Acalculous Ischemic Cholecystitis Caused by Spontaneous Celiac Artery Dissection

We herein report a case of spontaneous isolated dissection of the celiac artery. A Japanese man in his 50s visited an emergency unit, complaining of sudden epigastralgia. Contrast-enhanced computed tomography indicated dissection of the celiac artery with patent false and true lumina, extending to the splenic and common hepatic arteries. On day 3 of hospitalization, the dissection progressed to the proper and right hepatic arteries. Progression of the dissection to the right hepatic artery provoked acalculous ischemic cholecystitis, and cholecystectomy followed. The resected gallbladder revealed extensive aseptic necrosis with little inflammatory reaction, and the gallbladder neck was spared from ischemia.     

Optimizing therapy with factor VIII/von Willebrand factor concentrates in von Willebrand disease

In von Willebrand disease, the main goals of treatment are to correct the dual defect of haemostasis caused by a reduced or abnormal von Willebrand factor (vWF), i.e. the prolonged bleeding time (BT) and the deficiency of factor VIII coagulant activity (FVIII:C). The synthetic vasopressin analogue, desmopressin (DDAVP), has reduced the need for transfusions in most of the mild forms of von Willebrand disease but DDAVP is ineffective in type 3 and in other severe cases of types 1 and 2 von Willebrand disease. For many years cryoprecipitate has been the mainstay of replacement therapy but, after the introduction of virucidal methods, concentrates containing FVIII/vWF have been considered much safer than cryoprecipitate and proposed in von Willebrand disease management. FVIII/vWF concentrates have been produced and tested by many authors but there is only one report describing four virus-inactivated FVIII/vWF concentrates evaluated in a cross-over randomized trial. According to these in vitro and pharmacokinetic data, the following information can be derived: (a) no FVIII/vWF concentrate had an intact multimeric structure similar to that of normal plasma or of cryoprecipitate; (b) all FVIII/vWF concentrates were equally effective in attaining normal and sustained levels of FVIII:C postinfusion, although peak levels were more delayed in the concentrate devoid of FVIII:C; (c) no FVIII/vWF concentrate consistently normalized the BT in a sustained fashion. On the other hand, clinical haemostasis can be achieved in the management of bleeding episodes and of surgery for most of von Willebrand disease cases regardless of whether the BT is corrected; in the few rare cases with mucosal bleeding not controlled by FVIII/vWF concentrates, infusion of DDAVP or platelet concentrates can be administered in addition.     

von Willebrand因子与稳定冠心病

早期大量研究揭示了von Willebrand因子的生物学特点、结构和功能,近期研究发现von Willebrand因子可能在稳定冠心病发病、剪切力机制诱导血小板聚集、血栓形成,以及药物和介入治疗(包括支架置入等)方面有重要作用。     

von Willebrand disease type IIC with different abnormalities of von Willebrand factor in the same sibship

A family with von Willebrand disease has been identified in which different members of the same sibship exhibit different abnormalities of von Willebrand factor (vWF). The two most severely affected sibs (bleeding time over 20 min) had abnormalities of vWF similar to those seen in type IIC. The smallest detectable multimer was increased and the triplet structure of individual multimers was replaced with a single band. The largest multimers could not be detected and there were relatively more small multimers than intermediate sized forms. vWF antigen (vWF:Ag) was decreased to 12.5-17% by electroimmunoassay (EIA) and to 3.2-5.5% by immunoradiometric assay (IRMA). In the less severely affected sibling (bleeding time 12.5 min) there was a similar relative increase in the smallest detectable multimer. However, the larger multimers were present and the relative concentration of large to small multimers was similar to normal. The triplet structure was altered in that the relative proportion of satellite bands to the central predominant band was decreased. vWF:Ag concentrations were moderately decreased (40-80% by EIA and 25-35% by IRMA). The father and grandfather showed a vWF multimeric pattern similar to the less severely affected sibling but there was no decrease in vWF:Ag concentration and their bleeding times were normal. These observations suggest that the interplay of several genetic factors is responsible for the expression of von Willebrand disease in this family.     

Acquired von Willebrand disease in a patient with angiodysplasia resulting from immune-mediated clearance of von Willebrand factor

A patient with a severe bleeding tendency due to acquired von Willebrand disease (VWD) is presented. Although no underlying disorder has emerged during 6 years of follow-up, an immune-mediated mechanism was responsible for acquired VWD in this patient as demonstrated by detection of von Willebrand factor (VWF)/anti-VWF complexes in the patient's plasma and their removal by protein A–sepharose beads and resumption of normal haemostasis with correction of VWF antigen, VWF activity and VWF multimeric pattern after treatment of the patient with high-dose gammaglobulin. Detection of anti-VWF antibodies in the patient's plasma had a significant impact on the choice of therapeutic intervention to control bleeding.     

Spontaneous intramural duodenal hematoma in type 2B von Willebrand disease

Intramural duodenal hematoma is a rare cause of a proximal gastrointestinal tract obstruction.Presentation of intramural duodenal hematoma most often occurs following blunt abdominal trauma in children,but spontaneous non-traumatic cases have been linked to anticoagulant therapy,pancreatitis,malignancy,vasculitis and endoscopy.We report an unusual case of spontaneous intramural duodenal hematoma presenting as an intestinal obstruction associated with acute pancreatitis in a patient with established von Willebrand disease,type 2B.The patient presented with abrupt onset of abdominal pain,nausea,and vomiting.Computed tomography imaging identified an intramural duodenal mass consistent with blood measuring 4.7 cm×8.7 cm in the second portion of the duodenum abutting on the head of the pancreas.Serum lipase was 3828 units/L.Patient was managed conservatively with bowel rest,continuous nasogastric decompression,total parenteral nutrition,recombinant factorⅧ(humateP)and transfusion.Symptoms resolved over the course of the hospitalization.This case highlights an important complication of an inherited coagulopathy.     

Von Willebrand factor testing ratios in the diagnosis and subtyping of von Willebrand disease

Von Willebrand disease (VWD) is a common bleeding disorder of platelet adhesion with six currently recognized subtypes. Laboratory diagnosis consists of an initial test panel including antigen, activity and factor VIII measurements, sometimes followed by further specialized testing. VWF activity/antigen testing ratios help to differentiate type 1 and type 2 disease, which is important for selection of proper therapy. Recommended ratio cutoffs differ by guideline, ranging from 0.5 to 0.7, with 0.7 commonly recommended. The ratio cutoff used affects the sensitivity and specificity for type 2 diagnosis. Variability in VWD due to underlying mutations and patient factors, as well as variability in VWF tests, impact the accuracy of ratios for VWD subtyping. This review discusses the use of activity/antigen ratios in the diagnosis and subtyping of VWD with a focus on technical aspects of the tests.     

Studies of multimerin in patients with von Willebrand disease and platelet von Willebrand factor deficiency

In normal platelet α-granules von Willebrand factor (VWF) is stored with multimerin and factor V in an eccentric electron-lucent zone. Because the platelet stores of VWF are deficient in 'platelet low' type 1 and type 3 von Willebrand disease (VWD), we investigated their electron-lucent zone proteins. The patients with VWD had partial to complete deficiencies of plasma and platelet VWF but normal α-granular multimerin and factor V, and normal α-granular fibrinogen, thrombospondin-1, fibronectin, osteonectin and P-selectin. In type 3 VWD platelets, α-granular electron-lucent zones lacking VWF-associated tubules were identified and multimerin was found in its normal α-granular location. These findings indicate that the formation of the electron-lucent zone and the sorting of multimerin to this region occur independent of VWF. The isolated abnormalities in VWF suggests a VWF gene mutation is the cause of 'platelet low' type 1 VWD.     

Wilate use in 47 children with von Willebrand disease: the North London paediatric haemophilia network experience

Children with von Willebrand disease (VWD) in whom DDAVP is ineffective or contraindicated require treatment with a coagulation factor concentrate containing von Willebrand factor (VWF) and factor VIII (FVIII). The aim of this study was to monitor the safety, efficacy and tolerability of Wilate^® (a VWF:FVIII concentrate with a 1:1 ratio) used across the North London Paediatric Haemophilia Network since May 2010. In total, 47 children (aged 0.0–17.0 years) with type 1 (n = 28), type 2 (n = 7), type 3 (n = 10) and acquired VWS (n = 2) have been treated for bleeds, surgery and/or prophylaxis using 260 000 IU Wilate^®. Analysis of dose and frequency of treatment show expected responses to treatment with mean doses of 55, 50 and 50 IU kg^?1 for bleeds, surgery and prophylaxis respectively. Most bleeds responded to a single treatment. Surgical procedures were covered with clinician approved dosing schedules with 95% (39/41) reported as having excellent or good efficacy. There was no accumulation of FVIII or VWF and no thromboembolic events. This case series confirms the efficacy, safety and tolerability of Wilate^® in neonates, children and adolescents when used on‐demand, prophylactically and in the surgical setting.     

血管性血友病因子在心血管疾病中的研究进展

血管性血友病因子是一类主要由内皮细胞分泌的多聚糖蛋白,通过激活血小板,参与血栓形成。它与一系列心血管疾病如动脉粥样硬化、急性冠状动脉综合征、心房颤动等均关系密切,特异性抑制血管性血友病因子的新型抗血小板药物研发有望突破。     

Life-threatening reaction to factor VIII concentrate in a patient with severe von Willebrand disease and alloantibodies to von Willebrand factor

A 16-yr-old girl with severe von Willebrand disease complicated by the development of precipitating alloantibodies to von Willebrand factor (anti-VWF) had a life-threatening anaphylactoid reaction immediately after the infusion of a commercial plasma concentrate of factor VIII/von Willebrand factor. An early post-infusion activation of the complement system was demonstrated by the appearance of C3 split products and by the drop of serum CH50 activity, occurring in parallel with a post-infusion drop in the anti-VWF antibody levels. Immune complexes remained unchanged in the early post-infusion period and rose to a moderate extent only after 24 h. We conclude that biologically active products of the complement system contributed to the onset of this life-threatening reaction which occurred after concentrate infusion.     

Clinical efficacy of highly purified, doubly virus-inactivated factor VIII/von Willebrand factor concentrate (Fanhdi®) in the treatment of von Willebrand disease: a retrospective clinical study

The goal of therapy in patients with von Willebrand disease (vWD) is to correct the dual defect of primary haemostasis and intrinsic coagulation reflected by low levels of von Willebrand factor (vWF) and factor VIII coagulant activity (FVIII:C). Factor VIII/von Willebrand factor (FVIII/vWF) concentrates are currently the treatment of choice in vWD patients unresponsive to desmopressin (DDAVP). However, only few studies on their clinical use are available so far. The main objective of this study was to retrospectively evaluate the clinical efficacy of a highly purified, doubly virus-inactivated FVIII/vWF concentrate with a high content of FVIII/vWF (Fanhdi). Twenty-two patients with congenital vWD have been treated from 1999 to 2001 at eight specialized centres belonging to the Italian Association of Hemophilia Centers (AICE). Ten males and 12 females, median age 28.5 years, range 5-70 years) had type 3 vWD (six cases), DDAVP-unresponsive type 1 (nine cases) and type 2B (seven cases). The study drug was given to stop or prevent 12 bleeding episodes or to prevent excessive bleeding during 14 surgical or invasive procedures. Overall, replacement therapy with the concentrate showed an excellent to good clinical efficacy in 92% of bleeding episodes and in 93% of surgical procedures. No adverse events occurred during 1,601 infusions, accounting for a total of 304,500 IU of FVIII:C administered. These results confirm the efficacy and safety of this concentrate in the management of bleeding episodes and in the prevention of excessive bleeding during major and minor surgery.     

Spontaneous platelet aggregation in type IIB Tampa von Willebrand disease is inhibited by the 52/48-kDa fragment of normal von Willebrand factor, which contains the GPIb binding domain

The association of Type IIB von Willebrand disease (vWD) with chronic persistent thrombocytopenia and spontaneous platelet aggregation has recently been recognized. It has been shown that IIB von Willebrand factor (vWF) can initiate platelet aggregation by binding to the platelet glycoprotein (GP) lb receptor and inducing exposure of the GpIIb/IIIa fibrinogen receptor. In this study we demonstrate the increased binding of Type IIB Tampa vWF with normal platelets when compared with nonthrombocytopenic Type IIB vWF. Studies further demonstrate that spontaneous platelet aggregation initiated by IIB Tampa vWF can be blocked by a 52/48-kDa fragment of normal vWF, which contains the binding domain.     

DDAVP in acquired von Willebrand syndrome associated with multiple myeloma

The response to a single intravenous infusion of 1-deamino-8-D-arginine vasopressin (DDAVP, desmopressin) was studied in two patients with acquired von Willebrand syndrome associated with IgG-kappa myeloma. Following infusion of DDAVP (0.3-0.4 micrograms/kg), prolonged bleeding time was normalized; plasma ristocetin cofactor activity, von Willebrand factor antigen, and factor VIII activity were remarkably increased; and high-molecular-weight forms of von Willebrand factor were demonstrated by crossed immunoelectrophoresis in both patients. Excellent hemostasis was achieved following administration of DDAVP in one patient when it was used for the treatment of gum bleeding and for the prophylaxis of bleeding during and after dental extractions. These observations suggest that DDAVP is an effective alternative to blood products for at least some patients with acquired von Willebrand syndrome in addition to patients with inherited von Willebrand disease, hemophilia A, and uremia.     

Evaluation of recombinant von Willebrand factor in a canine model of von Willebrand disease

Dutch Kooiker dogs with hereditary von Willebrand disease have undetectable levels of von Willebrand factor (vWF), resulting in spontaneous haemorrhage of mucosal surfaces similar to the clinical picture of von Willebrand disease in humans. We used this canine model of von Willebrand disease to study the in vivo effects of a new recombinant von Willebrand factor (rvWF) preparation that contained all species of vWF multimers compared with a rvWF fraction containing only low molecular weight multimers (LMW-rvWF) and with a plasma-derived factor VIII/vWF concentrate (pdvWF). Administration of rvWF in these vWF-deficient dogs resulted in a vWF:Ag half-life of 21.6 h in one dog and 22.1 h in a second dog. Administration of pdvWF resulted in a half-life for vWF:Ag of 7.7 h, and LMW-rvWF, 9 h. The in vivo recovery of vWF:Ag after administration of rvWF was 59%, 64% and 70% in three dogs, respectively; 33% after pdvWF, and 92% after LMW-rvWF. The in vivo recovery of ristocetin cofactor (RCoF) was 78%, 110% and 120% for rvWF, and 25% for pdvWF. Both rvWF and pdvWF caused increases in FVIII. Although no effect was seen on bleeding time at the dosages used, the rate of blood flow from cuticle wounds was reduced after a single bolus administration of rvWF. The rvWF was able to control a severe nose bleed in one dog.     

Massive retroperitoneal pseudotumour in a patient with type 3 von Willebrand disease

Formation of destructive haemorrhagic pseudocysts or pseudotumours thought to arise from unresolved, encapsulated haematomas is a well-recognized, rare complication of severe haemophilia A or B, and has been reported in a single patient with von Willebrand disease (vWD). We report a 41-year-old patient with type 3 vWD who underwent incomplete resection of a large retroperitoneal pseudocyst in 1995 and presented with a recurrent, extensive right abdominal and flank mass and signs and symptoms of large bowel obstruction. He required emergency partial colectomy for bowel ischaemia and removal of his right kidney, which was hydronephrotic due to prolonged ureteral obstruction by the pseudocyst. Following repeat partial resection of the pseudotumour, he developed persistent bleeding into the operative site despite aggressive administration of von Willebrand factor (vWF)-rich factor VIII concentrates, resulting in retroperitoneal haematomas and abscesses, which resolved after 13 months of percutaneous drainage, extended supplementation of vWF and antibiotic therapy.     

Heightened proteolysis of the von Willebrand factor subunit in patients with von Willebrand disease hemizygous or homozygous for the C2362F mutation

We studied the proteolytic pattern of the mutant von Willebrand factor (VWF) in four patients with von Willebrand disease (VWD) who were either homozygous or hemizygous for the mutation C2362F. A significant decrease in the native fragment of 225 kDa was evident in all the patients, together with a marked increase in the 176 and 140 kDa fragments, a pattern usually observed in type 2A VWD. The proteolytic pattern measured in four heterozygotes for C2362F was within the normal range, suggesting that the mutant VWF C2362F present in the plasma of these patients may be protected from proteolysis by normal VWF.     

Postpartum von Willebrand factor levels in women with and without von Willebrand disease and implications for prophylaxis

The aim of this study was to elucidate the fall in von Willebrand factor (VWF) and factor VIII activity (FVIII) after childbirth in women with and without von Willebrand disease (VWD). VWF:RCo, VWF:Ag, and FVIII were obtained in the third trimester of pregnancy, on admission for childbirth, and 10 times postpartum. Specimens were processed within 4 h and analysed centrally. Means were calculated at each time point. Forty women (40 pregnancies) without VWD and 32 women (35 pregnancies) with VWD were enrolled. 15/32 with VWD were treated (30% of those with type 1 and all of those with type 2) in 17 pregnancies. Treatments prior to delivery consisted of desmopressin (2/17), VWF concentrate (15/17) and after delivery VWF concentrate (16/17). Duration of treatment was 0–21 days (median 6). VWF levels peaked at 250% of baseline – 4 h postpartum in women with VWD and 12 h postpartum in women without VWD. Thereafter, VWF levels fell rapidly, approached baseline at 1 week and reached baseline at 3 weeks. Except immediately postpartum, when the levels among treated cases were higher, levels among women with VWD appeared to parallel, but were lower than those among women without VWD. Levels were lowest among those who received treatment. VWF levels fall rapidly after childbirth. Except immediately postpartum, current treatment strategies do not raise VWF levels to the levels of women without VWD or even to the levels of women with milder, untreated VWD. Consequently, women with VWD may be at risk of postpartum haemorrhage despite treatment.