Acquired Type 2A Von Willebrand Research Articles

Heydeho syndróm

Gastrointestinal bleeding is a severe and potentially life-threatening condition associated with significant morbidity and mortality. In clinical practice, its differential dia­gnosis can sometimes be complicated, especially when bleeding is recurrent. One of the lesser-known reasons for recurrent gastrointestinal bleeding is the so called Heyde’s syndrome. It is a combination of bleeding from gastrointestinal angiodysplasia, aortic stenosis and acquired type 2A von Willebrand syndrome. In the submitted article, authors present a summary of the current knowledge on etiology and pathogenesis of the disease. The degenerative aortic valve disease, typically present in elderly patients, causes changes in the blood flow through stenotic opening. This results in elongation of otherwise globular von Willebrand’s factor (vWF) molecules, resulting in its reduced efficacy in hemostasis. According to new scientific discoveries, vWF also plays a role in angiogenesis and therefore in gastrointestinal angiodysplasia formation. This combination of factors results in recurrent bleeding typical for Heyde’s syndrome. Surgical aortic valve replacement is the gold standard treatment. A vicious circle can often be created between the gastroenterologist, who refers the patient for cardiac surgery procedures, and the cardiothoracic surgeon, who is waiting for a time when the patient will stop bleeding. A close communication and cooperation between the gastroenterologist, hematologist and cardiothoracic surgeon is required to properly manage the patient. The presence of angiodysplasia in an elderly patient, associated with recurrent gastrointestinal bleeding, should lead clinicians to look for aortic stenosis and consider Heyde’s syndrome as a potential dia­gnosis. Its interesting etiopathogenesis and rare occurrence led the authors to further investigate this topic. They also present a short summary of their own group of patients. Key words: Heyde’s syndrome – aortic stenosis – angiodysplasia – von Willebrand’s syndrome

The course of acquired von Willebrand syndrome during pregnancy among patients with essential thrombocytosis.

To investigate the course of acquired type 2A von Willebrand syndrome (AVWS) in relation to patient management and outcomes among pregnant patients with essential thrombocytosis (ET). A review of pregnant women with ET evaluated for AVWS at the beginning of pregnancy and at the third trimester. Eighteen women with 24 pregnancies were included in this study. A history of bleeding was noted in 8 (44%) patients. In 20 (83%) pregnancies AVWS was evident at the initial testing. Following initial testing, antithrombotic therapy was administered in 22 (92%) pregnancies (aspirin, n = 20 and low-molecular-weight heparin, n = 2). In the remaining two pregnancies, VWF:RCo levels were below 30%; thus, aspirin was given only after repeat testing at 14-16weeks. At third trimester testing, median VWF:RCo levels were significantly higher than at the initial testing (86 vs. 48%, P < 0.001), with no evidence of AVWS in any of the patients. Significant increases were also observed in the VWF:Ag level (127 vs. 84%, P < 0.001), the VWF:RCo/VWF:Ag ratio (0.75 vs. 0.54, P < 0.001) and the FVIII level (103 vs. 68%, P < 0.001); while platelet count (359 vs. 701 × 109/l, P < 0.001) and hemoglobin level (11.6 vs. 13.4g/dl, P < 0.001) decreased. Neuraxial anesthesia was safely performed in 17 (71%) pregnancies. No significant bleeding events occurred during pregnancy and delivery. AVWS-related abnormalities in women with ET mostly improved during pregnancy, with favorable maternal and fetal outcomes. VWF parameters should be tested at early pregnancy and repeated at the third trimester, to guide pregnancy and delivery management.

Angiodysplastic Lesions in the Gastrointestinal Tract of Heart Failure Patients Predates Post LVAD Bleeding

Gastrointestinal (GI) bleeding, primarily manifesting as angiodsyplasia (AGD) is one of the most common and challenging complications post CF LVAD. The possible mechanisms underlying LVAD induced AGD formation are the subject of intense research efforts and have focused on an association with low or absent pulsatility and acquired type 2A von Willebrand factor deficiency (vWD). We have previously reported a high prevalence of nasal mucosal vascular malformations, a possible surrogate marker for AGD, in patients with heart failure (HF) prior to LVAD implant. We have now extended our investigation to directly study the prevalence of GI AGD in HF patients prior to LVAD implant.

Life-threatening subdural hematoma after aortic valve replacement in a patient with Heyde syndrome: a case report

BackgroundHeyde syndrome is known as a triad of calcific aortic stenosis, anemia due to gastrointestinal bleeding from angiodysplasia, and acquired type 2A von Willebrand disease. This acquired hemorrhagic disorder is characterized by the loss of the large von Willebrand factor multimers due to the shear stress across the diseased aortic valve. The most frequently observed type of bleeding in these patients is mucosal or skin bleeding, such as epistaxis, followed by gastrointestinal bleeding. On the other hand, intracranial hemorrhage complicating Heyde syndrome is extremely rare.Case presentationA 77-year-old woman presented to our hospital with severe aortic stenosis and severe anemia due to gastrointestinal bleeding and was diagnosed with Heyde syndrome. Although aortic valve replacement was performed without recurrent gastrointestinal bleeding, postoperative life-threatening acute subdural hematoma occurred with a marked midline shift. Despite prompt surgical evacuation of the hematoma, she did not recover consciousness and she died 1 month after the operation.ConclusionsPostoperative subdural hematoma is rare, but it should be kept in mind as a devastating hemorrhagic complication, especially in patients with Heyde syndrome.

Valvular Heart Disease and Acquired Type 2A von Willebrand Syndrome: The "Hemostatic" Waring Blender Syndrome.

Few have witnessed the so-called Waring blender syndrome. This hemolysis of red blood cells, sometimes lifethreatening, typically occurs in the setting of a dysfunctional prosthetic heart valve. 1 Biomedical engineering and surgical advances have largely reduced this syndrome to textbooks. Unlike this exceedingly rare syndrome, acquired type 2A von Willebrand syndrome is a relatively common and typically unrecognized life-threatening condition with a similar etiology. 2 Acquired type 2A von Willebrand syndrome also arises from blood flow exposed to abnormally increased shear stress. Blackshear and colleagues 3 convincingly extend the recognition of acquired von Willebrand syndrome to dysfunctional prosthetic valves. They and others have previously described this phenomenon and confirmed its mechanism in native valve diseases, abnormal vascular structures, congenital heart lesions, and therapy with left ventricular assist devices. Advances in the last decade only now permit a detailed mechanistic understanding of this syndrome. While diagnostic and treatment criteria remain to be rigorously defined, pathophysiologic knowledge will help guide clinical recognition and management.

Effects of Transcutaneous Aortic Valve Implantation on Aortic Valve Disease-Related Hemostatic Disorders Involving von Willebrand Factor

BackgroundAortic valve stenosis (AVS) can be complicated by bleeding associated with acquired type 2A von Willebrand syndrome. The association of AVS and gastrointestinal bleeding from angiodysplasia is defined as Heyde syndrome. We sought to evaluate the effect of transcutaneous aortic valve implantation (TAVI) on hemostasis disorders and to assess its effectiveness to treat Heyde syndrome. MethodsWe prospectively enrolled 49 consecutive patients with severe AVS addressed for TAVI at our institution. Biological hemostasis parameters involving von Willebrand factor (vWF) were assessed at baseline and 1 week after the procedure. ResultsAt baseline, a significant link between vWF abnormalities and the severity of AVS was evidenced: mean aortic transvalvular gradient was negatively correlated with the levels of vWF antigen (vWF:Ag) (r = −0.29; P < 0.05), vWF ristocetin cofactor activity (r = −0.402; P = 0.006), and vWF collagen-binding activity (vWF:CB; r = −0.441; P = 0.005). One week after the procedure, a significant increase of vWF:Ag, vWF ristocetin cofactor activity, and vWF:CB was evidenced in the whole cohort (respectively, 3.32 vs 2.29 IU/mL, P < 0.001; 2.98 vs 1.86 IU/mL, P < 0.001; and 3.16 vs 2.16 IU/mL, P < 0.001). Patients with pre-TAVI vWF abnormalities consistent with a type 2A vWF syndrome (ratio vWF:CB/vWF:Ag < 0.7) preferentially improved their vWF function with respect to patients with a normal ratio (relative increase of vWF:CB of 63.8% vs 3.5%). ConclusionsHemostasis parameters involving vWF are improved after TAVI, especially in patients with pre-existing abnormalities consistent with acquired type 2A von Willebrand syndrome.

0353: Impact of TAVI on primary hemostasis, von Willebrand factor and Heyde’s syndrome: a prospective monocenter study

Aortic valve stenosis (AVS) can be complicated by bleeding associated with acquired type 2A von Willebrand syndrome. The association of AVS and gastrointestinal bleeding from angiodysplasia is defined as Heyde’s syndrome. We sought to evaluate the impact of TAVI on primary hemostasis disorders and to assess its effectiveness to treat Heyde’s syndrome. We prospectively enrolled 49 consecutive patients with severe AVS referred to our institution for TAVI. Biological primary hemostasis parameters were assessed at baseline and one week after the procedure. At baseline, a significant link between vWF abnormalities and the severity of AVS was evidenced: mean aortic transvalvular gradient was negatively correlated with the levels of vWF antigen (vWF: Ag) (r=–0.29, p<0.05), vWF ristocetin cofactor activity (vWF:RCo) (r=–0.402, p=0.006) and vWF collagen-binding activity (vWF:CB) (r=–0.441, p=0.005). One week after the procedure, a significant increase of vWF:Ag, vWF:RCo, and vWF:CB was evidenced in the whole cohort (respectively 3.32 vs 2.29 IU/mL, p<0.001; 2.98 vs 1.86 IU/mL, p<0.001; 3.16 vs 2.16 IU/mL, p<0.001). Patients with pre-TAVI vWF abnormalities consistent with a type 2A vWF syndrome (ratio vWF:CB/ vWF:Ag <0.7) preferentially improved their vWF function with respect to patients with a normal ratio (relative increase of vWF:CB of 63.8% vs 3.5%). Primary hemostasis parameters involving vWF are improved after TAVI, especially in patients with preexisting abnormalities consistent with acquired type 2A von Willebrand syndrome. Moreover, our observations, although limited to a small single-center study, suggest that Heyde’s syndrome can be cured by TAVI.

TCT-765 Impact Of TAVI On Primary Hemostasis, Von Willebrand Factor And Heyde’s Syndrome: A Prospective Monocenter Study

Aortic valve stenosis (AVS) can be complicated by bleeding associated with acquired type 2A von Willebrand syndrome. The association of AVS and gastrointestinal bleeding from angiodysplasia is defined as Heyde's syndrome. We sought to evaluate the impact of TAVI on primary hemostasis disorders and

Acquired type 2A von Willebrand syndrome caused by aortic valve disease corrects during valve surgery

Aortic valve (AV) defects can destroy high molecular weight multimers (HMWM) of von Willebrand factor (VWF), leading to acquired von Willebrand syndrome (aVWS) type IIA. This syndrome is considered a cause for increased perioperative bleeding in AV surgery. If diagnosed before operation, administration of VWF/FVIII concentrates is recommended. However, there is currently no evidence that the VWF HMWM defect persists during surgery long enough to require haemostatic therapy. We hypothesized that the preoperative VWF HMWM defect corrects already during cardiopulmonary bypass (CPB) before any haemostatic therapy. This prospective observational study enrolled 17 patients undergoing AV surgery, either isolated or associated with mitral valve or aorta surgery, and also 10 patients undergoing coronary artery bypass surgery (CABG) for comparison. VWF HMWM, VWF antigen (VWF:Ag) concentration, and collagen-binding capacity (VWF:CB) were measured before operation, directly after weaning from CPB, and on the first postoperative day. In 12 of the 17 subjects undergoing AV surgery (71%), VWF HMWM were abnormally absent before operation. At the end of CPB, VWF HMWM were normal in 15 of AV subjects (88%), and was normal in 16 subjects on the first postoperative day. VWF:Ag and VWF:CB were within or above the normal range at all three times. Two out of 10 subjects undergoing CABG (20%) had preoperative deficits of VWF HMWM that normalized after operation. Preoperative VWF HMWM defects corrected at the end of CPB in the absence of haemostatic therapy in most patients undergoing AV surgery. Diffuse bleeding occurring after CPB is unlikely to be related to persisting type 2A von Willebrand syndrome; other causes of coagulopathy should be suspected. Administration of VWF/FVIII concentrates appears unnecessary in this setting.

No excess surgical blood loss in patients with acquired type 2A von Willebrand disease

Objectives. Acquired type 2A von Willebrand disease may develop as a consequence of aortic valve stenosis and is associated with varying degrees of bleeding tendency. It remains unknown, whether it portends excess blood loss during aortic valve replacement. Design. We consecutively enrolled 45 patients with severe aortic valve stenosis undergoing aortic valve replacement. Patients with acquired type 2A von Willebrand disease were identified measuring the von Willebrand factor high molecular weight multimer. Data on the intraoperative, early postoperative, and the total blood loss within 24 hours of surgery was obtained and compared between groups. Results. Acquired type 2A von Willebrand disease was found in 33% (n = 15/45) of the patients. Baseline characteristics were similar between groups. Patients with acquired type 2A von Willebrand disease neither had excess median intraoperative blood loss (375 ml (interquartile range 100–450 ml) vs. 350 ml (interquartile range 250–500 ml), p = 0.59) nor increased median total blood loss (695 ml (interquartile range 450–850 ml) vs. 752 ml (interquartile range 575–1035 ml), p = 0.41) as compared to patients without acquired type 2A von Willebrand disease. Conclusion. Acquired type 2A von Willebrand disease was not associated with increased blood loss during aortic valve replacement in patients with severe aortic valve stenosis.

Report of a Case of Heyde's Syndrome Diagnosed by Abnormal Closure Times Despite Normal Von Willebrand's Activity

AbstractAbstract 1403In 1958, EC Heyde described a syndrome of iron deficiency anemia due to gastrointestinal bleeding (GI) in a patient with calcific aortic stenosis. In 1992, Warkentin et al. hypothesized a bleeding diathesis due to a link between Heyde's Syndrome and acquired Von Willebrand Syndrome. This bleeding syndrome has now been shown to result from the loss of the largest multimers of von Willebrand Factor (VWF) and is therefore classified as acquired Type 2A Von Willebrand Syndrome. Hypotheses suggest that the high shear stresses that are obtained in tortuous angiodysplastic lesions work with this deficiency of VWF, to produce gastrointestinal bleeding that is notoriously difficult to elucidate on endoscopy. It has been shown repeatedly that replacement of a stenotic aortic valve results in cessation of bleeding. Here we present a case of Heyde's Syndrome diagnosed with abnormal Closure Times and normal VWF Ristocetin cofactor activity. In this case, a 79-year-old man with known aortic stenosis and several episodes of GI bleeding was cured of a life threatening hemorrhage after the replacement of his stenotic aortic valve. At the time of his first notable gastrointestinal bleed, a tagged RBC scan showed a source of hemorrhage in the small bowel. Subsequently, two video capsule endoscopies showed jejunal angiodysplasia. After recurrent bleeding episodes, this patient presented with a life-threatening GI hemorrhage, which, in the context of aortic stenosis, raised the suspicion for Heyde's Syndrome. At this time, he presented with hematochezia requiring massive transfusions, and admission to the Intensive Care Unit. A tagged RBC scan showed active bleeding in a location that matched previous scans. The following tests were within normal limits: Factor VIII (1.53), VWF Ag (1.26), VWF:Rco activity (1.11), and the ratio of VWF Ag/VWF:Rco (0.88). However, the Dade Behring PFA-100 platelet function analyzer demonstrated that Closure Times with collagen/adenosine (> 300 sec) and with collagen/epinephrine (> 300 sec) were prolonged. In the clinical context consistent with Heyde's Syndrome, the patient's native aortic valve was replaced with a 21mm Carpentier-Edwards Magna Ease Bovine valve. As is classic for this syndrome, the valve replacement was curative. Since the surgery, the patient has not required further transfusions or interventions for gastrointestinal hemorrhage. In this case, our observations are consistent with previous reports by Warkentin et al. and Vincentellli et al. What is unique about our current report is that we measured both Ristocetin cofactor activity and Closure Times, two commonly available assays in most coagulation laboratories. Ristocetin cofactor activity is the current gold standard for measuring platelet function activity but may miss activities under high shear stress. The Closure Time, on the other hand, is able to detect defects in platelet aggregation under such conditions and may be the only manner by which such abnormalities in VWF function are detected. Therefore, we conclude that Closure Times should be used to screen for acquired Von Willebrand's Syndrome in Heyde's Syndrome. Disclosures:No relevant conflicts of interest to declare.

Occult Gastrointestinal Bleeding due to Acquired von Willebrand Syndrome in a Patient with Hypertrophic Obstructive Cardiomyopathy

A 69-year-old woman presented with a harsh systolic murmur and severe anemia. Echocardiography demonstrated hypertrophic obstructive cardiomyopathy with a peak pressure gradient of 154 mmHg. Endoscopic examinations disclosed an angiodysplasia and multiple diverticula in the colon, but no active bleeding was noted in these lesions. A selective defect of large multimers of von Willebrand factor was detected by electrophoresis. After collection of anemia and Ca antagonist therapy, left ventricular obstruction was relieved and cessation of the occult gastrointestinal bleeding was obtained. This is the first report whereby acquired type 2A von Willebrand syndrome was caused by hypertrophic obstructive cardiomyopathy.

Successful Aortic Valve Replacement for Heyde Syndrome With Confirmed Hematologic Recovery

Aortic valve stenosis can be complicated by recurrent gastrointestinal bleeding, particularly that due to angiodysplasia, also called Heyde syndrome. Recently, acquired type 2A von Willebrand disease, which is characterized by the loss of the large multimer of von Willebrand factor by the shear stress of aortic valve stenosis, was reported to be associated with this hemorrhagic syndrome. A 78-year-old woman, with severe aortic stenosis, presented with advanced anemia due to recurrent gastrointestinal bleeding and was diagnosed Heyde syndrome. By perioperative supplementation of von Willebrand factor and factor VIII, aortic valve replacement was safely performed without gastrointestinal bleeding. After the operation, the multimer of von Willebrand factor was normalized and thereafter no gastrointestinal bleeding occurred. This case reports the successful aortic valve replacement for Heyde syndrome, with confirmed hematologic recovery.

Acquired von Willebrand syndrome in aortic stenosis.

Aortic-valve stenosis can be complicated by bleeding that is associated with acquired type 2A von Willebrand syndrome. However, the prevalence and cause of the hemostatic abnormality in aortic stenosis are unknown. We enrolled 50 consecutive patients with aortic stenosis, who completed a standardized screening questionnaire to detect a history of bleeding. Forty-two patients with severe aortic stenosis underwent valve replacement. Platelet function under conditions of high shear stress, von Willebrand factor collagen-binding activity and antigen levels, and the multimeric structure of von Willebrand factor were assessed at base line and one day, seven days, and six months postoperatively. Skin or mucosal bleeding occurred in 21 percent of the patients with severe aortic stenosis. Platelet-function abnormalities under conditions of high shear stress, decreased von Willebrand factor collagen-binding activity and the loss of the largest multimers, or a combination of these was present in 67 to 92 percent of patients with severe aortic stenosis and correlated significantly with the severity of valve stenosis. Primary hemostatic abnormalities were completely corrected on the first day after surgery but tended to recur at six months, especially when there was a mismatch between patient and prosthesis (with an effective orifice area of less than 0.8 cm2 per square meter of body-surface area). Type 2A von Willebrand syndrome is common in patients with severe aortic stenosis. Von Willebrand factor abnormalities are directly related to the severity of aortic stenosis and are improved by valve replacement in the absence of mismatch between patient and prosthesis.