Platelet-type von Willebrand's disease: characterization of a new bleeding disorder

An autosomally transmitted bleeding diathesis sharing some, but not all, features previously described in von Willebrand's disease (vWd) was studied in five patients representing three generations of a single family. Bleeding times in the upper normal range in conjunction with low-normal platelet counts, normal factor VIII coagulant activity and VIII-related antigen, decreased VIII-ristocetin cofactor activity, selective decrease of the higher molecule weight factor VIII/von Willebrand factor (VIII/vWF) multimers, and increased ristocetin- induced platelet agglutination at low ristocetin concentrations were characteristic. Binding of patient VIII/vWF to washed normal platelets was within normal limits, whereas binding of normal VIII/vWF to patient platelets was significantly increased (p less than 0.001 at 0.6 mg/ml ristocetin). This disorder accordingly appears to involve an intrinsic platelet abnormality affecting platelet-VIII/vWF interactions. It is proposed that the concept of vWD be broadened to include patients with this abnormality, which may appropriately be called "Platelet-type von Willebrand's disease."     

Variant von Willebrand's disease and pregnancy

The clinical course and coagulation profile of a pregnant patient with variant von Willebrand's disease were followed from the second trimester through puerperium. The clinical course was characterized by a normal delivery and absence of abnormal bleeding or need for replacement therapy. The coagulation profile demonstrated an increase in factor VIII procoagulant activity, factor-VIII-related antigen, and platelet aggregation activity in response to ristocetin prior to delivery. Postpartum, these factors decreased to prepregnancy values with distinctly different patterns. Factor VIII procoagulant activity continued to rise for 5 days after delivery and then decreased with a half-life of approximately 6 days. Factor-VIII-related antigen began to decrease just prior to delivery, displaying a half-life or approximately 6 days. Ristocetin cofactor activity, however, dropped immediately postpartum and displayed a half-life of approximately 6 hr. The ristocetin cofactor activity was associated with factor-VIII- related antigen, which displayed a significantly smaller molecular weight than does normal factor-VIII-related antigen. Larger aggregates of factor-VIII-related antigen. Larger aggregates of factor-VIII- related antigen did not appear during the pregnancy, and ristocetin cofactor activity could not be demonstrated in fragments of less than 0,8 x 10(6).     

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.     

Massive postoperative intramuscular bleeding in acquired von Willebrand's disease

We describe a case of acquired von Willebrand's disease (vWD) associated with monoclonal gammopathy with undetermined significance (MGUS) in a 54-year-old man who was admitted with hemarthrosis and extensive thigh muscle hematoma following arthroscopic surgery and postoperative prophylaxis with low molecular weight heparin. Coagulation tests were compatible with acquired vWD: prolonged activated partial thromboplastin time (aPTT) (56.1 s), decreased levels of factor VIII coagulant activity (23%), low concentrations of von Willebrand's factor (vWF) antigen (13%), and undetectable ristocetin cofactor activity (<10%). Infusion of a vWF-containing factor VIII concentrate failed to normalize the plasma levels of vWF-related parameters. Only additional intravenous administration of immunoglobulins led to a transient normalization of ristocetin cofactor activity, vWF antigen, and factor VIII coagulant activity. While the spontaneous bleeding tendency in this case was mild, surgery and administration of prophylactic doses of low molecular weight heparin led to life-threatening bleeding.     

An atypical von Willebrand's disease with hyperreactivity of platelet aggregation

Two family members (daughter and mother) with a bleeding disorder showed prolonged bleeding time and activated partial thromboplastin time associated with decreased plasma levels of factor VIII procoagulant activity, factor VIII-related antigen, and factor VIII-ristocetin cofactor activity. The ristocetin-induced platelet agglutination (RIPA) was enhanced, ADP-, collagen- and Ca ionophore-induced platelet aggregation were also increased at low concentrations of these compounds. In the mother, spontaneous platelet aggregation (SPA) was also observed. Contrary to type II B von Willebrand's disease (vWd), pseudo-vWd and platelet-type vWd, the patients did not show any increased binding of factor VIII/vWf to platelets in the presence of ristocetin. The RIPA in normal controls were inhibited by addition of antifactor VIII antiserum to the platelet-rich plasma, but not in cases 1 and 2. In this atypical vWd, therefore, the hyperreactivity of platelet aggregation may be due to an intrinsic abnormality of the platelets, but not to any enhanced interaction between plasma factor VIII and the platelets.     

Failure of AHF concentration to control bleeding in von Willebrand's disease.

A newly available dried concentrate of antihemophilic factor (Profilate, Abbott Laboratories) was compared with standard, blood-bank prepared cryoprecipitate in the control of bleeding in a patient with von Willebrand's disease. Profilate effectively raised plasma levels of factor VIII but produced only half the expected increase in plasma ristocetin aggregation factor (RAF), and this RAF did not bind readily to the platelets in the presence of ristocetin. Furthermore, the Profilate had little effect upon the bleeding time or the clinical hemorrhage. In contrast, the cryoprecipitate did increase plasma RAF to the expected level, and this RAF bound readily to the patient's platelets in the presence of ristocetin. Cryoprecipitate promptly controlled bleeding. We conclude that the RAF present in Profilate retains in vitro activity but is incapable of augmenting platelet function in vivo.     

Platelet function and immunologic parameters in von Willebrand's disease following cryoprecipitate and factor VIII concentrate infusion.

Results of functional and immunologic tests of factor VIII and of platelet function were followed in two patients with severe von Willebrand's disease who were given cryoprecipitate during preparation for surgery. Initial correction of factor VIII coagulant activity was found to persist from 48 to 72 hours. Correction of immunologically measured factor VIII persisted for 48 hours and correlated with the patients' platelet response to ristocetin aggregation. Bleeding times were corrected for only 6 to 8 hours and showed fairly good correlation with the ristocetin aggregation factor, as suggested by Weiss. The administration of commercial factor VIII concentrate corrected all parameters except the bleeding time and the ristocetin aggregation factor measurement.     

von Willebrand's disease characterized by increased ristocetin sensitivity and the presence of all von Willebrand factor multimers in plasma

In eight members of one family, platelets in platelet-rich plasma aggregated at much lower ristocetin concentrations than normal. Ivy bleeding time was variously prolonged, and von Willebrand factor antigen (vWF:Ag), ristocetin cofactor activity, and factor VIII coagulant activity were decreased. Most of the affected members had had slight to rather severe bleeding symptoms. Platelet-type von Willebrand's disease (vWD) could be ruled out. All multimers of vWF:Ag were found in plasma as well as platelets. Administration of 1-desamino-8-D-arginine vasopressin (DDAVP) to the propositus did not cause thrombocytopenia, and platelet-poor plasma obtained immediately after did not aggregate normal platelets. The molecular defect in this family, inherited as an autosomal dominant, resembles the one in type IIB because of the response to ristocetin but differs from IIB because all vWF:Ag multimers are present in plasma and the response to DDAVP is atypical. We conclude that this family has a new subtype of vWD and propose that structural as well as functional criteria should be used for a proper classification of vWD.     

Acquired von Willebrand's disease in association with essential thrombocythemia: regression following treatment.

Acquired von Willebrand's disease in a 40-year-old woman affected with essential thrombocythemia (ET) is reported. The profile of plasma von Willebrand factor (vWF) revealed decreased ristocetin cofactor activity and diminished large multimers of vWF in spite of a normal vWF antigen level. There was no evidence of circulating inhibitor against the factor VIII complex. The vWF abnormality improved by controlling the platelet count following treatment for ET with interferon-alpha 2b and ranimustine. The possible mechanism of the development of AvWD in ET is briefly discussed.     

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.     

Acquired von Willebrand's disease due to aberrant expression of platelet glycoprotein Ib by marginal zone lymphoma cells

A 69-year-old woman presented with splenic marginal zone lymphoma associated with acquired von Willebrand's disease (AVWD). Laboratory abnormalities included markedly decreased plasma levels of factor VIII coagulant (C) activity (VIII:C 28%), von Willebrand's factor (VWF) antigen (Ag) (vWF:Ag < 6%), and VWF ristocetin cofactor (RCo) activity (VWF:RCo, < 12%). VWF multimer analysis revealed a severe type II defect. Treatment with cryoprecipitate, high-dose gamma globulin or desmopressin given intravenously was unsuccessful. Clinical bleeding and coagulation abnormalities showed transient improvement after replacement therapy with Humate-P concentrate. The coagulation abnormalities improved partially after splenectomy and completely after subsequent chemotherapy. The neoplastic lymphocytes in the blood and spleen strongly expressed platelet glycoprotein Ib (CD42) and VWF but not other platelet-associated antigens.     

A probable double heterozygous type II von Willebrand's disease with increased ristocetin induced platelet aggregation.

We have identified a patient with von Willebrand's disease (vWD) resembling type IIB vWD, with increased ristocetin induced platelet aggregation (RIPA), the absence of the large multimers of von Willebrand factor (vWF) in plasma, and the presence of the large multimers in platelets in whom a family study indicated a probable double heterozygous inheritance pattern. The propositus was a 12-year-old boy with frequent epistaxis and bruising. Abnormal hemostatic findings included a prolonged bleeding time (BT), decreased levels of factor VIII coagulant activity (VIIIC), von Willebrand factor antigen (vWF:Ag), ristocetin cofactor (RCof), and an increased RIPA. In the presence of ristocetin, binding of the patient's plasma vWF to normal platelets was increased but binding of normal vWF to his platelets was normal. SDS-agarose gel (1.5%) electrophoresis revealed that plasma vWF lacked the large multimers, and 3.0% gel electrophoresis revealed that the multimers had a 5-band pattern similar to normal. The above findings were consistent with type IIB vWD, but 1-deamino[8-D-arginine]-vasopressin (DDAVP) infusion resulted in a shortened BT and the transient appearance of large multimers without a decrease in the platelet count. Family studies revealed that his mother has mild bleeding symptoms, decreased VIIIC, vWF:Ag, and RCof levels and normal to slightly reduced RIPA with a multimer pattern consistent with type I vWD. In contrast, the father, sister, and paternal grandfather were asymptomatic, with a slightly decreased VIIIC level but a normal BT and vWF:Ag and RCof levels. Their RIPA and vWF binding to normal platelets were increased, but unlike the propositus their plasma contained large multimers. We concluded that the propositus is a type IIB-like variant differing from previously reported IIB variants in two ways: 1) his response to DDAVP and 2) a possible double heterozygous mode of inheritance rather than the usual dominant route.     

DDAVP in type IIa von Willebrand's disease

1-D-Amino(8-D-arginine)-vasopressin (DDAVP) infusion in three patients with type IIa von Willebrand's disease (vWD) resulted in a normalization of the factor VIII coagulant, factor VIII-related antigen, and von Willebrand factor (vWF) (ristocetin cofactor) activities and the bleeding time. The normalization of these hemostatic parameters persisted for four hours. Over the same time period there was a marked increase in the quantity of the vWF multimers when blood was collected in the presence of protease inhibitors. The vWF multimers present were even larger than the normal. When blood was collected in the absence of protease inhibitors, a smaller increase in the plasma vWF multimers was observed and fewer of the intermediate and larger vWF multimers were seen; multimers larger than those present in normal plasma were not visualized. The platelet vWF multimers and activities did not change with or without inhibitors. These studies suggest that there is a subgroup of patients with type IIa vWD who respond to DDAVP with complete normalization of their hemostatic abnormalities and whose vWF is sensitive to proteolysis.     

Platelet release abnormality associated with a variant of von Willebrand's disease.

A family with a platelet release abnormality (PRA) is described. The only son also showed a reduced rate of platelet aggregation in response to ristocetin, markedly reduced levels of von Willebrand's factor (vWf, ristocetin cofactor), and increased mobility of factor VIII-like antigen, features which were suggestive of von Willebrand's disease (vWd). No inhibition of vWf was found in his plasma. Family studies showed no evidence of vWd in the mother. The father's investigations showed a low rate of ristocetin aggregation on one of the two occasions when it was tested and low vWf on two of four occasions. Despite repeated testing, the findings in the father did not conclusively rule out the possibility of mild vWd, and it was impossible to determine whether the vWd in the son was inherited or arose as a mutation. The findings in this family suggest a possible relationship between abnormalities of the factor VIII complex and defective platelet function.     

Hereditary hemorrhagic telangiectasia associated with von Willebrand's disease; literature review

A 23-year-old female was admitted to our hospital in July 1987, because of cutaneous macular telangiectasia on her extremities and hypermenorrhea. In 1983, she began to notice small red spots on her palms. During next several years, these telangiectasia increased in number and spread all over her body. In 1986, she had a history of melena and prolonged bleeding after dental extraction. Her lower legs have turned red purple during the gait for a long time. Her older brother and two paternal cousins have experienced frequent epistaxis. The hemostatic laboratory data revealed prolonged IVY bleeding time and APTT, impaired capillary fragility, decreased vWf:Ag and VIII:C levels, depressed Rcof and severe decreased platelet adhesiveness, vWf mobility on two-dimensional crossed immunoelectrophoresis was normal. Platelet aggregation was reduced after addition of ristocetin and collagen. This case was diagnosed Osler-Weber-Rendu disease (Osler disease) associated with von Willebrand's disease (vW disease) type I. Previously, 28 Cases (8 families) with these two disease association have been reported. These disease seems to coexist as an inevitable consequence, because the disorder of vascular endothelial cells where von Willebrand factors are synthesized is a common pathogenetic factor in Osler disease. It is considered that such a case is secondary vW disease. Moreover, previous reports of Osler disease associated with various hemostatic defects are reviewed.     

Liver Transplantation in Pigs with von Willebrand's Disease

Nine pigs with von Willebrand's disease (_vWd pigs) received normal auxiliary livers; in the immediate postoperative period, three pigs died, three survived from 3 days to 3 weeks, and three were killed 5–13 weeks postoperatively. There was an increase in factor VIII (up to 90 u/dl) but with a type of factor VIII that was more labile than normal and that decreased after 2 weeks, probably as a result of liver rejection. There was a slight increase in the levels of the ristocetin-Willebrand factor postoperatively (up to 11%) but this activity was undetectable after 2 weeks. There was no correction of the abnormal bleeding time and platelet retention. When a _vWd liver was transplanted orthotopically into a normal pig, the factor-VIII coagulant activity and the ristocetin-Willebrand factor remained normal. The abnormality in porcine von Willebrand's disease is only partially corrected by liver transplantation, which suggests that there also is extrahepatic synthesis of the missing or abnormal plasmatic activity or activities.     

Heat-treated factor VIII/von Willebrand factor concentrate in platelet-type von Willebrand's disease

Cryoprecipitate has proved to correct the hemostatic defects in von Willebrand's disease (vWD) and platelet-type vWD. However, recent studies have revealed that transmission of the AIDS retrovirus (HIV) occurs through exposure to blood products including cryoprecipitate. Treatment with heat-treated factor VIII/von Willebrand factor (vWf) concentrates may have certain advantages over treatment with nonheated products, if these preparations are efficacious in these disorders. We found that a commercially available factor VIII/vWf concentrate, Haemate P, contained the high-molecular-weight multimers of vWf and had a ratio of ristocetin cofactor (RCof) to vWf antigen (vWf:Ag) close to unity. In addition, its capacity to directly induce aggregation of platelet-type vWD platelets in vitro was similar to that for cryoprecipitate. When infused into a patient with platelet-type vWD, Haemate P shortened the prolonged bleeding time and caused spontaneous platelet aggregation in vitro with a mild diminution of platelet count. These results indicate that some of the heat-treated factor VIII/vWf concentrates may provide a safer, yet still effective, treatment for platelet-type vWD.     

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     

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.     

Acquired von Willebrand's syndrome: a single institution experience

Acquired von Willebrand's disease or syndrome (AVWS) is a rare bleeding disorder distinguished from congenital von Willebrand's disease by age at presentation and absence of personal and family history of bleeding disorders. We report on 22 patients with AVWS seen over 25 years. Mean age at diagnosis was 61.3 years (range 38-86 years); most patients had a spontaneous or a post-operative hemorrhage at presentation. Gastrointestinal bleeding and epistaxis were the most common spontaneous symptoms. Bleeding time was prolonged in most patients, associated with marked reductions in plasma von Willebrand factor antigen and ristocetin cofactor activity. Plasma VWF multimer distribution was normal (type 1 pattern) in 5 patients, indeterminate (no multimers detectable) in 6 patients (type 3 pattern), and abnormal (decreased higher-molecular-weight multimers, type 2 pattern) in 11 patients. None of 17 patients tested had an inhibitor of ristocetin cofactor activity. An underlying malignant or benign hematologic disease was found in 18 patients, and 1 patient had Crohn's disease. Desmopressin was effective in only half the patients so treated, but all patients responded to treatment with VWF-containing concentrates. Resolution of AVWS occurred with therapy of lymphoma (1 patient) and chronic lymphocytic leukemia (1 patient). Sixteen patients were alive at last follow-up; no deaths were related to bleeding. AVWS may be more prevalent than has been appreciated; we estimate up to 0.04%. Awareness of the existence of AVWS is essential for diagnosis and appropriate management. Therapy of associated diseases may improve the bleeding disorder.