Acquired Von Willebrand Factor Deficiency Research Articles

Acquired Von Willebrand Factor Deficiency at Patient-Prosthesis Mismatch after AVR Procedure-A Narrative Review.

Acquired von Willebrand factor deficiency has been described in patients with aortic valve stenosis due to high shear forces developed during passage through the narrowed valve orifice, which determines structural changes in this molecule. Similar flow conditions are present in patients with an aortic prosthesis that presents a patient-prosthesis mismatch. Patient-prosthesis mismatch is described by the smaller effective orifice area of the prosthesis than the native valve, which would probably determine similar changes in the molecules of the von Willebrand factor, leading to acquiring von Willebrand deficiency.

Acquired Von Willebrand Deficiency in Adults With Aortic Stenosis: A Systematic Review.

Von Willebrand factor (VWF) deficiency is associated with bleeding complications. The congenital type of Von Willebrand disease(VWD) is a very well-known bleeding disorder and sometimes may be associated with life-threatening hemorrhage. This systematic review is aimed at gathering further knowledge regarding the pathology of an acquired VWD form within a population of patients with aortic stenosis (AS) by shortlisting quality articles on this theme, through the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) 2020 guidelines. High shear stress caused by the stenotic valve cleaves VWF multimers, causing a relative state of deficiency. The condition returns to baseline immediately following surgical replacement of the valve. Results across eight studies reviewed by a majority concluded that in an AS patient with bleeding, the most likely cause is an acquired deficiency of VWF, associated with factors influencing blood flow and caused by the in-situ valve. However, several studies suggested otherwise/were misclassifications. This review highlighted the relationship between AS and acquired VWF deficiency and should be foreseen as an adverse complication, attracting further research and future theragnostic strategies for this condition.

Seven Years of Ventricular Assist Device Support on Dabigatran

Introduction Currently, left ventricular assist device (LVAD) support mandates anticoagulation with coumarin derivatives such as warfarin and acenocoumarol as well as antiplatelet therapy with low-dose aspirin, for the prevention of thromboembolic events. Bleeding remains a major concern in LVAD recipients and is mainly attributed to the acquired von Willebrand factor deficiency exhibited in such patients. In addition, proper anticoagulation with vitamin K antagonists depend on targeted levels of international normalized ratio (INR) which can be influenced by several factors such as diet and liver function. Case Report A 64-year-old male patient underwent LVAD implantation as destination therapy 13 years ago due to end-stage heart failure caused by ischemic cardiomyopathy. The device used was the HeartMate II ventricular assist device. As per recommended guidelines, the patient was started on anticoagulation treatment using acenocoumarol and low-dose aspirin. The patient reports difficulty reaching therapeutic INR levels, necessitating very frequent coagulation blood tests. After six years on LVAD support, the patient presented to the emergency department with major intramuscular bleeding leading to compartment syndrome after a bicycle accident, necessitating transfusion of more than 2 units of packed red blood cells. His INR levels was within therapeutic range at the incident. The LVAD team then decided to change acenocoumarol to dabigatran exetilate, at the standard dose of 150mg bid as used in the prevention of thromboembolic disease in atrial fibrillation patients. Since then, after seven years of ventricular assist device support with dabigatran exetilate used for anticoagulation, the patient is still alive and has not had any bleeding or thromboembolic events. Summary The use of dabigatran exetilate as a second-line therapy in patients who have exhibited at least one major bleeding event on vitamin K antagonists seems intriguing.

Increased Intracranial Hemorrhage Amid Elevated Inflammatory Markers in Those With COVID-19 Supported With Extracorporeal Membrane Oxygenation.

COVID-19-related coagulopathy is a known complication of SARS-CoV-2 infection and can lead to intracranial hemorrhage (ICH), one of the most feared complications of extracorporeal membrane oxygenation (ECMO). We sought to evaluate the incidence and etiology of ICH in patients with COVID-19 requiring ECMO. Patients at two academic medical centers with COVID-19 who required venovenous-ECMO support for acute respiratory distress syndrome (ARDS) were evaluated retrospectively. During the study period, 33 patients required ECMO support; 16 (48.5%) were discharged alive, 13 died (39.4%), and 4 (12.1%) had ongoing care. Eleven patients had ICH (33.3%). All ICH events occurred in patients who received intravenous anticoagulation. The ICH group had higher C-reactive protein (P = 0.04), procalcitonin levels (P = 0.02), and IL-6 levels (P = 0.05), lower blood pH before and after ECMO (P < 0.01), and higher activated partial thromboplastin times throughout the hospital stay (P < 0.0001). ICH-free survival was lower in COVID-19 patients than in patients on ECMO for ARDS caused by other viruses (49% vs. 79%, P = 0.02). In conclusion, patients with COVID-19 can be successfully bridged to recovery using ECMO but may suffer higher rates of ICH compared to those with other viral respiratory infections.

P6. Abstract Title: Risks and Benefits of Antithrombotic Therapy in Polycythemia Vera: A Systematic Review

<h3>Background</h3> Thrombosis is the major cause of morbidity and mortality in patients with polycythemia vera (PV). Aspirin, and phlebotomy with or without cytoreductive therapy are key components of PV management to reduce thrombotic risk. However, patients with PV are also at risk for hemorrhagic complications, especially in the context of thrombocytosis and acquired Von Willebrand factor deficiency. The net benefit of antithrombotic therapy for primary and secondary thromboprophylaxis is uncertain. A systematic review conducted in 2013 identified 2 randomized control trials (RCTs) and concluded that low-dose aspirin does not increase the risk of major bleeding and is associated with a clinically but not statistically significant reduction in fatal thrombotic events. The risks and benefits of aspirin and other antithrombotics for primary and secondary thromboprophylaxis in PV remain uncertain. <h3>Objective</h3> To evaluate the benefits and harms of antithrombotic therapies in adult patients with PV. <h3>Methods</h3> MEDLINE, CENTRAL, and Pubmed were searched for relevant articles. Studies were included if they (i) were RCTs or observational studies, (ii) included adults (≥18 years of age) with PV, (iii) compared outcomes (thrombosis, bleeding or mortality) in patients receiving antithrombotic therapy versus control or no antithrombotic therapy, and (iv) were published in English. Case reports, abstracts, narrative reviews, and editorials were excluded. Screening, full text review, and data extraction were completed by two independent reviewers. The study protocol was developed according to PRISMA guidelines and registered on Prospero (PROSPERO 2017 CRD42017079688). Risk of bias was assessed using the Cochrane Risk of Bias Tool for RCTs and ROBINS-I Tool for observational studies. <h3>Results</h3> Out of 4523 studies identified, 12 studies (9 observational studies and 3 RCTs) were included in the analysis. Agreement by Cohen's kappa was excellent at the full text stage (0.89). Antithrombotics were associated with non-significant reductions in the risks of thrombosis (RR 0.83, CI 0.55 – 1.26, I2 72%) and all-cause mortality (RR 0.67, CI 0.44 – 1.01, I2 22%) and a non-significant increase in the risk of bleeding (RR 1.19, CI 0.87 – 1.63, I2 0%) compared to control/no antithrombotics. Most studies were judged to be at high risk of bias. There was insufficient data to conduct a subgroup analysis for heparin and the direct oral anticoagulants. <h3>Conclusion</h3> Our systematic review and meta-analysis is an updated comprehensive summary of available data regarding the benefits and harms of antithrombotic therapy in PV. In keeping with the findings of the previous meta-analysis, our results show non-significant reductions in thrombosis and death, and a non-significant increase in bleeding. However, this analysis is limited by heterogeneity and may be underpowered given the small sample sizes of included studies. Further, the included studies were at high risk of bias due to confounding. Prospective studies regarding anticoagulation in patients with PV are warranted.

HEYDE AND GO SEEK: SEARCHING FOR THE ASSOCIATION BETWEEN AORTIC STENOSIS AND GASTROINTESTINAL ANGIODYSPLASIA

The association between aortic stenosis and chronic gastrointestinal bleeding from angiodysplasia is known as Heyde syndrome, named after Edward Heyde who first described it in 1958. It is due to an acquired von Willebrand factor deficiency that results from shear stress on the blood caused by

Acquired von Willebrand factor deficiency is reduced in HeartMate 3 patients†.

The acquired von Willebrand syndrome (AvWS), which is associated with left ventricular assist device support, is caused by the loss of the von Willebrand factor (vWF) high molecular weight multimers (HMWMs). We investigated whether the implantation of the left ventricular assist device HeartMate 3 (HM 3) is superior to the HeartWare ventricular assist device (HVAD) in preserving the multimeric structure of vWF. In total, 70 patients with implanted HM 3 (n = 35) or HVAD (n = 35) were retrospectively investigated. HMWMs, intermediate molecular weight multimers and low molecular weight multimers were quantified by using a densitometric methodology. vWF antigen, vWF activity and vWF collagen-binding activity, as well as demographic and clinical data, were analysed. AvWS, which is characterized by a decrease in vWF HMWMs, was found in 97.1% of patients in the HM 3 group and 100% of patients in the HVAD group. Compared to normal pooled plasma, HM 3 induced a reduction in HMWMs (40.7 ± 8.2% vs 26.7 ± 7.5%, P < 0.01) and an increase in low molecular weight multimers (31.3 ± 11.8% vs 42.7 ± 9.8%, P < 0.01), whereas HVAD patients exhibited an increase in the percentage of intermediate molecular weight multimers (28.0 ± 5.0% vs 38.4 ± 7.7%, P < 0.01) in addition to a decrease in the percentage of HMWM (23.0 ± 11.0%, P < 0.01). A comparison of both left ventricular assist device types showed a difference in vWF multimeric structure (HMWMs: P < 0.01, intermediate molecular weight multimer: P = 0.05, low molecular weight multimer: P = 0.03). Furthermore, vWF activity was elevated in patients with an implanted HM 3 device (153.7 ± 54.4%) compared to those with an HVAD device (126.3 ± 39.7%, P = 0.02). Patients with an implanted HM 3 had more intact HMWMs and a higher vWF activity during device support. This may reduce the manifestation of AvWS in HM 3 patients and could thus lead to a lower bleeding complication rate.

Acquired Deficiency of Von Willebrand Factor (wWF) Associated with Intestinal Angiodysplasia

Acquired von Willebrand's Disease (AVWD) is a rare bleeding disorder that has been associated with angiodysplasia. We present a 79-year-old gentleman that presented with gradually progressive generalized weakness and easy fatigability with history of recurrent self-limiting epistaxis. He is known to have chronic lymphocytic leukemia (CLL), multiple myeloma and acquired Von Willebrand factor deficiency (Ristocetin cofactor of 25%) for which he received multiple chemotherapy cycles, last was two weeks before admission. Examination was evident of pallor with no signs of active epistaxis. Labs showed Hb of 4.8 g/dl, WBC of 8,400 and Platelets of 150,000. Ferritin was 4.64. He received 3 packed RBC's with improvement of his hemoglobin to 9.1 g/dl. Given inactive bleeding he was discharged for outpatient upper and lower endoscopy. Two weeks later he presented with same complain and was found to have Hb of 6.4. He denies any further epistaxis, neither hematemesis, melena or hematochezia. Colonoscopy was done showing diffuse diverticulosis and hyperplastic polyp. Enteroscopy was done showing bleeding angioectasia in the second portion of the duodenum. The bleeding site was coagulated multiple times using a heater probe set at 20J and resulted in cessation of the bleeding. Given the multiple coagulations further advancement of the enteroscope was deferred. Video capsule endoscopy was done with no further small bowel lesions. Hb stayed stable overnight and he was discharged with close clinic follow up Acquired von Willebrand syndrome (AVWS) is a rare and probably underestimated bleeding disorder which mimics most of the clinical symptoms and laboratory features of hereditary von Willebrand disease (VWD) in patients devoid of both personal and family history of bleeding diathesis. The diagnosis and treatment of recurrent GI bleeding in acquired VWD remains challenging and is associated with significant morbidity.1955_A Figure 1. Bleeding angiodysplasia in the second part of the duodenum1955_B Figure 2. Bleeding angiodysplasia in the second part of the duodenum1955_C Figure 3. Successful control of bleeding with coagulation using a heater probe

Gastrointestinal Bleeding Following LVAD Placement from Top to Bottom.

Left ventricular assist devices (LVADs) are an increasingly prevalent form of mechanical support for patients with end-stage heart failure. These devices can be implanted both as a bridge to transplant and as definitive/destination therapy. Gastrointestinal (GI) bleeding is one of the most common and recalcitrant long-term complications following LVAD implantation, with an incidence approaching 30%. This review will discuss what is known about the pathophysiology of GI bleeding in LVADs and the currently available options for medical and/or endoscopic management. The pathophysiology of bleeding is multifactorial, with hemodynamic alterations, acquired von Willebrand factor deficiency, and coagulopathy being most often implicated. The majority of bleeding events in this population result from angioectasias and gastroduodenal erosive disease. While these bleeding events are significant and often require transfusion therapy, they are rarely life threatening. Endoscopy remains the standard of care with upper endoscopy offering the highest diagnostic yield in these patients. However, the effectiveness of endoscopic hemostasis in this population is not well established. A small number of studies have evaluated medical therapy and alterations in LVAD settings as a means of preventing or treating bleeding with variable results. In summary, GI bleeding with LVADs is a common occurrence and will continue to be as more LVADs are being performed for destination therapy.

Acquired von Willebrand factor deficiency caused by LVAD is ADAMTS-13 and platelet dependent

IntroductionThe high shear rates induced by left ventricular assist devices cause acquired von Willebrand disease (aVWD). We hypothesised that an ex vivo model could be established to study whether mechanical shear stress alone causes aVWD or whether this process depends also on the VWF cleavage protein ADAMTS-13 and on platelets. Materials and methodsHealthy volunteers and two patients with congenital ADAMTS-13 deficiency donated blood. In vitro closed extracorporeal circuits were established using medically approved left ventricular assist devices (LVAD). VWF multimers were quantified by gel electrophoresis; VWF antigen, ristocetin cofactor activity (VWF:RCo), ADAMTS-13 levels and platelet function were assessed. ResultsThe high shear stress in the extracorporeal circulation rapidly decreased VWF:RCo and thereby the VWF:RCo/VWF:Ag ratio by 47% (p<0.01) to pathologically low values. Concomitantly, high molecular weight multimers (HMWM) decreased: up to 14–15 mers were visible on the gels at baseline, which were reduced by a maximum of 6–7 mers, corresponding to an average 68% lower densitometry signal of HMWM (p<0.001). This was accompanied by marked reduction of aggregation by various agonists (p<0.005). In contrast, the two patients with congenital thrombocytopenic purpura with virtually complete deficiency of ADAMTS-13 activity had only a minimal or no decrease in multimers (p<0.005 vs. healthy controls). Similarly, no or minimal depletion of large multimers occurred, when normal plasma circulated without platelets. ConclusionAn in vitro model for LVAD associated aVWD demonstrated that ADAMTS-13 and platelets contribute to the depletion of HMWM of VWF.

The association between aortic stenosis and intestinal angiodysplasia – the Heyde’s Syndrome (RCD code: VIII-1)

Heyde’s syndrome is defined as a combination of gastrointestinal bleeding from a gastrointestinal angiodysplasia in patients with aortic stenosis. An acquired von Willebrand factor deficiency secondary to aortic stenosis is considered to be the major abnormality in Heyde’s syndrome. Management of Heyde’s syndrome requires cooperation of many different kinds of specialists: cardiologists, gastroenterologists, hematologists, general surgeons and cardiosurgeon. We present a care report of 62 years old female with no history of cardiovascular disorders referred to the Centre of Rare Cardiovascular Diseases in Krakow for cardiological evaluation of a heart murmur prior to a surgical procedure of a vascular malformation in colon. JRCD 2014; 1 (7): 17–20

Acquired Von Willebrand Factor Deficiency Caused By Left Ventricular Assist Devices Is Adamts-13 Dependent

BackgroundThe high shear rates are induced by artificial heart valves or left ventricular assist devices cause acquired von Willebrand factor syndrome (aVWS). We hypothesised that an ex vivo model could be established to study whether mechanical shear alone causes aVWS or whether this process depends also on the VWF cleavage protein ADAMTS-13. MethodsHealthy volunteers and two patients with congenital ADAMTS-13 deficiency donated blood. In vitro extracorporeal circuits were established using medically approved left ventricular assist devices (Heartware®) and silicone tubings with blood inlets and outlets. The pump speed and circulating blood volume were adjusted to correspond to in vivo use in humans. Anticoagulated blood circulated for 1-4 hours in the extracorporeal circuits. VWF multimers were quantified by sodium dodecyl sulphate-agarose discontinuous gel (1.2%) electrophoresis followed by Western-Blotting and consequent quantification with a luminescence image analyzer and a commercially available software, VWF antigen was measured by an STA assay and ristocetin co-factor activity (VWF:RCo) was quantified by turbidometry using a commercial kit (BC von Willebrand reagent; Dade Behring/Siemens, Marburg, Germany). Platelet function was measured by multiple electrode aggregometry in whole blood. ResultsThe high shear stress in the extracorporeal circulation rapidly decreased VWF:RCo and thereby the VWF:RCo/VWF:Ag ratio by 47% (p<0.01) to pathologically low values. Concomitantly, high molecular weight multimers (HMWM) decreased, resembling the pathophysiological events that occur when an LVAD is implanted into humans. Up to 14-15 mers were visible on the gels at baseline, which were reduced by a maximum of 6-7 mers, corresponding to an average 68% lower densitometry signal of HMWM (p<0.01). This was accompanied by a 3-fold reduction in ristocetin induced aggregation (p<0.01). In contrast, the two patients with congenital thrombocytopenic purpura and virtually complete deficiency of ADAMTS-13 activity had only a minimal or no decrease in multimers (p<0.05 vs. healthy controls). ConclusionA model for LVAD associated aVWS was established, which demonstrated that ADAMTS-13 activity is essential for the depletion of HMWM of VWF that occurs in VAD-associated aVWS. Disclosures:No relevant conflicts of interest to declare.

RNA Sequencing Identifies Novel Genes That Could Modulate Bleeding Risk in Heart Failure Patients after LVAD Placement

Purpose The overall success of modern left ventricular assist devices (LVADs) has been mitigated by the complication of gastrointestinal (GI) bleeding. While evidence suggests that anticoagulation and acquired von Willebrand factor deficiency contribute, these two factors do not fully explain all bleeding events. Methods and Materials To identify new targets contributing to bleeding risk in patients with mechanical support we performed whole blood RNA sequencing on 9 patients before LVAD placement, then 7 days and 180 days postoperatively. A paired t-test and false discovery rate method were used to identify statistically significant changes in expression. Transcripts unique to patients with GI bleeding events were identified by comparing the transcriptome of those with GI bleeding (n = 3) to those without bleeding (n = 6) 7 days after LVAD placement. Results Bleeding events occurred between 12 and 202 days after LVAD implant (median 18 days). Glutaredoxin (GLRX) and glutaredoxin 2 (GLRX2) decreased in patients with bleeding 7 days after LVAD implant, but increased in those without bleeding events at 7 days (p = 0.0004 and p = 0.004, respectively). Furthermore, a family of RAB genes were differentially expressed in patients with bleeding compared to non-bleeders 7 days following LVAD implant. These genes include RAB18, RAB1A, RAB21, RAB11A, and RABEP1. Other genes of interest that were significantly and differentially expressed in bleeders versus non-bleeders included transmembrane protein 54 (TMEM54) and family with sequence similarity 26, member F (FAM26F). Conclusions We have identified novel genes that are differentially expressed in LVAD patients who develop GI bleeding. These findings provide an initial step towards uncovering mechanisms that may affect GI bleeding in patients with LVADs.

Sangramento gastrintestinal por angiodisplasia e estenose aórtica: síndrome de Heyde

There is a frequent association between aortic valve stenosis and gastrointestinal bleeding, also known as Heyde's syndrome. The pathophysiologic basis for this syndrome seems to be an acquired von Willebrand factor deficiency, leading to bleeding of angiodysplastic arteriovenous malformations. Treatment options include the location and cauterization of bleeding points, which is associated to high recurrence rates. Valve replacement appears to offer the best hope of long-term resolution of bleeding, and should be considered in most cases. We report a 79 year-old patient with aortic stenosis and gastrointestinal bleeding due to duodenal angiodysplasia treated by transcatheter aortic valve implantation.

Gastrointestinal Bleeding due to Angiodysplasia in a Patient with Severe Aortic Stenosis: Heyde’s Syndrome

There is a frequent association between aortic valve stenosis and gastrointestinal bleeding, also known as Heyde’s syndrome. The pathophysiologic basis for this syndrome seems to be an acquired von Willebrand factor deficiency, leading to bleeding of angiodysplastic arteriovenous malformations. Treatment options include the location and cauterization of bleeding points, which is associated to high recurrence rates. Valve replacement appears to offer the best hope of long-term resolution of bleeding, and should be considered in most cases. We report a 79 year-old patient with aortic stenosis and gastrointestinal bleeding due to duodenal angiodysplasia treated by transcatheter aortic valve implantation. Sangramento Gastrintestinal por Angiodisplasia e Estenose Aórtica: Síndrome de Heyde Existe uma associação frequente entre estenose valvar aórtica e sangramento gastrintestinal, também conhecida como síndrome de Heyde. A base fisiopatológica dessa síndrome parece ser uma deficiência adquirida do fator de von Willebrand, que leva ao sangramento de malformações arteriovenosas angiodisplásicas. As alternativas de tratamento incluem a localização de pontos de sangramento e a cauterização, mas tal opção terapêutica está associada a alta recorrência. A substituição da válvula parece oferecer a melhor esperança de resolução a longo prazo do sangramento e deve ser considerada na maioria das vezes. Relatamos aqui o caso de uma paciente de 79 anos com estenose aórtica e sangramento gastrintestinal devido à angiodisplasia duodenal, tratada por implante transcateter de válvula aórtica.

Aortic stenosis and angiodysplastic gastrointestinal bleeding: Heyde’s disease

Obscure gastrointestinal (GI) bleeding can be a perplexing and difficult problem in elderly patients, especially if they are hemodynamically unstable. If aortic stenosis is also present, the cause of the GI bleeding may be explained. We present a 66-year-old man with a medical history of coronary artery disease who presented with acute GI bleeding. During his hospital course, the patient had a colonoscopy showing diffuse angiodysplasia and an echocardiogram showing severe aortic stenosis. This combination of angiodysplasia and aortic stenosis is known as Heyde’s syndrome. It has been hypothesized that the aortic stenosis causes an acquired von Willebrand factor deficiency that leads to GI bleeding. Aortic valve replacement, when possible, can prevent recurrent GI bleeding in these cases, but medical decisions in these cases are complex and difficult.

Acquired factor VII deficiency associated with Wilms tumor

We present the case of a 2-year-old female with Wilms tumor whose initial evaluation revealed a prolonged prothrombin time (PT) and normal activated partial thromboplastin time. Mixing studies demonstrated correction of the PT and the Factor VII activity was 17% in the absence of a Factor VII inhibitor. She underwent successful resection of the tumor with fresh frozen plasma support and no excessive bleeding. Post-operative testing demonstrated normal PT at 3 days and 1-month. Although acquired von Willebrand factor deficiency has a known association with Wilms tumor, paraneoplastic factor VII deficiency associated with Wilms tumor is previously unreported.

Bleeding Risk in Patients with Essential Thrombocythemia and a Platelet Count of More Than 1.5 Million/μl: A Challenge of the Dogma of Mandatory Initiation of Cytoreductive Therapy.

Background: The most important limiting factors of patient survival in essential thrombocythemia (ET) are thromboembolic and hemorrhagic complications [1]. It has been postulated that the paradox of hemorrhagic events in a disease with highly elevated platelet counts is caused by an acquired von Willebrand Factor (vWF) deficiency syndrome which is found in ET patients with very high platelet counts [2]. Therefore, cytoreductive therapy is usually recommended by several international expert groups when platelets exceed 1,5 Million/μl.Aims: To critically examine the concept of cytoreductive therapy in high-platelet ET based upon the postulated increased bleeding risk.Methods: In a prospective study we observed 3 patients with a continously elevated platelet counts of more than 1.5 million/μl and secondary loss of large von Willebrand factor multimers, as shown in SDS electrophoresis, that did not receive cytoreductive therapy, but have been treated only with aspirin.Results: Patient 1 is a female which was 48 years at the time of diagnosis. She is negative for the JAK2V617F mutation and shows a secondary loss of large vWF multimers. We have now observed her for 7 years without any bleeding complications on aspirin therapy. During that period she has had more than 1.5 million platelets/μl for more than 46 months with a zenith of 2.27 million/μl. The second patient is a male who was 60 years old at the time of diagnosis. He is JAK2V617F negative and shows a relative decrease in large vWF multimers. He has been bleeding free since his diagnosis 6 years ago and had platelet levels of more than 1.5 million/μl for a cumulative period of more than 30 months. He has been treated only with aspirin. Patient 3 is a 59 year old male who has been diagnosed with ET 8 months ago. He is heterozygous positive for the JAK2V617F mutation. He also has a relative decrease in large multimers including a complete loss of the largest multimers. His platelet count has been elevated over 1.5 Million/μl (maximum: 2.18 Million) for a cumulative period of 6 months during which he has been treated only with aspirin. After that period he has been switched to anagrelide due to headaches. He has not shown any hemorrhagic complications except an increased bleeding tendency during shaving.Conclusion: Our observations challenge the recommendations by several groups to automatically initiate platelet reducing therapy above a platelet count of 1.5 million/μl. Acquired von Willebrand factor deficiency caused by ET does apparently not lead to hemorrhagic complications in all patients and therapy with aspirin should not be automatically excluded based on this dogma.

Platelet-mediated microvascular inflammation and thrombosis in thrombocythemia vera: a distinct aspirin-responsive arterial thrombophilia, which transforms into a bleeding diathesis at increasing platelet counts

Erythromelalgia is the main, pathognomonic and presenting symptom in patients with essential thrombocythemia and thrombocythemia associated with polycythemia vera. Complete relief from erythromelalgic and acrocyanotic pain is obtained with the cyclooxygenase inhibitors aspirin and indomethacin, but not with sodiumsalicylate, dipyridamol, sulfinpyrozone and ticlopedine. Thus, cyclooxygenase metabolites are necessary for erythromelalgia to develop. Local platelet consumption in erythromelalgic areas became evident by the demonstration of arteriolar fibromuscular intimal proliferation and occlusions by platelet-rich thrombi in skin biopsies, by the findings of shortened platelet survival times, significant higher levels of platelet activation markers β-thromboglobulin, thrombomoduline and increased urinary thromboxane B2 excretion in thrombocythemia patients suffering from erythromelalgia. Aspirin treatment of erythromelalgia in thrombocythemia patients resulted in the disappearance of the erythromelalgic, thrombotic signs and symptoms, correction of the shortened platelet survival times, and a significant reduction of the increased levels of β-TG, PF4, TM and urinary TxB2 excretion to normal. Erythromelalgia is frequently preceded or followed by atypical transient neurologic, ocular or coronary ischemic symptoms, which specifically respond to low-dose aspirin or reduction of platelet counts to normal. The broad spectrum of acropareshesias, erythromelalgia and acrocyanotic ischemia together with the episodic and transient atypical TIAs and ocular or coronary ischemic symptoms are caused by spontaneous activation and aggregation of hypersensitive platelets in the end-arterial microvasculature involving the peripheral, cerebral and coronary circulation of thrombocythemia patients. These microvacular circulation ischemic disturbances in thrombocythemia vera already occur at platelet counts in excess of 400 × 10 9 l –1. Low-dose aspirin is highly effective and safe in the cure and prevention of thrombotic and ischemic events and does not elicit bleedings at platelet counts below 1000 × 10 9 l –1. Spontaneous hemorrhages usually occur at very high platelet counts far in excess of 1000 × 10 9 l –1 (HT) due to an acquired von Willebrand factor deficiency at increasing platelet counts. At platelet counts between 1000 and 2000 × 10 9 l –1, thrombosis and bleeding (ETT and HT) frequently occur in sequence or paradoxically and low-dose aspirin does prevent thrombotic complications but aggravates or may elicit bleeding symptoms. Reduction of the platelet count to below 1000 × 10 9 l –1 by platelet lowering agents usually results in the disappearance of the bleeding tendency and improvement of the von Willebrand syndrome, but the thrombotic tendency persists as long as platelet counts are above the upper limit of normal.

Acquired von Willebrand factor deficiency during high-dose infusion of recombinant factor VIII.

Constant infusion of factor VIII (FVIII) into patients with haemophilia A after major surgery has been recommended as optimal treatment to avoid peaks and valleys in the circulating levels of FVIII and to allow the use of much lower doses of FVIII than are historically required. One of our young patients with severe (< 0.01 U/ml FVIII) haemophilia suffered a subdural haematoma for which he received treatment with 815190 recombinant FVIII (rFVIII) units over a period of 52d. 2 weeks after admission, because of low FVIII levels and the presence of FVIII inhibitors, the infusion rate was increased to > 100 U/kg/h for 14d. During this time the FVIII level fluctuated between 0.6 and 4.2 U/ml. For some period it was not possible to detect ristocetin co-factor activity in this patient's plasma and the von Willebrand factor (VWF) level and VWF multimer pattern resembled those of a patient with von Willebrand's disease. Subsequently, when the rFVIII dose was increased 2-fold, this was not reflected by the plasma level of FVIII although antibodies were not detected. The data suggest that the prolonged infusion of very high levels of rFVIII which is deficient in von Willebrand factor can result in depletion of VWF from existing stores, producing a laboratory picture which is consistent with the diagnosis of von Willebrand's disease. Further, in the absence of complexing with VWF, FVIII appears to be cleared from the circulation at an increased rate. This is expensive and potentially compromising. Therefore, when administering very high doses of FVIII concentrates devoid of VWF for prolonged periods of time, ristocetin cofactor and VWF levels should be monitored.