Acquired Von Willebrand Syndrome Type Research Articles

Acquired von Willebrand syndrome (AVWS) type 2, characterized by decreased high molecular weight multimers, is common in children with severe pulmonary hypertension (PH).

Emerging evidence suggests that increased degradation of von Willebrand factor and decrease in high molecular weight multimers occurs in patients with pulmonary hypertension (PH). However, the link between acquired von Willebrand Syndrome (AVWS) type 2 and PH remains poorly understood. We retrospectively evaluated the charts of 20 children with PH who underwent bilateral lung transplantation (LuTx) between 2013 and 2022. Von Willebrand variables were determined in 14 of these patients; 11 patients had complete diagnostics including multimer analysis. We confirmed AVWS in 82% of the children studied (9 of 11 patients by multimer analysis). The two remaining patients had suspected AVWS type 2 because of a VWF:Ac/VWF:Ag ratio of <0.7. Platelet dysfunction or suspicion of VWD type 1 were found in two separate patients. All but one of the 14 children with severe PH had a coagulation disorder. Most patients (9 proven, 2 suspected) had AVWS type 2. Notably, 3 of 5 patients (60%) with normal VWF:Ac/VWF:Ag ratio >0.7 had abnormal VWF multimers, indicating AVWS type 2. Hemostatic complications were observed in 4 of 12 (33%) patients with VWS and 3 of 6 (50%) patients without diagnostics and therapy. For children with moderate to severe PH, we recommend systematic analysis of von Willebrand variables, including multimer analysis, PFA-100 and platelet function testing. Awareness of the diagnosis "AVWS" and adequate therapy may help to prevent these patients from bleeding complications in case of surgical interventions or trauma.

Treatment Algorithm for Patients With von Willebrand Syndrome Type 2A and Congenital Heart Disease-A Treatment Algorithm May Reduce Perioperative Blood Loss in Children With Congenital Heart Disease.

In children with congenital heart disease (CHD), excessive perioperative bleeding is associated with increased morbidity and mortality, thus making adequate perioperative hemostasis crucial. We investigate the prevalence of acquired von Willebrand syndrome type 2A (aVWS) in CHD and develop a treatment algorithm for patients with aVWS and CHD (TAPAC) to reduce perioperative blood loss. Retrospective cohort study. Single-center study. A total of 627 patients with CHD, undergoing corrective cardiac surgery between January 2008 and May 2017. The evaluation of perioperative bleeding risk was based on the laboratory parameters von Willebrand factor (VWF) antigen, ristocetin cofactor activity, platelet function analyzer (PFA) closure time adenosine diphosphate, and PFA epinephrine. According to the bleeding risk, treatment was performed with desmopressin or VWF. aVWS was confirmed in 63.3 %, with a prevalence of 45.5% in the moderate and 66.3 % in the high-risk group. In addition, prevalence increased with ascending peak velocity above the stenosis (v max ) from 40.0% at less than or equal to 3 m/s to 83.3% at greater than 5 m/s. TAPAC reduced mean blood loss by 36.3% in comparison with a historical control cohort ( p &lt; 0.001), without increasing the number of thrombotic or thromboembolic events during the hospital stay. With ascending v max , there was an increase in perioperative blood loss in the historical cohort ( p &lt; 0.001), which was not evident in the TAPAC cohort ( p = 0.230). The prevalence of aVWS in CHD seems to be higher than assumed and leads to significantly higher perioperative blood loss, especially at high v max . Identifying these patients through appropriate laboratory analytics and adequate treatment could reduce blood loss effectively.

Acquired Von Willebrand Syndrome (AVWS) Type 2A as the Presenting Feature of JAK2 Wild type Thrombocythemia in a Child: Effectiveness of Platelet Reduction by Anagrelide

A 9-year-old Caucasian boy presented in 1994 with severe headache, attacks of migraine, aggressive behavior and minor bleeding symptoms. Initial abnormal laboratory data were a platelet count of 1596 × 109/L and slight splenomegaly on echogram. Low-dose aspirin 100 mg/day relieved the cerebral symptoms, but a pronounced spontaneous bleeding tendency became evident. Severe epistaxis, bruises, hematomas and gum bleedings resulted in an iron deficiency state (hemoglobin 5.7 mmol/L,hematocrit 0.30, MCV 77 fl, ferritine 6 ug/l) in November 1995. The combination of mucocutaneous bleeding, high platelet counts (1946 × 109/L), and increase of enlarged megakaryocytes in a bone marrow smear was consistent with the diagnosis of hemorrhagic thrombocythemia. Coagulation studies revealed the presence of an acquired von Willebrand syndrome type 2A featured by a prolonged Ivy bleeding time, near normal factor VIII coagulant activity (0.53 u/ml) and von Willebrand factor (VWF) antigen (0.55 u/ml), low VWF ristocetine cofactor activity (0.29), very low VWF collagen binding activity (0.16 u/ml) and absence of large VWF multimers. A severe epistaxis lasting for several hours stopped immediately after correction of the VWF parameters by substitution of 3000 units Bone marrow histopathology showed a pronounced increase of large immature megakaryocytes with hyperlobulated nuclei and maturation defects of nuclei and cytoplasm, and absence of reticuline fibrosis consistent with the diagnosis of JAK2 wild type thrombocythemia in primary megakaryocytic granulocytic myeloproliferation (PMGM). Initial treatment with hydroxyurea (500 mg daily) followed by anagrelide resulted in correction of platelet count from 2000 × 109/L to near normal (400-600 × 109/L) by), which was associated with relief of bleeding symptoms, and correction of plasma VWF values and VWF multimeric pattern to normal. The subsequent natural history was featured by spontaneous reduction of platelet count to near normal and no progression of JAK2 wild type myeloproliferative neoplasms for more than 13 years follow-up.

Impairment of platelet retention rate in patients with severe aortic valve stenosis

BackgroundRecent reports revealed the presence of acquired von Willebrand syndrome type 2A in patients with aortic valve stenosis (AS). von Willebrand factor (vWF) has been shown to play a vital role in platelet adhesion. Therefore, we measured the platelet retention rates, which reflect platelet adhesion, in patients with severe AS. MethodsIn addition to echocardiography, routine blood screening tests were performed and the platelet retention rates were measured using collagen-coated bead columns in 21 patients with severe AS and in 21 control subjects. ResultsPatients with severe AS showed the maximum aortic valve pressure gradients of 110.9±22.7mmHg, and effective orifice areas of 0.59±0.20cm2. The results of routine blood tests in patients with severe AS were comparable to those of control subjects; however, the platelet retention rates in the AS patients (7.3±5.0%) were significantly lower than those in control subjects (30.5±11.8%, p<0.001). A significant negative correlation was observed between maximum aortic valve pressure gradients and platelet retention rates (r=−0.81, p<0.001). In 8 patients with severe AS, the platelet retention rates increased from 5.8±3.6% to 16.0±2.4% after aortic valve replacement (p<0.001). ConclusionThese findings suggest that impairment of platelet retention rate is seen in almost all patients with severe AS. Clinicians should be aware of the possibilities of vWF-mediated platelet dysfunction and bleeding tendency in patients with severe AS.

Acquired von Willebrand Syndrome Associated with Hypothyroidism: A Mild Bleeding Disorder to Be Further Investigated

Acquired von Willebrand syndrome (AVWS) is a rare bleeding disorder with laboratory findings similar to those for congenital von Willebrand disease (VWD). Unlike VWD, AVWS usually occurs in individuals with no personal or family history of bleeding. The prevalence of AVWS in the general population is unknown because data from large prospective studies of this syndrome are not available. Although AVWS is more frequently associated with lympho-myeloproliferative and cardiovascular disorders, it can also occur in solid tumors and in immunological and other miscellaneous conditions. Among these miscellaneous conditions, hypothyroidism has been associated with AVWS type 1 with a frequency of ~2 to 5%. In the 47 cases reported in the literature, the low VWF is apparently due to a reduction in its synthesis and/or secretion. Diagnosis of AVWS is based on assays measuring the level and activity of von Willebrand factor (VWF). These tend to be low, whereas factor VIII (FVIII) coagulant activity can be normal. In patients with AVWS associated with hypothyroidism, mucocutaneous bleeding episodes are the most frequent and can be managed with local therapy and/or systemic administrations of antifibrinolytic agents and desmopressin. VWF/FVIII concentrates have been used in only a few patients. The use of thyroid hormones can reverse this abnormality.

Acquired von Willebrand syndrome type 2A in a JAK2-positive essential thrombocythaemia -affected member of a large von Willebrand disease family with a novel autosomal dominant A1716P mutation

Acquired von Willebrand syndrome type 2A in a JAK2-positive essential thrombocythaemia-affected member of a large von Willebrand disease family with a novel autosomal dominant A1716P mutation -

Loss of high-molecular-weight von Willebrand factor multimers mainly affects platelet aggregation in patients with aortic stenosis

Severe aortic stenosis is associated with a haemostatic abnormality that resembles acquired von Willebrand syndrome type 2. It is assumed that high shear conditions render large von Willebrand factor (VWF) multimers accessible to cleavage by ADAMTS-13. However, whether loss of these large multimers affects platelet function by impairing adhesion, aggregate formation, or both has not been evaluated in clinical studies. We prospectively enrolled 47 patients with severe aortic stenosis, and studied them prior to aortic valve surgery and at a median of six months after valve replacement. We investigated levels of large VWF multimers, platelet function under high shear conditions, and residual response to suboptimal concentrations of ADP to express P-selectin. As expected, there was a significant reduction of VWF large multimers before surgery that resolved thereafter in most patients (p<0.0001). The closure time of the ADP cartridge of the PFA-100 was also corrected in most patients after the operation (p<0.0001). We used the cone and plate(let) analyser Impact-R to differentiate between adhesion and aggregation. Both adhesion (p=0.03) and ADP-inducible platelet aggregation (p=0.002) improved considerably after valve replacement. Consequently, ADP-inducible expression of P-selectin was higher after valve replacement (p=0.001). We conclude that reduced levels of large VWF multimers associated with aortic stenosis lead to impairment of both adhesion and, especially, ADP-inducible platelet aggregation.

Acquired von Willebrand syndrome after exchange of the HeartMate XVE to the HeartMate II ventricular assist device

Instead of pulsatile ventricular assist devices an increasing number of nonpulsatile ventricular assist devices are introduced to clinical practice. The different flow characteristics of this new technique lead to alteration in shear stress on blood components, which may affect the coagulation system. Repeated von Willebrand factor analyses were performed in a patient who first was implanted with a pulsatile ventricular assist device (Thoratec HeartMate XVE), which had to be replaced after 405 days with an axial flow device (HeartMate II). During support with the pulsatile ventricular assist device there was no sign of any coagulation disorder. However, on the axial flow device acquired von Willebrand syndrome Type 2 developed. Inhibition of platelet function was also observed, which may be in part due to the von Willebrand syndrome. The HeartMate II axial flow device may induce von Willebrand syndrome, which was not observed in HeartMate XVE pulsatile ventricular assist device. Patients put on continuous flow devices should be screened for acquired von Willebrand syndrome.

Immune-Mediated Etiology of Acquired von Willebrand Syndrome in Systemic Lupus Erythematosus and in Benign Monoclonal Gammopathy: Therapeutic Implications

The most common nonimmune etiology of acquired von Willebrand syndrome (AvWS) includes hypothyroidism, Wilms' tumor, thrombocythemia, or congenital heart defects, and the use of various drugs. AvWS type 1 in patients with hypothyroidism is due to decreased Willebrand factor (vWF) synthesis and is reversible by treatment with thyroxin. AvWS type 1 or 3 in children with Wilms' tumor disappears after successful chemotherapy or tumor resection but the mechanism of the vWF deficiency is unknown. The AvWS type 2 in patients with thrombocythemia of various myeloproliferative disorders is caused by increased proteolysis of large vWF multimers at increasing platelet counts to above 1000 x 10 (9)/L. Reduction of platelet counts to normal results in correction of the vWF parameters together with disappearance of the bleeding tendency. Type 2-like AvWS in children with congenital heart valve defects is caused by shear stress-induced proteolysis of large vWF multimers and is reversible after surgical correction. AvWS associated with the use of drugs disappears after discontinuation of the causative agent. Immune-mediated AvWS is associated with either systemic lupus erythematosus (SLE) or immunoglobulin G (IgG) benign monoclonal gammopathy (BMG), and usually shows a type 2 vWF deficiency. Using a simple enzyme-linked immunosorbent assay, an IgG antibody against vWF is detectable in AvWS associated with SLE and IgG BMG. The IgG-autoantibody-factor (F) vWF/VIII complex is rapidly cleared from the circulation, which explains the combined FVIII:coagulant activity (C) and vWF deficiency and the poor responses of FVIII:C and vWF parameters to intravenous desmopressin acetate and vWF/FVIII concentrates. A transient correction of both FVIII:C and vWF parameters to normal for a few weeks after high-dose intravenous immunoglobulin is seen in AvWS associated with SLE and IgG BMG. AvWS associated with SLE uniformly shows a curative response to corticosteroids. AvWS associated with IgG BMG does not respond to corticosteroids, immune suppression, or chemotherapy. AvWS associated with IgM BMG is rare and does not respond to any conventional treatment.

Disorders of hemostasis and excessive menstrual bleeding: prevalence and clinical impact

The prevalence and impact of most underlying disorders of hemostasis are reviewed in women with excessive menstrual bleeding. The most common underlying bleeding disorder is von Willebrand disease, which occurs in only 1% to 2% of the general population but in approximately 13% of women with excessive menstrual bleeding.

Acquired von Willebrand syndrome type IIA in a patient with aortic valve stenosis and myeloproliferative disorder

Acquired von Willebrand syndrome type IIA in a patient with aortic valve stenosis and myeloproliferative disorder

Acquired von Willebrand syndrome type 1 in hypothyroidism: reversal after treatment with thyroxine.

In 16 cases, acquired von Willebrand syndrome (AvWS) and hypothyroidism have been described that occur with each other: 15 women and one man, at a mean age of 32 years, range, 13 to 82 years of age. Activated partial thromboplastin time (APTT) was normal in six patients, and five patients had factor VIII concentration (factor VIIIc) levels in excess of 60%. The bleeding time was prolonged in nine of 13 evaluable patients. Activated partial thromboplastin time was prolonged in seven patients, and five of these had factor VIIIc levels between 18 and 45%, with two patients having levels in excess of 60%. A deficiency of other coagulation factors, including factor VII, V, IX, and X, caused by a generalized diminution in protein synthesis in hypothyroidism, may have contributed to the prolongation of the APTT. The AvWS was very likely type 1 in all cases because of a normal von Willebrand factor antigen/ristocetin cofactor (vWF Ag/RCF) ratio. Acquired von Willebrand syndrome was documented via cross immunoelectrophoresis in three patients and via multimeric analysis of vWF in six patients. A definite diagnosis of AvWS type I has to be confirmed by a normal response to 1-desamino-8-D-arginine vasopressin (DDAVP). Treatment of hypothyroidism with thyroxine was associated with the disappearance of the AvWS and the bleeding diathesis. Decreased factor VIIIc, vWF Ag and vWF RCF levels (50%, 33%, and 36% respectively) before thyroxine treatment increased to normal values (97%, 93%, and 107% respectively) after treatment. The absence of bleeding, or mild bleeding, symptoms, in relation to those more commonly recognized with hypothyroidism, has led to the complication of acquired vWF deficiency being underdiagnosed. Acquired von Willebrand syndrome type I should be considered whenever hypothyroidism is diagnosed and thyroid biopsy or surgery is contemplated. The complete relief of AvWS via treatment of hypothyroidism with thyroxine is the final proof of this association and causal relationship.