Treatment of von Willebrand's Disease
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《新英格兰医药杂志》
To the Editor: In his scholarly review of the treatment of von Willebrand's disease, Mannucci (Aug. 12 issue)1 omits a discussion of hypothyroidism as a cause of acquired von Willebrand's disease. Hypothyroid patients may have bleeding symptoms such as easy bruising, menorrhagia, or prolonged bleeding after tooth extraction. The most frequent defects in hemostasis are a prolonged bleeding time, decreased platelet adhesiveness, and low plasma concentrations of factor VIII and von Willebrand factor.2 Desmopressin rapidly ameliorates these abnormalities3 and is of value for the acute treatment of bleeding or when surgery is necessary. Long-term thyroxine replacement reverses these abnormalities.3,4 Acquired von Willebrand's disease is very likely to be type 1 in all cases because of a normal ratio of von Willebrand factor antigen to ristocetin cofactor.4 The postulated mechanism is decreased synthesis of von Willebrand factor in the absence of adequate levels of thyroxine.5
Ajit Singh Kashyap, M.D.
Armed Forces Medical College
Pune 411 040, India
kashyapajits@hotmail.com
Kuldip Parkash Anand, M.D.
Command Hospital (Eastern Command)
Kolkata 700 027, India
Surekha Kashyap, M.D.
Armed Forces Medical College
Pune 411 040, India
References
Mannucci PM. Treatment of von Willebrand's disease. N Engl J Med 2004;351:683-694.
Ford HC, Carter JM. Haemostasis in hypothyroidism. Postgrad Med J 1990;66:280-284.
Erfurth EM, Ericsson U-BC, Egervallah K, Lethagen SR. Effect of acute desmopressin and of long-term thyroxine replacement on haemostasis in hypothyroidism. Clin Endocrinol (Oxf) 1995;42:373-378.
Michiels JJ, Schroyens W, Berneman Z, van der Planken M. Acquired von Willebrand syndrome type 1 in hypothyroidism: reversal after treatment with thyroxine. Clin Appl Thromb Hemost 2001;7:113-115.
Nitu-Whalley IC, Lee CA. Acquired von Willebrand syndrome -- report of 10 cases and review of the literature. Haemophilia 1999;5:318-326.
To the Editor: With regard to the review by Mannucci, little attention has been paid to the health of the unborn child. We know that the risk of fetal bleeding is increased in women with von Willebrand's disease.1 Von Willebrand factor, a large polymer, does not cross the placenta, making replacement therapy ineffective for the fetus. Fetal bleeding, including intracranial hemorrhage, has long been described in association with vaginal delivery.2,3 In type 2 disease, the child will invariably be affected.
Since prenatal diagnosis of the fetus is difficult and dangerous,4 I believe that elective cesarean section should be used in women with moderate or severe disease or those for whom assisted vaginal delivery is likely in order to minimize fetal trauma. In addition, it is important to rule out in utero fetal hemorrhage before delivery, for both medical and legal reasons.
Although in type 1 disease, the bleeding tendency decreases during pregnancy, this is not the case in type 2 or type 3 disease. In type 2B von Willebrand's disease, the thrombocytopenia often gets worse during pregnancy.5
Tawee Tanvetyanon, M.D.
Loyola University Chicago Stritch School of Medicine
Maywood, IL 60153
tan73@hotmail.com
References
Sherer DM, Anyaegbunam A, Onyeije C. Antepartum fetal intracranial hemorrhage, predisposing factors and prenatal sonography: a review. Am J Perinatol 1998;15:431-441.
Mullaart RA, Van Dongen P, Gabreels FJ, van Oostrom C. Fetal periventricular hemorrhage in von Willebrand's disease: short review and first case presentation. Am J Perinatol 1991;8:190-192.
Chediak JR, Alban GM, Maxey B. von Willebrand's disease and pregnancy: management during delivery and outcome of offspring. Am J Obstet Gynecol 1986;155:618-624.
Ash KM, Mibashan RS, Nicolaides KH. Diagnosis and treatment of feto-maternal hemorrhage in a fetus with homozygous von Willebrand's disease. Fetal Ther 1988;3:189-191.
Rick ME, Williams SB, Sacher RA, McKeown LP. Thrombocytopenia associated with pregnancy in a patient with type IIB von Willebrand's disease. Blood 1987;69:786-789.
r. Mannucci replies: Tanvetyanon raises the issue of an increased risk of bleeding in affected fetuses and newborns of women with von Willebrand's disease and states that in women with type 2 disease the child will invariably be affected. However, because autosomal dominant transmission of type 2 disease implies that only half of the offspring are affected, this latter statement is inaccurate. In the most severe recessively transmitted form of the disease (type 3), no heterozygous child is affected. Two large clinical series indicate that fetal or neonatal bleeding is rare in von Willebrand's disease.1,2 This is biologically plausible, considering that patients with severe hemophilia rarely have fetal or neonatal bleeding (including cephalhematomas), in spite of the fact that their levels of factor VIII are usually lower than those in patients with von Willebrand's disease (whatever the degree of severity). On the whole, I believe that there is very little ground for recommending elective cesarean section for women with von Willebrand's disease for reasons pertaining to the health of the fetus or newborn.
Kashyap and colleagues point out that hypothyroidism is one of the conditions associated with acquired von Willebrand's disease. This is a relatively rare association. Data from an international registry (based on 186 cases) and from a review of the literature (266 cases) yield frequencies of this association of 2 percent and 8 percent, respectively.3 The most frequent conditions associated with von Willebrand's disease are lymphoproliferative disorders (48 and 30 percent, respectively), myeloproliferative disorders (15 and 18 percent), and congenital and acquired cardiac defects (21 and 12 percent).3
P.M. Mannucci, M.D.
Istituto di Ricovero e Cura a Carattere Scientifico at Maggiore Hospital
20122 Milan, Italy
piermannuccio.mannucci@unimi.it
References
Silwer J. von Willebrand's disease in Sweden. Acta Pediatr Scand Suppl 1973;238:1-159.
Lak M, Peyvandi M, Mannucci PM. Clinical manifestations and complications of childbirth and replacement therapy in 385 Iranian patients with type 3 von Willebrand disease. Br J Haematol 2000;111:1236-1239.
Federici AB, Rand JH, Bucciarelli P, et al. Acquired von Willebrand syndrome: data from an international registry. Thromb Haemost 2000;84:345-349.
Ajit Singh Kashyap, M.D.
Armed Forces Medical College
Pune 411 040, India
kashyapajits@hotmail.com
Kuldip Parkash Anand, M.D.
Command Hospital (Eastern Command)
Kolkata 700 027, India
Surekha Kashyap, M.D.
Armed Forces Medical College
Pune 411 040, India
References
Mannucci PM. Treatment of von Willebrand's disease. N Engl J Med 2004;351:683-694.
Ford HC, Carter JM. Haemostasis in hypothyroidism. Postgrad Med J 1990;66:280-284.
Erfurth EM, Ericsson U-BC, Egervallah K, Lethagen SR. Effect of acute desmopressin and of long-term thyroxine replacement on haemostasis in hypothyroidism. Clin Endocrinol (Oxf) 1995;42:373-378.
Michiels JJ, Schroyens W, Berneman Z, van der Planken M. Acquired von Willebrand syndrome type 1 in hypothyroidism: reversal after treatment with thyroxine. Clin Appl Thromb Hemost 2001;7:113-115.
Nitu-Whalley IC, Lee CA. Acquired von Willebrand syndrome -- report of 10 cases and review of the literature. Haemophilia 1999;5:318-326.
To the Editor: With regard to the review by Mannucci, little attention has been paid to the health of the unborn child. We know that the risk of fetal bleeding is increased in women with von Willebrand's disease.1 Von Willebrand factor, a large polymer, does not cross the placenta, making replacement therapy ineffective for the fetus. Fetal bleeding, including intracranial hemorrhage, has long been described in association with vaginal delivery.2,3 In type 2 disease, the child will invariably be affected.
Since prenatal diagnosis of the fetus is difficult and dangerous,4 I believe that elective cesarean section should be used in women with moderate or severe disease or those for whom assisted vaginal delivery is likely in order to minimize fetal trauma. In addition, it is important to rule out in utero fetal hemorrhage before delivery, for both medical and legal reasons.
Although in type 1 disease, the bleeding tendency decreases during pregnancy, this is not the case in type 2 or type 3 disease. In type 2B von Willebrand's disease, the thrombocytopenia often gets worse during pregnancy.5
Tawee Tanvetyanon, M.D.
Loyola University Chicago Stritch School of Medicine
Maywood, IL 60153
tan73@hotmail.com
References
Sherer DM, Anyaegbunam A, Onyeije C. Antepartum fetal intracranial hemorrhage, predisposing factors and prenatal sonography: a review. Am J Perinatol 1998;15:431-441.
Mullaart RA, Van Dongen P, Gabreels FJ, van Oostrom C. Fetal periventricular hemorrhage in von Willebrand's disease: short review and first case presentation. Am J Perinatol 1991;8:190-192.
Chediak JR, Alban GM, Maxey B. von Willebrand's disease and pregnancy: management during delivery and outcome of offspring. Am J Obstet Gynecol 1986;155:618-624.
Ash KM, Mibashan RS, Nicolaides KH. Diagnosis and treatment of feto-maternal hemorrhage in a fetus with homozygous von Willebrand's disease. Fetal Ther 1988;3:189-191.
Rick ME, Williams SB, Sacher RA, McKeown LP. Thrombocytopenia associated with pregnancy in a patient with type IIB von Willebrand's disease. Blood 1987;69:786-789.
r. Mannucci replies: Tanvetyanon raises the issue of an increased risk of bleeding in affected fetuses and newborns of women with von Willebrand's disease and states that in women with type 2 disease the child will invariably be affected. However, because autosomal dominant transmission of type 2 disease implies that only half of the offspring are affected, this latter statement is inaccurate. In the most severe recessively transmitted form of the disease (type 3), no heterozygous child is affected. Two large clinical series indicate that fetal or neonatal bleeding is rare in von Willebrand's disease.1,2 This is biologically plausible, considering that patients with severe hemophilia rarely have fetal or neonatal bleeding (including cephalhematomas), in spite of the fact that their levels of factor VIII are usually lower than those in patients with von Willebrand's disease (whatever the degree of severity). On the whole, I believe that there is very little ground for recommending elective cesarean section for women with von Willebrand's disease for reasons pertaining to the health of the fetus or newborn.
Kashyap and colleagues point out that hypothyroidism is one of the conditions associated with acquired von Willebrand's disease. This is a relatively rare association. Data from an international registry (based on 186 cases) and from a review of the literature (266 cases) yield frequencies of this association of 2 percent and 8 percent, respectively.3 The most frequent conditions associated with von Willebrand's disease are lymphoproliferative disorders (48 and 30 percent, respectively), myeloproliferative disorders (15 and 18 percent), and congenital and acquired cardiac defects (21 and 12 percent).3
P.M. Mannucci, M.D.
Istituto di Ricovero e Cura a Carattere Scientifico at Maggiore Hospital
20122 Milan, Italy
piermannuccio.mannucci@unimi.it
References
Silwer J. von Willebrand's disease in Sweden. Acta Pediatr Scand Suppl 1973;238:1-159.
Lak M, Peyvandi M, Mannucci PM. Clinical manifestations and complications of childbirth and replacement therapy in 385 Iranian patients with type 3 von Willebrand disease. Br J Haematol 2000;111:1236-1239.
Federici AB, Rand JH, Bucciarelli P, et al. Acquired von Willebrand syndrome: data from an international registry. Thromb Haemost 2000;84:345-349.