1105
concentration had stabilised at 37°C, the temperature was reduced to 24°C, this change being achieved in less than 90 s. When the effect of cooling had stabilised, the temperature was returned to 37°C, and on stabilisation the next concentration was administered. Contractile responses at 37°C are presented as the mean increase in tension above basal before cooling and after rewarming to 37°C.2 The contractile response at 24°C represents the nadir of the response during cooling. Maximum contractile values were 1095 (183) mg at 37°C and 513 (120) mg at 24°C. At every ET concentration, contractions were inhibited by acute cooling and restored upon rewarming (figure). As reported for other vessels, ET was a potent agonist in the human resistance arteries. The effect of cooling was a profound inhibition of the contractions. This does not reflect an overall inhibition of contractile processes by cooling because contractions evoked by noradrenaline and potassium chloride are not similarly affected. Our data do not support a causal role for ET in the cold-induced vasospasm of Raynaud’s syndrome.
Divison of Vascular
Surgery,
Oregon Health Sciences University, Portland, Oregon 97201, USA
CHRISTIAN T. HARKER JAMES M. EDWARDS LLOYD M. TAYLOR, JR JOHN M. PORTER
1. Aalkjaer C, Pederson EB, Heagerty AM, et al. Relaxation of isolated resistance vessels from humans with vascular disease. Acta Med Scand 1986; 714 (suppl): 59-64. 2. Harker CT, Ousley PJ, Harris EJ, Edwards JM, Taylor LM, Porter JM. The effects of cooling on human saphenous vein reactivity to adrenergic agonists. J Vasc Surgery
FVIII, vWF, AND BLEEDING TIME BEFORE AND AFTER LIVER TRANSPLANTATION*
*Factor assays expressed as % of reference plasma (calibrated against the International Standard for FVIII-related activities), with normal values of 50-150%.
desmopressin did not trigger any further increases. This natural experiment indicates that the liver produces only a small proportion of the plasma pool ofvWF, too small to correct the defect of primary haemostasis in severe von Willebrand disease. By contrast, in congenital deficiencies of haemostasis proteins synthesised by the hepatocytes (such as factor VIII and protein C), transplantation increases plasma levels to a clinically relevant degree. A Bianchi Bonomi Haemophilia and Thrombosis Centre, and Liver Transplantation Unit, IRCCS Maggiore Hospital, University of Milan,
Milan, Italy
1990; 12: 45-49.
PIER MANNUCCIO MANNUCCI AUGUSTO FEDERICI MARCO CATTANEO RANIERO FASSATI DINANGELO GALMARINI
1. Bowie EJW,
Solberg LA, Fass DN, et al. Transplantation of normal bone marrow into pig with severe von Willebrand’s disease. J Clin Invest 1986; 78: 26-30. 2. Stel HV, van der Kwast Th H, Veerman ECI Detection of factor VIII/coagulant antigen in human liver tissue. Nature 1983; 309: 530-32. 3. Zelechowska MG, von Mourik JA, Brodniewicz-Proba T. Ultrastructural localization of factor VIII procoagulant antigen in human liver hepatocytes. Nature 1985; 317: a
Liver transplantation in severe von Willebrand disease SIR,-von Willebrand factor (vWF), congenital deficiency
or
dysfunction of which results in the bleeding disorder von Willebrand disease, is synthesised by vascular endothelial cells.1 The liver contains many endothelial cells but it is not certain if specialised cells, such as those lining the hepatic sinusoids, also contain vWF.2-4 A 44-year-old man with a history of frequent soft-tissue and mucosal bleeding since childhood had had several treatments with whole blood, cryoprecipitate, and factor VIII (FVIII) concentrates. His FVIII level was only 10%, with less than 6% ristocetin cofactor activity of vWF, and only 0-04% vWF antigen. His bleeding time was over 30 min, and he had antibodies to hepatitis B surface and core antigens and hepatitis C virus, and a persistently raised alanine aminotransferase. He was HIV seronegative. Hepatic synthetic function had progressively deteriorated over the previous 10 years and he had episodes of variceal bleeding since 1985 and several episodes of hepatic encephalopathy. In 1990, a liver mass was diagnosed as hepatocellular carcinoma. Liver transplantation was done on Nov 29,1990, for which he was given 12 000 units of FVIII concentrate containing large amounts of vWF (’Hemate P’, Behring), 12 units of red blood cell concentrate, and 4 litres of fresh-frozen plasma. Postoperatively the patient was treated with the same concentrate until day 26 (total dose 10 000 units). The liver is functioning well, 5 months after the operation, and since discharge the patient has had no bleeding episodes or replacement therapy. The table shows the results of FVIII and vWF measurements, and bleeding time before the operation, and on day 45 and 5 months afterwards. FVIII levels increased 2-fold and vWF antigen increased more than 20-fold, but was still very low. The bleeding time remained abnormal. On day 45 the patient gave informed consent to an infusion with desmopressin, but FVIII and vWF measurements did not change (table). Thus, when postoperative replacement therapy had been stopped for at least 3 weeks vWF levels, albeit remaining very low, were more than 20 times higher than before transplantation. The precision and sensitivity of our immunoradiometric assay are such that an increase from 0-04% to 1 02% cannot be due to experimental error, so there was probably heightened production of vWF by the endothelial cells of the new liver. The post-transplantation increase in FVIII can perhaps be explained by the fact that there was more vWF in plasma to carry and stabilise FVIII. No factor VIII nor vWF was stored, because
729-30. 4. Wion KL, Kelly D, Summerfield JA, Tuddenham EGD, Lawn RM. Distribution of factor VIII mRNA and antigen in liver and other tissues. Nature 1985; 317: 726-29.
Response of central
nervous
system
vasculitis to irradiation SIR,-Isolated vasculitis of the central nervous system (IVCNS) is a rare entity confined to CNS vessels with few signs of systemic involvement.1 If untreated, IVCNS is fatal. However, immunosuppressive therapy may lead to sustained remission. We report a child who failed to respond to this therapy, and who entered temporary remission on two occasions after cranial irradiation. A 11-year-old boy was admitted with signs of intracranial hypertension of one month’s duration. Cranial computed tomography showed a low-density area in the left fronto-basal region. A biopsy was completed which showed thrombosis and necrosis of some vessel walls in the leptomeninges, and in cortical tissue and white matter. Arteriography showed lesions consistent with the diagnosis of vasculitis, with multiple irregularities of the left anterior choroid artery walls. An infectious cause and systemic vasculitis were excluded. IVCNS was diagnosed, and treatment with cyclophosphamide and prednisolone was started, but neurological deterioration progressed with extension of the lesion to the basal ganglia and brainstem. Irradiation of the affected area was selected because of the patient’s critical condition. He received 2 Gy per day up to a total of 46 Gy, in the frontoparietal region. From that time onwards, his symptoms remitted gradually and subsequent radiographic studies were normal. Despite this success, the patient presented seven months later with cerebellar involvement that
responded again to radiotherapy. Immunosuppressive drugs were continued in the interval between radiotherapy sessions. The patient deteriorated further, with left parietal involvement fifteen months later. Since irradiation of previously irradiated areas not
not possible, medical treatment with high doses of cyclophosphamide and prednisone was restarted. This proved ineffective, and the patient died fifteen days later. Permission for
is
necropsy
was
refused.
Satisfactory results of treatment of IVCNS with cyclophosphamide and prednisone have been reported. However, irradiation has not been described previously. Our case is especially interesting since, although diagnosed according to Moore’s
concentration had stabilised at 37°C, the temperature was reduced to 24°C, this change being achieved in less than 90 s. When the effect of cooling had stabilised, the temperature was returned to 37°C, and on stabilisation the next concentration was administered. Contractile responses at 37°C are presented as the mean increase in tension above basal before cooling and after rewarming to 37°C.2 The contractile response at 24°C represents the nadir of the response during cooling. Maximum contractile values were 1095 (183) mg at 37°C and 513 (120) mg at 24°C. At every ET concentration, contractions were inhibited by acute cooling and restored upon rewarming (figure). As reported for other vessels, ET was a potent agonist in the human resistance arteries. The effect of cooling was a profound inhibition of the contractions. This does not reflect an overall inhibition of contractile processes by cooling because contractions evoked by noradrenaline and potassium chloride are not similarly affected. Our data do not support a causal role for ET in the cold-induced vasospasm of Raynaud’s syndrome.
Divison of Vascular
Surgery,
Oregon Health Sciences University, Portland, Oregon 97201, USA
CHRISTIAN T. HARKER JAMES M. EDWARDS LLOYD M. TAYLOR, JR JOHN M. PORTER
1. Aalkjaer C, Pederson EB, Heagerty AM, et al. Relaxation of isolated resistance vessels from humans with vascular disease. Acta Med Scand 1986; 714 (suppl): 59-64. 2. Harker CT, Ousley PJ, Harris EJ, Edwards JM, Taylor LM, Porter JM. The effects of cooling on human saphenous vein reactivity to adrenergic agonists. J Vasc Surgery
FVIII, vWF, AND BLEEDING TIME BEFORE AND AFTER LIVER TRANSPLANTATION*
*Factor assays expressed as % of reference plasma (calibrated against the International Standard for FVIII-related activities), with normal values of 50-150%.
desmopressin did not trigger any further increases. This natural experiment indicates that the liver produces only a small proportion of the plasma pool ofvWF, too small to correct the defect of primary haemostasis in severe von Willebrand disease. By contrast, in congenital deficiencies of haemostasis proteins synthesised by the hepatocytes (such as factor VIII and protein C), transplantation increases plasma levels to a clinically relevant degree. A Bianchi Bonomi Haemophilia and Thrombosis Centre, and Liver Transplantation Unit, IRCCS Maggiore Hospital, University of Milan,
Milan, Italy
1990; 12: 45-49.
PIER MANNUCCIO MANNUCCI AUGUSTO FEDERICI MARCO CATTANEO RANIERO FASSATI DINANGELO GALMARINI
1. Bowie EJW,
Solberg LA, Fass DN, et al. Transplantation of normal bone marrow into pig with severe von Willebrand’s disease. J Clin Invest 1986; 78: 26-30. 2. Stel HV, van der Kwast Th H, Veerman ECI Detection of factor VIII/coagulant antigen in human liver tissue. Nature 1983; 309: 530-32. 3. Zelechowska MG, von Mourik JA, Brodniewicz-Proba T. Ultrastructural localization of factor VIII procoagulant antigen in human liver hepatocytes. Nature 1985; 317: a
Liver transplantation in severe von Willebrand disease SIR,-von Willebrand factor (vWF), congenital deficiency
or
dysfunction of which results in the bleeding disorder von Willebrand disease, is synthesised by vascular endothelial cells.1 The liver contains many endothelial cells but it is not certain if specialised cells, such as those lining the hepatic sinusoids, also contain vWF.2-4 A 44-year-old man with a history of frequent soft-tissue and mucosal bleeding since childhood had had several treatments with whole blood, cryoprecipitate, and factor VIII (FVIII) concentrates. His FVIII level was only 10%, with less than 6% ristocetin cofactor activity of vWF, and only 0-04% vWF antigen. His bleeding time was over 30 min, and he had antibodies to hepatitis B surface and core antigens and hepatitis C virus, and a persistently raised alanine aminotransferase. He was HIV seronegative. Hepatic synthetic function had progressively deteriorated over the previous 10 years and he had episodes of variceal bleeding since 1985 and several episodes of hepatic encephalopathy. In 1990, a liver mass was diagnosed as hepatocellular carcinoma. Liver transplantation was done on Nov 29,1990, for which he was given 12 000 units of FVIII concentrate containing large amounts of vWF (’Hemate P’, Behring), 12 units of red blood cell concentrate, and 4 litres of fresh-frozen plasma. Postoperatively the patient was treated with the same concentrate until day 26 (total dose 10 000 units). The liver is functioning well, 5 months after the operation, and since discharge the patient has had no bleeding episodes or replacement therapy. The table shows the results of FVIII and vWF measurements, and bleeding time before the operation, and on day 45 and 5 months afterwards. FVIII levels increased 2-fold and vWF antigen increased more than 20-fold, but was still very low. The bleeding time remained abnormal. On day 45 the patient gave informed consent to an infusion with desmopressin, but FVIII and vWF measurements did not change (table). Thus, when postoperative replacement therapy had been stopped for at least 3 weeks vWF levels, albeit remaining very low, were more than 20 times higher than before transplantation. The precision and sensitivity of our immunoradiometric assay are such that an increase from 0-04% to 1 02% cannot be due to experimental error, so there was probably heightened production of vWF by the endothelial cells of the new liver. The post-transplantation increase in FVIII can perhaps be explained by the fact that there was more vWF in plasma to carry and stabilise FVIII. No factor VIII nor vWF was stored, because
729-30. 4. Wion KL, Kelly D, Summerfield JA, Tuddenham EGD, Lawn RM. Distribution of factor VIII mRNA and antigen in liver and other tissues. Nature 1985; 317: 726-29.
Response of central
nervous
system
vasculitis to irradiation SIR,-Isolated vasculitis of the central nervous system (IVCNS) is a rare entity confined to CNS vessels with few signs of systemic involvement.1 If untreated, IVCNS is fatal. However, immunosuppressive therapy may lead to sustained remission. We report a child who failed to respond to this therapy, and who entered temporary remission on two occasions after cranial irradiation. A 11-year-old boy was admitted with signs of intracranial hypertension of one month’s duration. Cranial computed tomography showed a low-density area in the left fronto-basal region. A biopsy was completed which showed thrombosis and necrosis of some vessel walls in the leptomeninges, and in cortical tissue and white matter. Arteriography showed lesions consistent with the diagnosis of vasculitis, with multiple irregularities of the left anterior choroid artery walls. An infectious cause and systemic vasculitis were excluded. IVCNS was diagnosed, and treatment with cyclophosphamide and prednisolone was started, but neurological deterioration progressed with extension of the lesion to the basal ganglia and brainstem. Irradiation of the affected area was selected because of the patient’s critical condition. He received 2 Gy per day up to a total of 46 Gy, in the frontoparietal region. From that time onwards, his symptoms remitted gradually and subsequent radiographic studies were normal. Despite this success, the patient presented seven months later with cerebellar involvement that
responded again to radiotherapy. Immunosuppressive drugs were continued in the interval between radiotherapy sessions. The patient deteriorated further, with left parietal involvement fifteen months later. Since irradiation of previously irradiated areas not
not possible, medical treatment with high doses of cyclophosphamide and prednisone was restarted. This proved ineffective, and the patient died fifteen days later. Permission for
is
necropsy
was
refused.
Satisfactory results of treatment of IVCNS with cyclophosphamide and prednisone have been reported. However, irradiation has not been described previously. Our case is especially interesting since, although diagnosed according to Moore’s
