (II 7, II 13, III 2 an~ II! 9). These females presented with thrombosis during their first pregnancy and all in their third decade. Patient II 7 had six completed pregnancies and had three miscarriages between 1931 and 1947. One delivery was forceps assisted, all labours were prolonged and all prod~ced lar~e babies ~eighing over 10 pounds; two developed diabetes 10 adult hfe. All deliveries took place in a croft house in Bernara, a remotely located area of Lewis. This woman had multiple episodes of venous thrombosis and presumptive pulmonary embolism ("pneumonia, pleurisy and haemoptysis") which continued after child bearing ceased. By 1977 she had chronically swollen legs, varicose veins, stasis dermatitis and recurrent ulceration. The details of the pregnancies and associated thrombotic episodes of other five affected women are summarised in Table 1. After 1981 pregnancies have been managed with monitored self administered subcutaneous heparin before conception or, in previously asymptomatic patients, from soon after conception with planned delivery under intravenous antithrombin III cover with reduced heparin and introduction or reintroduction of warfarin in the puerperium. Patient III 9 who had sustained deep venous thrombosis (DVT) in her first pregnancy at 36 weeks gestation, became Table I Patient 117
Pregnancy resulting in birth of III 1 III 2 III3 III 4
119
IllS III 6 3 miscarriages III 7
1Il3
III 16 III 17
III 2
IVS IV6
III 9
IV 17 Termination
IV18 IV 19 III 17
IV 24
Thrombotic events in pregnancy See text
See text - enigmatic no thrombosis miscarriage Right leg one week into puerperium - pulmonary embolism Right leg - recurrence at 9 weeks gestation Left leg 20 weeks gestation miscarriage Right leg 24 weeks gestation Right leg 36 weeks miscarriage Left leg 8 weeks pulmonary embolism (three pregnancies (managed without (occurrence (or recurrence (of venous events
Table 1: This table is a summary or the pregnancies in the affected females from 1931·1987.
pregnant again in 1981 and at seven weeks started subcutaneous heparin in standard dosage of 5000 units bd. Within a few days she developed further DVT with pulmonary embolism. The heparin dosage had been proved inadequate. Thereafter the policy outlined above of managing pregnancy with self administered monitored subcutaneous heparin with delivery covered by ATIll infusion was adopted. This requires the achievement of an activated partial thromboplastin time APTT of approximately 2.5 times normal at the peak level following heparin injection with a ratio of approximately 1.5 times normal prior to the next heparin injection throughout pregnancy. The normal is the laboratory pool plasma not a time related pregnancy plasma. In normal pregnancy the APTf shortens. Careful monitoring is necessary as heparin requirement increases throughout pregnancy. The heparin requirement falls rapidly at delivery and regular monitoring over the period of labour, delivery and early days of the puerperium during which ATIII infusions are administered, is required. APTf is checked to ensure that it is not unduly prolonged, heparin is reduced to 5000 units bd and epidural anaesthesia is avoided. Warfarin is reintroduced in the puerperium. On this regimen the patient III 9 who had DVT on two previous pregnancies had two further pregnancies successfully carried to term without DVT in 1982 and 1987. This patient is on long term warfarin and on both of the above occasions discontinued this, started on subcutaneous heparin and conceived within one or two cycles on each occa~ion. As her pregnancies advanced her heparin requirement rose from 8,000 IV to 10,000 IV three times daily to achieve the target APTT levels. Daily ATIll infusions have been initiated 2-4 days prior to planned induction of labour and continued for some days into the puerperium, heparin dosage reduced to 5000 units twice daily during this time under close laboratory control but continued post partum until full warfarinisation was established 5-6 days after delivery. One of the two infants delivered by this patient had a reduced cord blood ATIll level of 25% (normal range 35-70% of adult levels) while the other had values in the normal range. Patient III 17 who had had no DVT and was not on warfarin therapy reported for management of a pregnancy within six days of her first missed period and was managed as above. She delivered a child with a normal cord blood ATIll level at term after an uneventful pregnancy. At ten weeks gestation her heparin requirement rose from 21,000 to 2,700 units per day. All these three deliveries were normal and there was no undue haemorrhage. In addition to the three pregnancies described here in this Hebridean family, we have experience of a further three pregnancies in two patients in two other Type 1 antithrombin III deficient families. These were managed successfully along similar lines and bring our total experience to six. Not including patient II 9 (see below) the affected females in this family prior to 1981 had 11 full term pregnancies and five abortions. These abortions occurred in women with a history of thromboembolism in previous pregnancy; the leg vein thrombosis may well have involved the venous pelvic system. Of patient II 7's nine pregnancies the last three were miscarriages. In the wives of affected men there were seven full term pregnancies and one abortion - the normal rate. This suggests that the abortion rate in affected women was high as a consequence of the clinical expression of their disease.
109
A Scottish Hebrldean antithrombin m deficiency
The enigma of patient II 9 This lady who had ATIll defiency died at the age of 75. She had no thrombotic event despite two pregnancies, one carried to term and one resulting in miscarriage, and a lobectomy for pulmonary tuberculosis. She is thus unique in avoiding the thrombotic problems of low ATIll levels despite at least three major challenges. Possible reasons for this have been proposed in previous publications.P" She had for instance low levels of von Willebrand factor and fibrinogen and elevated oc:2 macroglobulin. Whether these protected her-from the thrombotic risks of a low A TIll level remains conjectural. Interestingly she had an abnormal lipid profile, raised serum cholesterol and xanthelasmata and her unaffected son (III 7) died at the age of 39 suddenly and unexpectedly death being attributed to cardiac disease. Causes of death in affected members Five of the family have died. II 10 and III 4 (prior to 1977) II 7, II 9 and III 3 since then. II 7. Despite frequent venous thrombo-embolic events prior to 1977 she died from a "stroke" in 1983 at the age of 79, while still on warfarin. II 10. This patient died suddenly from pulmonary embolism a few weeks after surgery on varicose veins a sequel to long standing venous insufficiency from thrombotic disease. Clearly caution in recommending vein surgery in these patients is required. II 9. This was the enigmatic lady with the defect who never developed venous thrombo-embolic disease despite the challenge of pregnancy and surgery. She died from lung infection and cardiac failure with atrial fibrillation without clinical thrombosis. III 3. This patient was diagnosed in 1977 but had never received warfarin because of a gastric ulcer which had bled. He was hypertensive and diabetic and in 1984 he suffered a stroke aged 48. He died in 1986 at the age of 51 years. In 1986 he underwent extensive surgery for a squamous cell cancer of the mouth and after a stormy post-operative course was well when five weeks post operatively he died suddenly in hospital. The death was ascribed to pulmonary embolism, but it could have been cardiac. He had a large dose of antithrombin III less than 24 hours before death. This is the first cancer in an affected member of the family. This member of the family smoked more than 25 cigarettes per day and had a cigarette related cancer as well as clinical manifestation of atheroma. III 4. This patient not only had extensive venous disease but also very aggressive arterial disease dying at the age of 32 in 1970, before the family was identified as being ATIll deficient. The patient and the pathology have been described in detail previously" and essential features only are summarised here. This patient also smoked over 25 cigarettes per day. He started with venous thrombotic lower limb disease at the age of 18 years. When 29 he had a right brachial artery occlusion. In the year of his death he had congestive cardiac failure and aortic systolic and diastolic murmers. The final fatal illness started with mesenteric vascular occlusion. At autopsy he had a non sclerosed incompetent mitral valve and sclerosed stenosed aortic valve. There was extensive atheroma in the aorta and vessels arising from it including the coronary arteries. The 110
Douglas, Walker, Bennett
aorta was totally occluded by thrombus from the coeliac axis to the femoral vessels and partially occluded up to the diaphragm. Coeliac, mesenteric and renal arteries were occluded and marked atheroma was present in the pulmonary arteries. In the veins the inferior vena cava was occluded by thrombus at the right renal vein level. Hepatic, splenic, portal and mesenteric veins were occluded by thrombus. There were old arterial infarctions in liver, kidney and spleen and the myocardium and recent infarction in the spleen. Use of antithrombin III This was used in pregnancy to cover planned termination in III 9, for the management of delivery in two pregnancies in III 9 and one in III 17. It was also used in III 3 to cover surgical management of cancer of the mouth. Antithrombin III is available commercially and through the transfusion services. The antithrombin III is given once daily to raise the level to 120% (half an hour after completion of infusion to allow extravascular equilibration) and a nadir of 80% immediately preceding the next infusion. The anticipation is for 0.74 unit/kg of infused ATIII to raise the level by 1%. 6 It may be possible to lower the daily doses as days go past, presumably because of equilibration with the extravascular compartment but it is not uncommon to find that the daily dose has to be sustained at its starting level. These issues are described in more detail elsewhere."·8,9
Avoidance of venography While lung scans have been used to diagnose pulmonary embolism it has been found possible to do without venography. The venographic contrast material is known to be irritant in normal individuals but ATIll deficient patients might well be expected to be at additional risk. Such an experience in another ATill deficient family has been reported to us.!" Duplex ultrasound, impedance plethysmography with 1125 fibrinogen, or indium labelled platelets are safer ways of diagnosing venous thrombosis in ATIll deficiency. Genetic counselling Genetic research has advanced knowledge and is described in the discsussion.!': 12, 13 A probe is available for this family and in conjunction with chorionic villous sampling could be applied in antenatal diagnosis. The family members have been told of this, but it has never yet been applied. With growing confidence in the management, particularly of pregnancy, such an approach may not be requested by affected women; the biopsy carries some hazard. This family has Type I ATIll deficiency the commonest genetic disorder of antithrombin with similarly reduced levels in the immunological assay, functional assay in the absence of heparin and in the heparin cofactor assay. Type 2 differs in that the immunological assay is normal but the structure of ATIII is altered so that it is functionally disturbed.l" In patients suspected of ATIll deficiency an immunological screening assay is insufficient and a functional test is required. Discussion Anticoagulant therapy - a controlled clinical trial of long-term warfarin therapy in ATIll deficiency is unlikely ever to be conducted and it is appropriate to continue to report routine clinical experience. No patient who has had a previous thromboembolic event has had any recurrence while on warfarin. The experience of warfarin in this family total over 80 patient years; apart from one patient whose
Douglas, Walker, Bennett
warfarin control failed due to alcohol, all others have been free from haemorrhagic side effects, The nature of their underlying coagulation defect may protect them from bleeding. The literature/: 15, 16, 17, 18, 19, 20, 21, 22, 23 is confused on the issue of ATIll levels in deficient patients given warfarin. Some have found significant increases but others have not; further work and clarification is needed. Studies need to be made on plasma not serum; coumarin serum contains more A TIll than normal serum because it is consumed during physiological coagulation.24 In our family with Type I ATIll deficiency no rise in ATIll levels has occurred during warfarin therapy. These observations and those of other workers suggest that warfarin therapy does not give any rise or only a very minor increase in plasma A TIll levels in patients with classical type I ATIII deficiency.f 25, 26, 2", 28 Therefore, it is possible to make the diagnosis of classical Type I A TIll deficiency in subjects receiving warfarin therapy. Haemorrhagic cutaneous necrosis has a major association with protein C deficiency. An example of this has now been reported in a patient with antithrombin III deficiency.29 For this reason institution of warfarin therapy needs careful supervision ensuring that the dosage is not too high. Two asymptomatic young adults (IV 10, IV 11) in the family have been on warfarin since the age of 18 years. Institution of therapy at this age is a difficult and controversial decision; while II 9 was asymptomatic for 75 years all other deficient individuals have had thrombotic problems starting usually in the third decade. Patient III 17 has only been anticoagulated during pregnancy. Management of pregnancy There is little doubt that the measures adopted after 1981 have proved successful. As mentioned in addition to the patients described here we have experience of similar successful management of three pregnancies in two affected members of two other ATIll deficient families. Detailed discussion with the patient is needed prior to the start of the pregnancy. Warfarin has to be stopped prior to conception because of the risk (possibly one in 100) to the fetus of development of warfarin embryopathy if the mother is taking warfarin during the first three months of gestation.P" Warfarin embryopathy is characterised by nasal hypoplasia with the nose sunken into the face. Further bony and other abnormalities have been reported. 30 These possibly arise because of interference with the vitamin K dependent protein osteocalcin in bone by warfarin. There is- a possibility that phenindione does not have these teratogenic risks associated with warfarin.U Unfortunately experience in the use of phenindione is much less than that of warfarin; clinicians will be reluctant to accept this drug as a viable alternative without further evidence, which is unlikely to be forthcoming. The implications, discomforts and risks of self-administered subcutaneous heparin must be explained. The most common maternal complication is bruising at the injection site. This can be kept to a minimum by good injection technique but not eliminated. Patients should be warned to report backache as this may alert to the development of heparin-induced osteopenia causing vertebral collapse. While only single case reports concerning osteopenia exist 32,33,34,35,36 these provide convincing evidence of an important risk from heparin in pregnancy. In one of these case reports only 10,000 units of heparin were given daily. This suggests an idiosyncratic response. In addition, taken
A Scottish Hebridean antithrombin m deficient CamBy
with other clinical evidence of heparin-induced osteopenia in non-pregnant patients, it is probable that most women develop a degree of demineralisation proportional to the total dose of heparin (throughout pregnancy).37,38 It is not known whether any healing occurs in the bone on stopping heparin and this requires further study. Patients can be left with crippling deformity. 36 Recurrence would be anticipated if heparin was given in a further pregnancy to those patients with clinically evident osteopenia. In one patienr'" there was a convincing lowering of 1,25 dihydroxyvitamin D3 (calcitriol) in association with the devel~ment of the clinical problem. In a subsequent study calcitriol (1,25(OH)2D3) levels were compared in normal pregnant women and in pregnant patients receiving heparin. Those receiving heparin had lower levels. There exists an untested case for the mother receiving calcitriol in association with heparin in pregnancy. This therapeutic possibility is strengthened by the evidence that, amongst the genes regulated (at the level of m RNA accumulation) by the dihydroxyderivative of vitamin D3 (1,25(OH)2 D3), is that for the bone matrix vitamin K dependent protein,39,40 osteocalcin. Provided serum calcium levels were monitored this could provide prophylactic therapy, but is untested. The successful methods used in pregnancy followed half a century of thrombotic problems during pregnancy in this family and it is reasonable to assume that the freedom from problems arises from the therapeutic regimen. It is highly improbable that a controlled study will be conducted. In the early 19808 experience was accumulating on the management of pregnancy. An important contribution was by Hellgren, Tengborn and Abilgaard in 1982.41 They advocated heparin throughout pregnancy with the covering of delivery with A TIll infusions. They suggested that low dosage heparin regimens did not protect against new thrombotic events; this was also our experience with patient III 9. Success with management regimes similar to ours is reported by others.l" A further approach, because of the osteopenic hazard of prolonged heparin, was the reported success of twice weekly intravenous infusions of ATIll from the 22nd week. 42 While understanding the anxiety related to heparin this regimen would not have our support until applied throughout pregnancy; venous thromboembolism occurred often in our family much earlier than 22 weeks gestation. An overview of the evidence indicates that success with heparin therapy in this situation is dependent on the larger dose of heparin. Others (Hellgren et al1982 and Samson et al 1984) indicate that an APTT prolongation of 5-10 sec preceding the next heparin injection is sufficient. In the three pregnancies described an APTT prolongation to around 1.5 times control values at that time was used with an initial prolongation not exceeding a ratio of 2.5. More recently other patients have been managed by us with 12 hourly injections and accepting slightly lower trough APTT ratios of around 1.2-1.3. Arterial disease While III 4 died before the family was first studied it is highly probable that he had the defect. There are now two other A TIll deficient patients reported with acute aortic thrombosis.l? Both these patients (30-year-old male and 36-year-old female) were smokers as was III 4; aortography showed aortic occlusion below the level of the renal arteries. No atheroma was identified in these reports but this was based on aortography and not autopsy as in III 4. One patient'" presented with arterial occlusion of the right 111
A Scottish HebrideaD antithrombin m deficiency
leg and curiously, like III 4, had aortic stenosis and an incompetent mitral valve. These authors suggest that areas of retarded blood flow in the heart in ATIll deficient patients are particulaw liable to thrombus formation and embolisation. Others reported two young men (28/39 years) with arterial occlusions of the lower limb, in a typical ATIII deficient family. On aortography, like III 4, they had occlusions of visceral arteries - hepatic, renal and splenic. Causes of death
Two deaths occurred before we became involved with the family - III 4 from aortic thrombosis and II 10 from pulmonary embolism a few weeks after varicose vein surgery. If alive in 1977 both of these patients would have been treated with warfarin. III 4 would have been discouraged from smoking and varicose vein surgery would have been discouraged in II 10. II 7 died aged 79 from a stroke. The enigmatic III 9 died from a non-thrombotic problem - pulmonary infection and cardiac failure with atrial fibrillation. III 3 died a sudden vascular death in a convalescent phase after surgery from a cancer of the mouth. In a previous report/ we commented on the absence of cancer in ATIll deficiency. III 3 and III 4 were the heaviest smokers, both had arterial disease, and this may have had a particular aggravating effect in the presence of the ATIll deficiency; this is of course speculative. Genetics
Gene probe for ATIll is now available for this family but has never been applied to chorionic villous sampling. In this family a defective ATill zene has been located on the long arm of Chromosome 1. 11 ;12,13 The antithrombin III locus in this family is linked to the Duffy Blood Group and to 1qh. The regional location for the ATIll locus is within 1q22-1q25.12 ,13 Genetic heterogeneity is a feature in ATIII deficient families; some have found deletion of the gene. In this family structural and segregation analysis has shown a mutant ATIII gene.!' From our own experiencevP and that of others gene mutation may not be uncommon. ATIll deficiency is a common cause of familial venous thrombosis, but remains relatively uncommon in absolute terms. Controlled trials of management are not likely to prove possible. Experience with this large family suggests that oral anticoagulation with warfarin when no contraindication exists is highly effective in prevention of thrombosis in affected individuals and that aggressive but carefully monitored regimes can avoid the major risks of pregnancy in deficient mothers. REFERENCES 1 Mackie M, Bennett B, Ogston D, Douglas AS. Familial thrombosis due to antithrombin III deficiency. Br Med J 1978; 1: 136-138. 2 Winter J, Fenech A, Ridley W, Bennett B, Cumming AM, Mackie M, Douglas AS. Familial antithrombin III deficiency. QJ Med 1982; 204: 373-395. 3 Winter JH, Bennett B, McTaggart F, Douglas AS. Lipoprotein fraction and antithrombin III consumption during clotting. Thromb Haemost 1982; 47: 236-238. 4 Winter JH, Bennett B. Factors influencing thrombosis in familial antithrombin III deficiency. Br J Haematol1983; 53: 527-534. 5 Winter JH, Donald D, Bennett B, Douglas AS. Arterial thrombosis and accelerated atheroma in a member of a family with familial antithrombin III deficiency. Postgrad Med J 1982; 58: 108-Hl9. 6 Mannucci PM, Boyer CM, Waif M, Tripodi A, Larrien MJ. Treatment of congenital antithrombin III deficiency with concentrates. Br J Haematol1982; 50: 531-535. 7 Winter JH, Fenech A, Bennett B, Douglas AS. Transfusion studies in patients with familial antithrombin III (ATIIl) deficiency, half disappearance time of infused ATill and influence of such infusion on platelet life span. Br J Haematol1981; 49: 449-453.
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8 Winter JH, Fenech A, Mackie M, Bennett B, Douglas AS. Treatment of venous thrombosis in antithrombin III deficient patients with concentrates of antithrombin Ill. Clin Lab Haematol1982; 4: 101-108. 9 Hambley H, Davidson JF, Walker ID, Menzies T. Prophylactic use of antithrombin III concentrate following surgery in congenital antithrombin III deficiency. Clin Lab Haematol1987; 9: 27-31. 10 Winter JH, Fenech A, Bennett B, Douglas AS. Thrombosis after venography in familial antithrombin III deficiency. Br Med J 1981; 283: 1436-1437. 11 Sacks SH, Old JM, Reeders ST, et al. Evidence linking familial thrombosis with a defective antithrombin III gene in two British kindreds. J Med Genet 1988; 25: 20-24. 12 Winter JH, Watt JL, Bennett NB, et al. The antithrombin III locus is linked to the Duffy Blood Group and to Igh assignment of ATI to lq22-1q25. Scott Med J 1982; 27: 60-61. 13 Winter JH, Bennett B, Watt JL, et al. Confirmation of linkage between antithrombin III and Duffy blood group and assignment of ATI to lq22-1q25. 1982; Ann Hum Genet; 46: 29-34. 14 Barrowcliffe TW, Thomas DP. Antithrombin III and heparin in: Bloom AL and Thomas DP. Haemostasis and Thrombosis 2nd Edition. Churchill-Livingstone, Edinburgh, London, Melbourne and New York 1987; 849-869. 15 Winter JH, Douglas AS. Familial venous thrombosis. Postgrad Med J 1983; 59: 677-689. 16 Samson D, Stirling Y, Woolf L, Howarth D. Seghatchian MJ, de Chazaer. Management of planned pregnancy in a patient with congenital antithrombin III deficiency. Br J Haematol 1984; 56: 243-249. 17 Shapiro ME, Rodvien R, Bauer KA, Salzman EW. Acute aortic thrombosis in antithrombin III deficiency. JAMA 1981; 245: 17591761. 18 Refvemy 0, Fagerhol MK, Abildgaard U. Changes in antithrombin III levels following cessation of anticoagulant therapy. Acta Med Scand 1973; 193: 307-309. 19 Wessler S, Gitel SN, Bank H, Martinowitz U, Stephenson RC. An assay of the antithrombotic action of Warfarin: its correlation with the inhibition of stasis thrombosis in rabbits. Thromb Haemost 1978; 40: 486-498. 20 Bull H, Mackie I, Brozovic H, Woodings D. Antithrombin III in patients on long-term anticoagulants. J Clin Pathol 1980; 33: 1202-1205. 21 Frost T, Loveday D. Oral anticoagulants and antithrombin Ill. Med J Aust 1980; 2: 220. 22 Marciniak E, Farley CH, De Simol PA. Familial thrombosis due to antithrombin III deficiency. Blood 1974; 43: 219-31. '23 Zucker ML, Gomperts ED, Marcus RG. Prophylactic and therapeutic use of anticoagulants in inherited antithrombin III deficiency. S Afr Med J 1976; 50: 1743-1751. 24 Stefano D, Leone G, De Martini D, Donfrancisco A Di, Accora F, Bizzi BM. Effect of oral anticoagulant treatment on plasma and serum antithrombin Ill: a study of 172 patients at different levels of anticoagulation. Haemostasis 1987; 17: 195-200. 25 Leone G, Valori VM, Storti S, Myers TJ. Inferior vena cava thrombosis in a child with familial antithrombin III deficiency. Thromb Haemost 1980; 43: 74. 26 Laharrague P, Bierme R, Cerene A, Boucays A, Massip P. Antithrombin Ill: substitutive treatment of the hereditary deficiency. Thromb Haemost 1980; 43: 72. 27 Longy M, Delmas M, Leman C, de Bras M, Moretti G, Hourdille P. Thrombose de la veine cava inferieure avec deficit congenital en antithrombine III. Nouv Pr Med 1980; 9: 1957-1960. 28 Trippodi A, Boyer C, Canciani MT, D'Angelo A, Mannucci DM. Inherited deficiency of antithrombin III in an Italian kindred. Ric Clin Lab 1980; 10: 521-524. 29 Kiehl R, Hellstern P, Wenzel R. Hereditary antithrombin III (ATIII) deficiency and atypical localisation of a coumarin necrosis. Thromb Res 1987; 45: 191-193. 30 Hall JG, Pauli RM, Wilson KM. Maternal and fetal sequelae of anticoagulation during pregnancy. Am J Med 1980; 68: 122-140. 31 Oakley C. Pregnancy in patients with prosthetic heart valves. Br Med J 1983; 286: 1680-1681. 32 Wise PH, Hall AJ. Heparin induced osteopenia in pregnancy. Br Med J 1980; 28: 110-111. 33 Aarskog C, Aksnes L, Lehmann V. Low 1,25 hydroxy vitamin D in heparin induced osteopenia. Lancet 1980; 2: 650-651. 34 Aarskog D, Aksnes L, Markestad T, Ulstein M, Sagen N. Heparin induced inhibition of 1,25 - dihydroxyvitamin D formation. Am J Obstet GynecaI1984; 148: 1141-1142. 35 Griffiths HT, Liu DTY. Severe heparin osteoporosis in pregnancy. Postgrad Med J 1984; 60: 424-425. 36 LiuDTY.1989-Personalcommunication.
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37 de Swiet M. 1989- Personal communication. 38 de Swiet M, in 'Medical Disorders in Obstetric Practice' Second Edition. Ed: M de Swiet. Blackwell Scientific Publications 1989; 183-197. 39 Fraser JD, Otawara Y, Price PA.l ,25 hydroxyvitamin D3 stimulates the synthesis of matrix gamma-carboxyglutamic acid protein by osteosarcoma cells. J BioI Chern 1988;262: 4165-4171. 40 Reichel H, Koeffler P, Norman AW. Role of the vitamin D endocrine system in health and disease. N End J Med 1989; 320: 980-991. 41 Hellgren M, Tengborn L, Abildgaard U. Pregnancy in women with
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congenital antithrombin III deficiency: experience of treatment with heparin and antithrombin. Gynecol Obstet Invest 1982; 14: 127-141. 42 Tengborn L, Bengtsson T. Antithrombin III concentrate. Thromboprophylaxis during pregnancy in a patient with congenital ATIll deficiency. Acta Obstet Gynecal Scand 1986; 65: 375-376. 43 Coller BS, Owen J, Jesty J, et al. Deficiency of plasma protein S, protein C or antithrombin III and arterial thrombosis. Arteriosclerosis 1987; 7: 456-462. 44 Candrina R, Goppini A, Salvi A, Zuccato F, Guistina G. Arterial thrombosis in antithrombin III deficiency. Clin Lab HaematoI1986; 8: 267-268.
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Scot Med J 1990;35: 108-113
A SCOTTISH HEBRIDEAN ANTITHROMBIN III DEFICIENT FAMILY - TWELVE YEARS ON
A.S. Douglas, *I.D. Walker, N.B. Bennett Department of Medicine and Therapeutics, University of Aberdeen and "Department of Haematology, Royal Infirmary, Glasgow
Abstract: The members of this family with A TIll deficiency have been followed for at least 12 years (1976-1989). All those with previous venous thrombo-embolism have been free from recurrence when on warfarin. During the halfcentury 1931-1981, all 11 full term pregnancies in four affected patients were associated with venous thromboembolism; one patient was enigmatic having one full term pregnancy, without thrombotic event; between 1982 and 1989 three pregnancies have been actively managed with no clinical thrombosis. Management involved use of monitored, self administered, subcutaneous heparin before or very soon after conception and throughout pregnancy (warfarin having been stopped), planned delivery under cover of intravenous antithrombin Ill, reduction of heparin dosage at delivery and reintroduction of warfarin in the puerperium. The recognised hazards ofheparin therapy in pregnancy did not occur. The involvement of the arterial system is reviewed. Clinical evidence provides tentative suggestions on (a) possible additional risk of cigarette smoking (b) avoidance of venography (c) avoidance of varicose vein surgery. A probe is now available for the defective antithrombin III gene in this famiy, but there has been no occasion yet to apply this in antenatal diagnosis. Key words: Familial antithrombin III deficiency, pregnancy, warfarin, management. Introduction
HIS family was first reported by us in 1978. 1 •2 It was the first affected antithrombin III (A Till) deficient family recorded in the United' Kingdom, is the largest reported kindred and the experience of the affected members has been gathered over 12 years. The history of the family provides a useful guide to the clinician required to manage this condition. This is a single family "case report' with the appropriate limitations on conclusions.
T
Patients and methods
The kindred is shown in Fig. 1. Patients II 7, II 9 and III 3, have died since 1976; there are two new affected members - IV 17 and IV 18. This family is a type 1 ATIII deficiency ie with approximately 50% of normal levels of functional and immunological antithrombin III - and of heparin co-factor activity. Probable efficacy of warfarin in prevention of new events of venous thromboembolism. When first studied in 1976n7, seven living affected
members (aged 22-73years) had suffered previous episodes of venous thrombembolism (II 7, II 13, III 2, 1113, III 5, III 6 and III 9). III 3 was not anticoagulated because of a gastric ulcer and he died in 1986. The other six patients were treated with warfarin. II 7 died in 1983.,The other five patients are alive and well 12 years after diagnosis. To compare the thrombotic history of these patients while receiving no therapy with what occurred whilst on warfarin we studied the events occurrring in the 12 years before diagnosis in patients II 13, III 2,5,6 and 9 with those during the 12 years after diagnosis while they received warfarin. For patient II 7, the events in the six years prior to diagnosis were compared with those in the six years thereafter while she received warfarin up to the time of death. In the 66 patient-years thus examined while the patients were receiving no warfarin therapy there were eight venous thrombotic events while in the 66 years during which warfarin was administered there were none. A further 14 years warfarin experience without occurrence or recurrence has accumulated in three younger Correspondence and reprint requests: A.S. Douglas, Department of Medicine and Therapeutics, Polwarth Building, Foresterhill, Aberdeen AB92ZD.
108
patients. IV 10 and IV 11 now aged 20 and 23 have been asymptomatic since started prophylactically at the age of 18 years. IV 6 has been on warfarin since 1981 when she was started on warfarin followingpulmonary embolism. In affected males prior to diagnosis and warfarin treatment the first thrombotic event occurred mainly in the third decade (between the ages of 18 and 38). In four (II 10, 1114, III 5 and III 6) the first thrombosis occurred with no recognisable precipitating factor. In one, II 3, a precipitating event was identifiable; diabetic ketoacidosis with coma. All those anticoagulated have been free of thrombosis on warfarin therapy. In affected females prior to diagnosis, the first thrombosis was commonly associated with pregnancy. In two subjects, II 7 and III 2, (but not II 13) recurrent thromboembolism occurred after completion of childbearing. In no female did venous thromboembolism occur or recur while on warfarin therapy. All ten affected patients who developed venous thrombosis suffered pulmonary embolism at that time or later. During warfarin anticoagulation no patient has suffered pulmonary embolism. The risks of stopping warfarin are clear. Patient III 9 stopped warfarin because she was pregnant and had recurrence (see below). Patient III 6 (the propositus) had been free of thrombotic disease for 12 years; in 1989 warfarin was stopped for three weeks in order to have an
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Fig. 1. Family tree 1940-1990.
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A Scottish Hebridean antithrombin m deficient family
Douglas, Walker, Bennett
ENT operation and further venous thromboembolism developed. Pregnancy Betwe~n 1931 and 1981 pregnancy was inevitably associated with venous thromboembolism in affected women with the ~xception of p~tient II 9. This enigmatic patient requires to be descnbed separately - see below. In this half .centur~ there were 11 full term pregnancies all associated With venous thromboembolism (II 7, II 13, III 2 an~ II! 9). These females presented with thrombosis during their first pregnancy and all in their third decade. Patient II 7 had six completed pregnancies and had three miscarriages between 1931 and 1947. One delivery was forceps assisted, all labours were prolonged and all prod~ced lar~e babies ~eighing over 10 pounds; two developed diabetes 10 adult hfe. All deliveries took place in a croft house in Bernara, a remotely located area of Lewis. This woman had multiple episodes of venous thrombosis and presumptive pulmonary embolism ("pneumonia, pleurisy and haemoptysis") which continued after child bearing ceased. By 1977 she had chronically swollen legs, varicose veins, stasis dermatitis and recurrent ulceration. The details of the pregnancies and associated thrombotic episodes of other five affected women are summarised in Table 1. After 1981 pregnancies have been managed with monitored self administered subcutaneous heparin before conception or, in previously asymptomatic patients, from soon after conception with planned delivery under intravenous antithrombin III cover with reduced heparin and introduction or reintroduction of warfarin in the puerperium. Patient III 9 who had sustained deep venous thrombosis (DVT) in her first pregnancy at 36 weeks gestation, became Table I Patient 117
Pregnancy resulting in birth of III 1 III 2 III3 III 4
119
IllS III 6 3 miscarriages III 7
1Il3
III 16 III 17
III 2
IVS IV6
III 9
IV 17 Termination
IV18 IV 19 III 17
IV 24
Thrombotic events in pregnancy See text
See text - enigmatic no thrombosis miscarriage Right leg one week into puerperium - pulmonary embolism Right leg - recurrence at 9 weeks gestation Left leg 20 weeks gestation miscarriage Right leg 24 weeks gestation Right leg 36 weeks miscarriage Left leg 8 weeks pulmonary embolism (three pregnancies (managed without (occurrence (or recurrence (of venous events
Table 1: This table is a summary or the pregnancies in the affected females from 1931·1987.
pregnant again in 1981 and at seven weeks started subcutaneous heparin in standard dosage of 5000 units bd. Within a few days she developed further DVT with pulmonary embolism. The heparin dosage had been proved inadequate. Thereafter the policy outlined above of managing pregnancy with self administered monitored subcutaneous heparin with delivery covered by ATIll infusion was adopted. This requires the achievement of an activated partial thromboplastin time APTT of approximately 2.5 times normal at the peak level following heparin injection with a ratio of approximately 1.5 times normal prior to the next heparin injection throughout pregnancy. The normal is the laboratory pool plasma not a time related pregnancy plasma. In normal pregnancy the APTf shortens. Careful monitoring is necessary as heparin requirement increases throughout pregnancy. The heparin requirement falls rapidly at delivery and regular monitoring over the period of labour, delivery and early days of the puerperium during which ATIII infusions are administered, is required. APTf is checked to ensure that it is not unduly prolonged, heparin is reduced to 5000 units bd and epidural anaesthesia is avoided. Warfarin is reintroduced in the puerperium. On this regimen the patient III 9 who had DVT on two previous pregnancies had two further pregnancies successfully carried to term without DVT in 1982 and 1987. This patient is on long term warfarin and on both of the above occasions discontinued this, started on subcutaneous heparin and conceived within one or two cycles on each occa~ion. As her pregnancies advanced her heparin requirement rose from 8,000 IV to 10,000 IV three times daily to achieve the target APTT levels. Daily ATIll infusions have been initiated 2-4 days prior to planned induction of labour and continued for some days into the puerperium, heparin dosage reduced to 5000 units twice daily during this time under close laboratory control but continued post partum until full warfarinisation was established 5-6 days after delivery. One of the two infants delivered by this patient had a reduced cord blood ATIll level of 25% (normal range 35-70% of adult levels) while the other had values in the normal range. Patient III 17 who had had no DVT and was not on warfarin therapy reported for management of a pregnancy within six days of her first missed period and was managed as above. She delivered a child with a normal cord blood ATIll level at term after an uneventful pregnancy. At ten weeks gestation her heparin requirement rose from 21,000 to 2,700 units per day. All these three deliveries were normal and there was no undue haemorrhage. In addition to the three pregnancies described here in this Hebridean family, we have experience of a further three pregnancies in two patients in two other Type 1 antithrombin III deficient families. These were managed successfully along similar lines and bring our total experience to six. Not including patient II 9 (see below) the affected females in this family prior to 1981 had 11 full term pregnancies and five abortions. These abortions occurred in women with a history of thromboembolism in previous pregnancy; the leg vein thrombosis may well have involved the venous pelvic system. Of patient II 7's nine pregnancies the last three were miscarriages. In the wives of affected men there were seven full term pregnancies and one abortion - the normal rate. This suggests that the abortion rate in affected women was high as a consequence of the clinical expression of their disease.
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A Scottish Hebrldean antithrombin m deficiency
The enigma of patient II 9 This lady who had ATIll defiency died at the age of 75. She had no thrombotic event despite two pregnancies, one carried to term and one resulting in miscarriage, and a lobectomy for pulmonary tuberculosis. She is thus unique in avoiding the thrombotic problems of low ATIll levels despite at least three major challenges. Possible reasons for this have been proposed in previous publications.P" She had for instance low levels of von Willebrand factor and fibrinogen and elevated oc:2 macroglobulin. Whether these protected her-from the thrombotic risks of a low A TIll level remains conjectural. Interestingly she had an abnormal lipid profile, raised serum cholesterol and xanthelasmata and her unaffected son (III 7) died at the age of 39 suddenly and unexpectedly death being attributed to cardiac disease. Causes of death in affected members Five of the family have died. II 10 and III 4 (prior to 1977) II 7, II 9 and III 3 since then. II 7. Despite frequent venous thrombo-embolic events prior to 1977 she died from a "stroke" in 1983 at the age of 79, while still on warfarin. II 10. This patient died suddenly from pulmonary embolism a few weeks after surgery on varicose veins a sequel to long standing venous insufficiency from thrombotic disease. Clearly caution in recommending vein surgery in these patients is required. II 9. This was the enigmatic lady with the defect who never developed venous thrombo-embolic disease despite the challenge of pregnancy and surgery. She died from lung infection and cardiac failure with atrial fibrillation without clinical thrombosis. III 3. This patient was diagnosed in 1977 but had never received warfarin because of a gastric ulcer which had bled. He was hypertensive and diabetic and in 1984 he suffered a stroke aged 48. He died in 1986 at the age of 51 years. In 1986 he underwent extensive surgery for a squamous cell cancer of the mouth and after a stormy post-operative course was well when five weeks post operatively he died suddenly in hospital. The death was ascribed to pulmonary embolism, but it could have been cardiac. He had a large dose of antithrombin III less than 24 hours before death. This is the first cancer in an affected member of the family. This member of the family smoked more than 25 cigarettes per day and had a cigarette related cancer as well as clinical manifestation of atheroma. III 4. This patient not only had extensive venous disease but also very aggressive arterial disease dying at the age of 32 in 1970, before the family was identified as being ATIll deficient. The patient and the pathology have been described in detail previously" and essential features only are summarised here. This patient also smoked over 25 cigarettes per day. He started with venous thrombotic lower limb disease at the age of 18 years. When 29 he had a right brachial artery occlusion. In the year of his death he had congestive cardiac failure and aortic systolic and diastolic murmers. The final fatal illness started with mesenteric vascular occlusion. At autopsy he had a non sclerosed incompetent mitral valve and sclerosed stenosed aortic valve. There was extensive atheroma in the aorta and vessels arising from it including the coronary arteries. The 110
Douglas, Walker, Bennett
aorta was totally occluded by thrombus from the coeliac axis to the femoral vessels and partially occluded up to the diaphragm. Coeliac, mesenteric and renal arteries were occluded and marked atheroma was present in the pulmonary arteries. In the veins the inferior vena cava was occluded by thrombus at the right renal vein level. Hepatic, splenic, portal and mesenteric veins were occluded by thrombus. There were old arterial infarctions in liver, kidney and spleen and the myocardium and recent infarction in the spleen. Use of antithrombin III This was used in pregnancy to cover planned termination in III 9, for the management of delivery in two pregnancies in III 9 and one in III 17. It was also used in III 3 to cover surgical management of cancer of the mouth. Antithrombin III is available commercially and through the transfusion services. The antithrombin III is given once daily to raise the level to 120% (half an hour after completion of infusion to allow extravascular equilibration) and a nadir of 80% immediately preceding the next infusion. The anticipation is for 0.74 unit/kg of infused ATIII to raise the level by 1%. 6 It may be possible to lower the daily doses as days go past, presumably because of equilibration with the extravascular compartment but it is not uncommon to find that the daily dose has to be sustained at its starting level. These issues are described in more detail elsewhere."·8,9
Avoidance of venography While lung scans have been used to diagnose pulmonary embolism it has been found possible to do without venography. The venographic contrast material is known to be irritant in normal individuals but ATIll deficient patients might well be expected to be at additional risk. Such an experience in another ATill deficient family has been reported to us.!" Duplex ultrasound, impedance plethysmography with 1125 fibrinogen, or indium labelled platelets are safer ways of diagnosing venous thrombosis in ATIll deficiency. Genetic counselling Genetic research has advanced knowledge and is described in the discsussion.!': 12, 13 A probe is available for this family and in conjunction with chorionic villous sampling could be applied in antenatal diagnosis. The family members have been told of this, but it has never yet been applied. With growing confidence in the management, particularly of pregnancy, such an approach may not be requested by affected women; the biopsy carries some hazard. This family has Type I ATIll deficiency the commonest genetic disorder of antithrombin with similarly reduced levels in the immunological assay, functional assay in the absence of heparin and in the heparin cofactor assay. Type 2 differs in that the immunological assay is normal but the structure of ATIII is altered so that it is functionally disturbed.l" In patients suspected of ATIll deficiency an immunological screening assay is insufficient and a functional test is required. Discussion Anticoagulant therapy - a controlled clinical trial of long-term warfarin therapy in ATIll deficiency is unlikely ever to be conducted and it is appropriate to continue to report routine clinical experience. No patient who has had a previous thromboembolic event has had any recurrence while on warfarin. The experience of warfarin in this family total over 80 patient years; apart from one patient whose
Douglas, Walker, Bennett
warfarin control failed due to alcohol, all others have been free from haemorrhagic side effects, The nature of their underlying coagulation defect may protect them from bleeding. The literature/: 15, 16, 17, 18, 19, 20, 21, 22, 23 is confused on the issue of ATIll levels in deficient patients given warfarin. Some have found significant increases but others have not; further work and clarification is needed. Studies need to be made on plasma not serum; coumarin serum contains more A TIll than normal serum because it is consumed during physiological coagulation.24 In our family with Type I ATIll deficiency no rise in ATIll levels has occurred during warfarin therapy. These observations and those of other workers suggest that warfarin therapy does not give any rise or only a very minor increase in plasma A TIll levels in patients with classical type I ATIII deficiency.f 25, 26, 2", 28 Therefore, it is possible to make the diagnosis of classical Type I A TIll deficiency in subjects receiving warfarin therapy. Haemorrhagic cutaneous necrosis has a major association with protein C deficiency. An example of this has now been reported in a patient with antithrombin III deficiency.29 For this reason institution of warfarin therapy needs careful supervision ensuring that the dosage is not too high. Two asymptomatic young adults (IV 10, IV 11) in the family have been on warfarin since the age of 18 years. Institution of therapy at this age is a difficult and controversial decision; while II 9 was asymptomatic for 75 years all other deficient individuals have had thrombotic problems starting usually in the third decade. Patient III 17 has only been anticoagulated during pregnancy. Management of pregnancy There is little doubt that the measures adopted after 1981 have proved successful. As mentioned in addition to the patients described here we have experience of similar successful management of three pregnancies in two affected members of two other ATIll deficient families. Detailed discussion with the patient is needed prior to the start of the pregnancy. Warfarin has to be stopped prior to conception because of the risk (possibly one in 100) to the fetus of development of warfarin embryopathy if the mother is taking warfarin during the first three months of gestation.P" Warfarin embryopathy is characterised by nasal hypoplasia with the nose sunken into the face. Further bony and other abnormalities have been reported. 30 These possibly arise because of interference with the vitamin K dependent protein osteocalcin in bone by warfarin. There is- a possibility that phenindione does not have these teratogenic risks associated with warfarin.U Unfortunately experience in the use of phenindione is much less than that of warfarin; clinicians will be reluctant to accept this drug as a viable alternative without further evidence, which is unlikely to be forthcoming. The implications, discomforts and risks of self-administered subcutaneous heparin must be explained. The most common maternal complication is bruising at the injection site. This can be kept to a minimum by good injection technique but not eliminated. Patients should be warned to report backache as this may alert to the development of heparin-induced osteopenia causing vertebral collapse. While only single case reports concerning osteopenia exist 32,33,34,35,36 these provide convincing evidence of an important risk from heparin in pregnancy. In one of these case reports only 10,000 units of heparin were given daily. This suggests an idiosyncratic response. In addition, taken
A Scottish Hebridean antithrombin m deficient CamBy
with other clinical evidence of heparin-induced osteopenia in non-pregnant patients, it is probable that most women develop a degree of demineralisation proportional to the total dose of heparin (throughout pregnancy).37,38 It is not known whether any healing occurs in the bone on stopping heparin and this requires further study. Patients can be left with crippling deformity. 36 Recurrence would be anticipated if heparin was given in a further pregnancy to those patients with clinically evident osteopenia. In one patienr'" there was a convincing lowering of 1,25 dihydroxyvitamin D3 (calcitriol) in association with the devel~ment of the clinical problem. In a subsequent study calcitriol (1,25(OH)2D3) levels were compared in normal pregnant women and in pregnant patients receiving heparin. Those receiving heparin had lower levels. There exists an untested case for the mother receiving calcitriol in association with heparin in pregnancy. This therapeutic possibility is strengthened by the evidence that, amongst the genes regulated (at the level of m RNA accumulation) by the dihydroxyderivative of vitamin D3 (1,25(OH)2 D3), is that for the bone matrix vitamin K dependent protein,39,40 osteocalcin. Provided serum calcium levels were monitored this could provide prophylactic therapy, but is untested. The successful methods used in pregnancy followed half a century of thrombotic problems during pregnancy in this family and it is reasonable to assume that the freedom from problems arises from the therapeutic regimen. It is highly improbable that a controlled study will be conducted. In the early 19808 experience was accumulating on the management of pregnancy. An important contribution was by Hellgren, Tengborn and Abilgaard in 1982.41 They advocated heparin throughout pregnancy with the covering of delivery with A TIll infusions. They suggested that low dosage heparin regimens did not protect against new thrombotic events; this was also our experience with patient III 9. Success with management regimes similar to ours is reported by others.l" A further approach, because of the osteopenic hazard of prolonged heparin, was the reported success of twice weekly intravenous infusions of ATIll from the 22nd week. 42 While understanding the anxiety related to heparin this regimen would not have our support until applied throughout pregnancy; venous thromboembolism occurred often in our family much earlier than 22 weeks gestation. An overview of the evidence indicates that success with heparin therapy in this situation is dependent on the larger dose of heparin. Others (Hellgren et al1982 and Samson et al 1984) indicate that an APTT prolongation of 5-10 sec preceding the next heparin injection is sufficient. In the three pregnancies described an APTT prolongation to around 1.5 times control values at that time was used with an initial prolongation not exceeding a ratio of 2.5. More recently other patients have been managed by us with 12 hourly injections and accepting slightly lower trough APTT ratios of around 1.2-1.3. Arterial disease While III 4 died before the family was first studied it is highly probable that he had the defect. There are now two other A TIll deficient patients reported with acute aortic thrombosis.l? Both these patients (30-year-old male and 36-year-old female) were smokers as was III 4; aortography showed aortic occlusion below the level of the renal arteries. No atheroma was identified in these reports but this was based on aortography and not autopsy as in III 4. One patient'" presented with arterial occlusion of the right 111
A Scottish HebrideaD antithrombin m deficiency
leg and curiously, like III 4, had aortic stenosis and an incompetent mitral valve. These authors suggest that areas of retarded blood flow in the heart in ATIll deficient patients are particulaw liable to thrombus formation and embolisation. Others reported two young men (28/39 years) with arterial occlusions of the lower limb, in a typical ATIII deficient family. On aortography, like III 4, they had occlusions of visceral arteries - hepatic, renal and splenic. Causes of death
Two deaths occurred before we became involved with the family - III 4 from aortic thrombosis and II 10 from pulmonary embolism a few weeks after varicose vein surgery. If alive in 1977 both of these patients would have been treated with warfarin. III 4 would have been discouraged from smoking and varicose vein surgery would have been discouraged in II 10. II 7 died aged 79 from a stroke. The enigmatic III 9 died from a non-thrombotic problem - pulmonary infection and cardiac failure with atrial fibrillation. III 3 died a sudden vascular death in a convalescent phase after surgery from a cancer of the mouth. In a previous report/ we commented on the absence of cancer in ATIll deficiency. III 3 and III 4 were the heaviest smokers, both had arterial disease, and this may have had a particular aggravating effect in the presence of the ATIll deficiency; this is of course speculative. Genetics
Gene probe for ATIll is now available for this family but has never been applied to chorionic villous sampling. In this family a defective ATill zene has been located on the long arm of Chromosome 1. 11 ;12,13 The antithrombin III locus in this family is linked to the Duffy Blood Group and to 1qh. The regional location for the ATIll locus is within 1q22-1q25.12 ,13 Genetic heterogeneity is a feature in ATIII deficient families; some have found deletion of the gene. In this family structural and segregation analysis has shown a mutant ATIII gene.!' From our own experiencevP and that of others gene mutation may not be uncommon. ATIll deficiency is a common cause of familial venous thrombosis, but remains relatively uncommon in absolute terms. Controlled trials of management are not likely to prove possible. Experience with this large family suggests that oral anticoagulation with warfarin when no contraindication exists is highly effective in prevention of thrombosis in affected individuals and that aggressive but carefully monitored regimes can avoid the major risks of pregnancy in deficient mothers. REFERENCES 1 Mackie M, Bennett B, Ogston D, Douglas AS. Familial thrombosis due to antithrombin III deficiency. Br Med J 1978; 1: 136-138. 2 Winter J, Fenech A, Ridley W, Bennett B, Cumming AM, Mackie M, Douglas AS. Familial antithrombin III deficiency. QJ Med 1982; 204: 373-395. 3 Winter JH, Bennett B, McTaggart F, Douglas AS. Lipoprotein fraction and antithrombin III consumption during clotting. Thromb Haemost 1982; 47: 236-238. 4 Winter JH, Bennett B. Factors influencing thrombosis in familial antithrombin III deficiency. Br J Haematol1983; 53: 527-534. 5 Winter JH, Donald D, Bennett B, Douglas AS. Arterial thrombosis and accelerated atheroma in a member of a family with familial antithrombin III deficiency. Postgrad Med J 1982; 58: 108-Hl9. 6 Mannucci PM, Boyer CM, Waif M, Tripodi A, Larrien MJ. Treatment of congenital antithrombin III deficiency with concentrates. Br J Haematol1982; 50: 531-535. 7 Winter JH, Fenech A, Bennett B, Douglas AS. Transfusion studies in patients with familial antithrombin III (ATIIl) deficiency, half disappearance time of infused ATill and influence of such infusion on platelet life span. Br J Haematol1981; 49: 449-453.
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8 Winter JH, Fenech A, Mackie M, Bennett B, Douglas AS. Treatment of venous thrombosis in antithrombin III deficient patients with concentrates of antithrombin Ill. Clin Lab Haematol1982; 4: 101-108. 9 Hambley H, Davidson JF, Walker ID, Menzies T. Prophylactic use of antithrombin III concentrate following surgery in congenital antithrombin III deficiency. Clin Lab Haematol1987; 9: 27-31. 10 Winter JH, Fenech A, Bennett B, Douglas AS. Thrombosis after venography in familial antithrombin III deficiency. Br Med J 1981; 283: 1436-1437. 11 Sacks SH, Old JM, Reeders ST, et al. Evidence linking familial thrombosis with a defective antithrombin III gene in two British kindreds. J Med Genet 1988; 25: 20-24. 12 Winter JH, Watt JL, Bennett NB, et al. The antithrombin III locus is linked to the Duffy Blood Group and to Igh assignment of ATI to lq22-1q25. Scott Med J 1982; 27: 60-61. 13 Winter JH, Bennett B, Watt JL, et al. Confirmation of linkage between antithrombin III and Duffy blood group and assignment of ATI to lq22-1q25. 1982; Ann Hum Genet; 46: 29-34. 14 Barrowcliffe TW, Thomas DP. Antithrombin III and heparin in: Bloom AL and Thomas DP. Haemostasis and Thrombosis 2nd Edition. Churchill-Livingstone, Edinburgh, London, Melbourne and New York 1987; 849-869. 15 Winter JH, Douglas AS. Familial venous thrombosis. Postgrad Med J 1983; 59: 677-689. 16 Samson D, Stirling Y, Woolf L, Howarth D. Seghatchian MJ, de Chazaer. Management of planned pregnancy in a patient with congenital antithrombin III deficiency. Br J Haematol 1984; 56: 243-249. 17 Shapiro ME, Rodvien R, Bauer KA, Salzman EW. Acute aortic thrombosis in antithrombin III deficiency. JAMA 1981; 245: 17591761. 18 Refvemy 0, Fagerhol MK, Abildgaard U. Changes in antithrombin III levels following cessation of anticoagulant therapy. Acta Med Scand 1973; 193: 307-309. 19 Wessler S, Gitel SN, Bank H, Martinowitz U, Stephenson RC. An assay of the antithrombotic action of Warfarin: its correlation with the inhibition of stasis thrombosis in rabbits. Thromb Haemost 1978; 40: 486-498. 20 Bull H, Mackie I, Brozovic H, Woodings D. Antithrombin III in patients on long-term anticoagulants. J Clin Pathol 1980; 33: 1202-1205. 21 Frost T, Loveday D. Oral anticoagulants and antithrombin Ill. Med J Aust 1980; 2: 220. 22 Marciniak E, Farley CH, De Simol PA. Familial thrombosis due to antithrombin III deficiency. Blood 1974; 43: 219-31. '23 Zucker ML, Gomperts ED, Marcus RG. Prophylactic and therapeutic use of anticoagulants in inherited antithrombin III deficiency. S Afr Med J 1976; 50: 1743-1751. 24 Stefano D, Leone G, De Martini D, Donfrancisco A Di, Accora F, Bizzi BM. Effect of oral anticoagulant treatment on plasma and serum antithrombin Ill: a study of 172 patients at different levels of anticoagulation. Haemostasis 1987; 17: 195-200. 25 Leone G, Valori VM, Storti S, Myers TJ. Inferior vena cava thrombosis in a child with familial antithrombin III deficiency. Thromb Haemost 1980; 43: 74. 26 Laharrague P, Bierme R, Cerene A, Boucays A, Massip P. Antithrombin Ill: substitutive treatment of the hereditary deficiency. Thromb Haemost 1980; 43: 72. 27 Longy M, Delmas M, Leman C, de Bras M, Moretti G, Hourdille P. Thrombose de la veine cava inferieure avec deficit congenital en antithrombine III. Nouv Pr Med 1980; 9: 1957-1960. 28 Trippodi A, Boyer C, Canciani MT, D'Angelo A, Mannucci DM. Inherited deficiency of antithrombin III in an Italian kindred. Ric Clin Lab 1980; 10: 521-524. 29 Kiehl R, Hellstern P, Wenzel R. Hereditary antithrombin III (ATIII) deficiency and atypical localisation of a coumarin necrosis. Thromb Res 1987; 45: 191-193. 30 Hall JG, Pauli RM, Wilson KM. Maternal and fetal sequelae of anticoagulation during pregnancy. Am J Med 1980; 68: 122-140. 31 Oakley C. Pregnancy in patients with prosthetic heart valves. Br Med J 1983; 286: 1680-1681. 32 Wise PH, Hall AJ. Heparin induced osteopenia in pregnancy. Br Med J 1980; 28: 110-111. 33 Aarskog C, Aksnes L, Lehmann V. Low 1,25 hydroxy vitamin D in heparin induced osteopenia. Lancet 1980; 2: 650-651. 34 Aarskog D, Aksnes L, Markestad T, Ulstein M, Sagen N. Heparin induced inhibition of 1,25 - dihydroxyvitamin D formation. Am J Obstet GynecaI1984; 148: 1141-1142. 35 Griffiths HT, Liu DTY. Severe heparin osteoporosis in pregnancy. Postgrad Med J 1984; 60: 424-425. 36 LiuDTY.1989-Personalcommunication.
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37 de Swiet M. 1989- Personal communication. 38 de Swiet M, in 'Medical Disorders in Obstetric Practice' Second Edition. Ed: M de Swiet. Blackwell Scientific Publications 1989; 183-197. 39 Fraser JD, Otawara Y, Price PA.l ,25 hydroxyvitamin D3 stimulates the synthesis of matrix gamma-carboxyglutamic acid protein by osteosarcoma cells. J BioI Chern 1988;262: 4165-4171. 40 Reichel H, Koeffler P, Norman AW. Role of the vitamin D endocrine system in health and disease. N End J Med 1989; 320: 980-991. 41 Hellgren M, Tengborn L, Abildgaard U. Pregnancy in women with
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congenital antithrombin III deficiency: experience of treatment with heparin and antithrombin. Gynecol Obstet Invest 1982; 14: 127-141. 42 Tengborn L, Bengtsson T. Antithrombin III concentrate. Thromboprophylaxis during pregnancy in a patient with congenital ATIll deficiency. Acta Obstet Gynecal Scand 1986; 65: 375-376. 43 Coller BS, Owen J, Jesty J, et al. Deficiency of plasma protein S, protein C or antithrombin III and arterial thrombosis. Arteriosclerosis 1987; 7: 456-462. 44 Candrina R, Goppini A, Salvi A, Zuccato F, Guistina G. Arterial thrombosis in antithrombin III deficiency. Clin Lab HaematoI1986; 8: 267-268.
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