Von Willebrand disease--type 2N (case report)

Isolated reduced coagulation activity of FVIII may be a manifestation of haemophilia A, carriership of haemophilia A, haemophilia A in a woman, acquired haemophilia A and type 2N of von Willebrand's disease. The authors were concerned with the cause of isolated reduction of the coagulation activity of factor VIII (19 IU/dl) in a 40-year-old woman with a history of excessive haemorrhage of the type of mild haemophilia A with a negative family history. The personal history, family history and laboratory examination suggested type (variant) 2N of von Willebrand's disease. For indirect evidence the authors used a therapeutic study where they investigated the effect of administration of a concentrate of coagulation factors VIII/von Willebrand's factor (1/2), 28 IU factor VIII/kg body weight, on the coagulation activity of factor VIII. They recorded a half-life prolonged to 53 hours as compared with controls where the half-life was less than 12 hours. The therapeutic study confirmed sufficient coagulation activity of factor VIII, the utilization of which improved as a result of administration of von Willebrand's factor. This investigation confirmed indirectly as the cause of reduced coagulation activity of factor VIII in the examined patient the assumed type (variant) 2N of von Willebrand's disease.     

The Post-Aspirin Bleeding Time: a Screening Test for Evaluating Haemostatic Disorders

To evaluate the usefulness of the template bleeding time post-aspiring ingestion, this test was performed with other tests of haemostasis in 28 controls and 71 patients. The mean bleeding time (B.T.) in 24/28 true controls was 3.5 +/- 1 min (1 SD). Following the ingestion of 600 mg aspirin the B.T. was 6.3 +/- 1.4 min. Four out of 28 false 'controls' with negative bleeding histories were documented to have asymptomatic von Willebrand's disease and abnormal post-aspirin B.T. Of the 71 patients studied, 22 had initial B.T. that were abnormal (16 with classical von Willebrand's disease and six with platelet dysfunction). Of the remaining 49 patients with initially normal B.T., 30 had abnormal post-aspirin B.T. Of these 30 patients 13 had von Willebrand's disease. In eight, initially the abnormal B.T. post-aspirin was the only abnormality demonstrable but later they were shown to have von Willebrand's disease. In four the abnormal post-aspirin B.T. was combined with abnormal Ristocetin aggregations and a positive family history. These patients were presumed to have a variant of von Willebrand's disease. The remaining five had platelet dysfunctional states. Of the 19 patients with normal initial post-aspirin B.T., 16 demonstrated no haemostatic abnormality, and three were proven to have von Willebrand's disease. The aspirin tolerance test raised the sensitivity of the B.T. as a screening test for haemostasis from 40% to 94% in the abnormal patient population.     

Acquired von Willebrand's disease in association with Wilm's tumor: regression following treatment

A 9-yr-old female presented with a Wilm's tumor and a coagulopathy consistent with von Willebrand's disease. Factor VIII procoagulant activity (VIII C), factor VIII related antigen (VIIIR:Ag), and von Willebrand factor activity (VIII:vWf) were decreased. There was no evidence for a circulating inhibitor of the factor VIII molecular complex. von Willebrand's antigen II (vW AgII), which is deficient in hereditary von Willebrand's disease, was decreased below detectable levels in this patient. The coagulation studies, VIIIR:Ag, and vW AgII levels returned to normal following therapy of the Wilm's tumor. Wilm's tumor must be included as one of the malignancies associated with acquired von Willebrand's disease. Immunofluorescent studies of the tumor specimen showed normal endothelial staining of VIIIR:Ag by semiquantitative techniques and a lack of specific tumor adsorption of VIIIR:Ag The presence of normal amounts of tissue VIIIR:Ag has not previously been demonstrated in acquired von Willebrand's disease. Since we failed to demonstrate an inhibitor in the plasma in this patient, the etiology of the acquired von Willebrand's disease in this patient appears to differ from other cases of acquired von Willebrand's disease. The finding that vW AgII is decreased in this patient, similar to that reported in hereditary von Willebrand's disease, supports the close association of vW AgII to VIIIR:Ag, even though they are immunologically and biochemically distinct.     

Gastrointestinal angiodysplasia in a patient with type 2 von Willebrand's disease and analysis of exon 28 of the von Willebrand factor gene

Although the association between gastrointestinal angiodysplasia and von Willebrand's disease has been suggested, molecular mechanisms involved in the formation of angiodysplasia in patients with von Willebrand's disease remained undetermined. We examined exon 28 of the von Willebrand factor gene in a patient with both von Willebrand's disease and recurrent bleeding from angiodysplasia in the duodenum as well as his father's, and found a point mutation, C 3916-->T (amino acid substitution; Arg 543-->Trp), in the A1 domain of the von Willebrand factor gene. This mutation was identical with a previously reported mutation in a patient with von Willebrand's disease complicated with gastrointestinal angiodysplasia.     

Type IIB von Willebrand''s disease presenting as thrombocytopenia during pregnancy

Type IIb von Willebrand's disease has been found to be associated with the development of thrombocytopenia following the infusion of DDAVP (desmopressin). It has also been associated with sporadic thrombocytopenia and evidence of spontaneous platelet aggregation. A family with documented Type IIb von Willebrand's disease is described, where two of the affected females presented with moderate to severe thrombocytopenia developing during pregnancy with reversal to normal or minimally reduced platelet counts in the early post gestational period. In each case, the levels of factor VIII:C, von Willebrand factor antigen and von Willebrand factor ristocetin co-factor activity rose during pregnancy but there were notable discrepancies between the levels of each in any one individual. It is suggested that pregnancy resulted in increased synthesis of the variant form of von Willebrand factor resulting in progressively increasing platelet/variant form von Willebrand factor interaction and subsequent thrombocytopenia. Whether this reflects consumption or sequestration remains uncertain. Although spontaneous platelet aggregation was observed in some family members, the majority did not exhibit this phenomenon. Circulating platelet aggregates could not be detected. Both pregnancies were relatively uneventful and there is no history of unusual bleeding associated with pregnancy in the family. These observations suggest that Type IIb von Willebrand's disease should be considered in the differential diagnosis of thrombocytopenia developing during pregnancy, particularly in those individuals where evidence supporting the diagnosis of immune mediated thrombocytopenia is not forthcoming. Where the diagnosis of Type IIb von Willebrand's disease is established, active intervention other than confinement in a hospital with experience in haemostatic disorders is probably not required as the development of thrombocytopenia does not appear to exert an additive effect on the underlying defect relating to the variant form of von Willebrand's disease.     

Angiodysplasia and von Willebrand's disease type IIB treated with estrogen/progesterone therapy.

The association between angiodysplasia and von Willebrand's disease was first reported in 1967. The cases reported to date have involved patients with type I and IIA von Willebrand's disease. We report a patient with type IIB von Willebrand's disease who suffered gastrointestinal bleeding attributable to gastric angiodysplasia. The patient underwent endoscopic electrocautery acutely and has been treated long-term with estrogen/progesterone therapy. She has suffered no recurrent gastrointestinal bleeding at over 11 months of follow-up. We suggest hormonal therapy as an alternative to repeated blood product transfusion or extensive surgical resection in patients with von Willebrand's disease and gastrointestinal bleeding from angiodysplasia.     

Type IIB von Willebrand's disease: differential clearance of endogenous versus transfused large multimer von willebrand factor

The abnormal multimeric composition of plasma von Willebrand factor in type IIB von Willebrand's disease is transiently corrected after infusion of 1-deamino-[8-D-arginine]-vasopressin. However, the larger multimers released into the circulation disappear more rapidly in these patients than in type I von Willebrand's disease or normals. We demonstrate that the larger multimers of normal von Willebrand factor transfused into a type IIB patient are cleared from the circulation more slowly than multimers of similar size endogenously released from tissue stores. The rate of disappearance of large von Willebrand factor multimers after infusion of cryoprecipitate is similar in IIB, IIA, and severe homozygous-like von Willebrand's disease. Platelets from the IIB patient exhibited normal ristocetin-induced binding of normal von Willebrand factor. However, like normal platelets, they bound IIB von Willebrand factor at lower ristocetin concentrations than required for normal von Willebrand factor. These findings provide evidence that absence of the larger multimers from IIB plasma is related to a molecular abnormality of von Willebrand factor rather than to enhanced affinity of abnormal tissue or cellular binding sites, as is the case in the recently described "pseudo" von Willebrand's disease and "platelet-type" von Willebrand's disease.     

The von Willebrand Syndrome

S ummary . Five patients with an original diagnosis of von Willebrand's disease are described because their levels of factor VIII related protein, Ristocetin-induced platelet aggregation and/or family studies differed from the main group of patients with classical von Willebrand's disease. Two had normal levels of factor VIII related protein with reduced Ristocetin aggregation when this was tested in platelet rich plasma. In one, however, this was due to a plasma defect and in the other to a platelet abnormality. After cryoprecipitate infusion all abnormal tests were corrected in both these patients. The first patient, however, failed to show a secondary rise of factor VIII whereas the second showed a secondary rise of both factor VIII and of factor VIII related protein. The other three cases, who were all very severely affected, have been separated from the main group as none of their families was segregating for classical von Willebrand's disease.
It is suggested that the term von Willebrand's disease should be confined to those patients who have reduced factor VIII related protein and Ristocetin aggregation, and that von Willebrand's syndrome should be used for the various sub-groups that are emerging.     

Von Willebrand's Syndrome Presenting as an Acquired Bleeding Disorder in Association With a Monoclonal Gammopathy

The clinical and laboratory findings of apatient with a bleeding disorder, laboratoryfeatures of von Willebrand's disease, and amonoclonal gammopathy are described.There was no evidence of von Willebrand'sdisease in his five children. Laboratory features of von Willebrand's disease in thepatient included a long bleeding time, lowfactor VIII level by one- and two-stageclotting assays and by immunoassay, decreased platelet glass adhesiveness usingnative and heparinized blood, and correction of platelet adhesiveness by additionof cryoprecipitate in vitro. Attempts to implicate the monoclonal IgG in the pathogenesis of the von Willebrand's syndromewere unsuccessful using the followingtests: immunoprecipitation with normalplasma, antibody activity identified bypassive cutaneous anaphylaxis, inhibitionof biological factor VIII activity, and binding to factor VIII. Despite these negativefindings, it is suggested that the clinicalpattern of this and previously describedcases of "acquired" von Willebrand's disease has an immunologic basis that maybe mediated by either humoral or cellularmechanisms.

Submitted on September 26, 1972 Revised on February 8, 1973 Accepted on February 9, 1973     

In vivo dissociation of factor VII (AHF) activity and factor VII-related antigen in von Willebrand's disease.

Using monospecific rabbit antihuman factor VIII antiserum, we have examined the amounts of factor VIII-related antigen and compared these to the levels of factor VIII procoagulant activity in normal subjects and patients with von Willebrand's disease. We have observed that even without transfusion all nine probands with von Willebrand's disease and 20 of their 34 relatives possessed a significantly elevated factor VIII activity/factor VIII-related antigen ratio when compared to that of 55 normal subjects. It is suggested that an elevated factor VIII activity/factor VIII-related antigen ratio may be used for detection of the carriers of von Willebrand's disease.     

Percutaneous coronary intervention in a patient with von Willebrand's disease presenting with an acute coronary syndrome

The optimal management strategy for patients with von Willebrand's disease presenting with acute coronary syndromes is unclear. We present a clinical case of percutaneous coronary intervention following an acute coronary syndrome in a man with von Willebrand's disease. Other published case reports are reviewed. The central role of von Willebrand factor in the pathophysiology of acute coronary syndrome and the possible cardioprotective effects of low levels of the protein are discussed. Practical considerations regarding hemostasis and antiplatelet therapy are addressed. Finally, recommendations for the management of patients with von Willebrand's disease presenting with acute coronary syndromes are suggested.     

Factor VIII-Related Antigen and von Willebrand's Disease

Immunological methods for the detection and assay of factor VIII-related antigen have proved to be valuable tools in the study of factor VIII, haemophilia and von Willebrand's disease. The antibody neutralization tests, with their inherent difficulties and variability, have been largely replaced by the electroimmunoassay based on the method of Laurell. Using this latter method, it has been convincingly shown that whereas normal individuals and haemophiliacs have an antigen which precipitates with the rabbit anti-factor VIII antibody, patients with von Willebrand's disease have a reduced amount of the antigen.
The relationship of the antigen to factor VIII activity is not yet clear; nevertheless the assay of factor VIII-related antigen is proving of some value in the diagnosis of von Willebrand's disease and in the detection of carriers of haemophilia. In von Willebrand's disease the test for the antigen along with the ristocetin test for platelet aggregation has thrown new light on the condition and has helped to define several variants of the disease.     

Recurrent haemoperitoneum in a mild von Willebrand's disease combined with a storage pool deficit.

Haemoperitoneum secondary to haemorrhagic corpus luteum has been described in severe bleeding disorders such as afibrinogenaemia, type 3 von Willebrand's disease and patients under oral anticoagulation. We have studied one patient who presented three episodes of severe bleeding at ovulation, requiring surgery twice, with the diagnosis of mild von Willebrand's disease and mild storage pool deficiency. Mild von Willebrand's disease (associated with other thrombopathies or coagulopathies) should be considered in this pathology, although physicians would prefer to find a severe haemorrhagic disorder as the underlying condition in these cases.     

Diagnosis of von Willebrand's disease. A comparative study of diagnostic tests on nine families with von Willebrand's disease and its differential diagnosis from hemophilia and thrombocytopathy.

Nine probands with von Willebrand's disease, and their family members, totalling 43 people, were examined. Twenty-seven had a history of bleeding; 29 had an increased factor VIII activity:factor VIII related antigen ratio; 24 had a decreased factor VIII related antigen; 23 had a prolonged bleeding time; 19 had a reduced platelet adhesiveness; 16 had a decreased factor VIII activity; and 14 had an abnormal ristocetin-induced platelet aggregation. Eight members with both normal beleeding time and normal factor VIII activity were found to have other abnormal tests: elevated ratio of factor VIII activity to factor VIII related antigen in seven; decreased factor VIII related antigen in four; and reduced platelet adhesiveness in one. Therefore, ratio of factor VIII activity to factor VIII related antigen and factor VIII related antigen are more sensitive and may be used for the detection of heterozygous carriers of von Willebrand's disease. Although patients with thrombocytopathy may have a prolonged bleeding time, decreased platelet adhesiveness and reduced platelet aggregation by ristocetin, their factor VIII activity, factor VIII related antigen and ratio of factor VIII activity to factor VIII related antigen are normal and their abnormal ristocetin test cannot be corrected by the addition of factor VIII concentrate. Hemophilic subjects and hemophilic carriers, who are deficient in factor VIII activity, usually have a normal bleeding time, normal platelet adhesiveness, and normal ristocetin test. In contrast to patients with von Willebrand's disease, their factor VIII related antigen is normal or slightly increased and their ratio of factor VIII activity to factor VIII related antigen is significantly reduced. We conclude that ratio of factor VIII activity to factor VIII related antigen and factor VIII related antigen are not only more sensitive but also more specific for the diagnosis of von Willebrand's disease.     

Treatment of von Willebrand's disease and hypofibrinogenemia with single donor cryoprecipitate from plasma exchange donation

Conventional replacement therapy for hypofibrinogenemia and von Willebrand's disease requires multiple donor exposures and a correspondingly high risk of blood-borne infection. We describe the collection and successful use of cryoprecipitate derived from a single donor by plasma exchange donation to support such patients through major hemostatic stresses. The father of an epileptic patient with von Willebrand's disease produced cryoprecipitate containing 23,546 units of von Willebrand factor (vWF) in nine desmopressin-stimulated donations; this provided total factor replacement for neurosurgery to remove a seizure focus. The average yield was 2,616 units per donation and the average VWF concentration in cryoprecipitate was 17.7 units/ml. The husband of a hypofibrinogenemic patient with a history of postpartum hemorrhage provided cryoprecipitate containing 13.4 g of fibrinogen in five donations; this supported his wife through parturition without recourse to other blood products. The average yield was 2.7 g per donation, and the average fibrinogen concentration was 15.3 g/liter. Plasma exchange donation is a practical alternative source for cryoprecipitate. It can provide vWF and fibrinogen that carry a reduced risk of infectious disease transmission.     

Absence of functional activity of tissue plasminogen activator in patients with severe forms of von Willebrand''s disease

Some patients with von Willebrand's disease do not respond to stimuli such as venous occlusion and infusion of a vasopressin analogue DDAVP. In these patients, fibrinolytic activity is not enhanced and von Willebrand's factor is not released into the blood. Skin biopsies and cryostat sections were used to study the fibrinolytic activity of skin vessels and localization of tissue plasminogen activator (t-PA) in three patients with severe form of von Willebrand's disease. On fibrin films, no fibrinolysis developed around the skin vessels of the patients; however, using specific polyclonal and monoclonal antibodies to t-PA, and peroxidase coupled specific IgG, presence of t-PA antigen was demonstrated in endothelial cells (EC) of all of them. In plasma no t-PA activity was detected either before or after venous occlusion although t-PA inhibitor activity was in a normal range. Small amounts of t-PA antigen was measured in blood by ELISA. From these results, it is concluded that in patients with severe forms of von Willebrand's disease, t-PA present in EC is not functional and can not transform plasminogen into plasmin.     

Treatment of the severe bleeding episode in type III von Willebrand's disease by simultaneous administration of cryoprecipitate and platelet concentrate.

A severe, life-threatening bleeding episode in a 24-year-old woman suffering from type III von Willebrand's disease was treated by large doses of cryoprecipitate with unsatisfactory results. Bleeding ceased and the bleeding time normalized only after concomitant administration of platelet concentrates. In the treatment of von Willebrand's disease patients possessing platelets with absent or insufficient von Willebrand factor activity the administration of plasma concentrates together with platelets appears to be justified.     

Use of a high-purity factor VIII concentrate (Hemate P) in von Willebrand's disease

In previous studies, we have found Hemate P (Behring) to be the only commercial virus-inactivated high-purity factor VIII concentrate that contains native von Willebrand factor. In the present study, Hemate P was given to 7 patients with the severe recessive form of von Willebrand's disease, to 2 patients with type Ia, to 1 patient with type IIB, and to 1 patient with type IIC von Willebrand's disease. A correction of the hemostatic defect was seen in all patients. Satisfactory hemostasis was also obtained in clinical situations, 1 patient undergoing major surgery and another being delivered, both without undue loss of blood. We conclude that Hemate P is an efficacious and safe product for use in cases of von Willebrand's disease when pharmacological correction of the hemostatic defect is not possible.     

A Variant of Factor VIII Related Antigen

S ummary . The factor VIII related antigen in a patient with von Willebrand's disease gave qualitatively different precipitation peaks on electroimmunoassay and showed a faster anodal migration on crossed immunoelectrophoresis than antigen obtained from normal subjects, haemophiliacs and other patients with von Willebrand's disease. In addition, less of the patient's antigen could be recovered from ethanol precipitates and cryoprecipitates of plasma. It is suggested that the patient's plasma contained an atypical form of factor VIII related antigen.     

Two consecutive pregnancies and deliveries in a patient with von Willebrand''s disease type 3

Pregnancy and delivery are critical events in women with von Willebrand's disease type 3. Prophylactic treatment for delivery and early postpartum period is recommended. Vaginal delivery is considered safe. However, experience is based on rare case reports. We report the management of two pregnancies and successful deliveries in a woman with von Willebrand's disease type 3.