Potentially inappropriate medications and anticholinergic and sedative burden in older patients with haemophilia or von Willebrand disease: The M'HEMORRH-AGE study.

WHAT IS KNOWN AND OBJECTIVE: In older patients, multiple chronic conditions lead to the intake of multiple medications and a higher risk of adverse drug events. The exposure to inappropriate medications in older patients with bleeding disorders is poorly explored. The aim of this study was to describe the exposure to potentially inappropriate medications (PIMs) and medications with anticholinergic and sedative properties in older community-dwelling patients with haemophilia or von Willebrand Disease (VWD). METHODS: The M'HEMORRH-AGE study (Medication in AGEd patients with HAEMORRHagic disease) is a multicentre prospective observational study. Community-dwelling patients over 65 years with haemophilia or VWD were included in the study. PIMs were identified using the EU(7)-PIM list, and the anticholinergic and sedative drug exposure was measured using the Drug Burden Index. RESULTS AND DISCUSSION: 142 older community-dwelling patients with haemophilia (n = 89) or VWD (n = 53) were included (mean age: 72.8 ± 5.8 years). PIMs were used by 45.8% of older patients and were mainly represented by cardiovascular (34.9%), nervous systems (26.7%) and alimentary tract and metabolism PIMs (25.6%). Regarding anticholinergic and/or sedative medications, 37.3% of older patients were exposed mainly due to nervous system medications (68.3%), for example analgesics. WHAT IS NEW AND CONCLUSION: The M'HEMORRH-AGE study showed the exposure to PIMs and anticholinergic/sedative medications was high in older community-dwelling patients with haemophilia or VWD. Interventions focusing on deprescription of these inappropriate medications should be conducted in this specific population.

Rodenticidal hepatotoxicity: Raised plasma Von Willebrand factor levels predict in-hospital survival and preliminary report of the outcome of Von Willebrand factor reducing management protocol.

BACKGROUND: High Von Willebrand factor (VWF) levels may predispose to multi-organ failure in acute liver failure (ALF). In rodenticide-induced hepatotoxicity patients, we analyzed if plasma VWF levels predicted survival and also the outcome of VWF lowering by N-acetyl cysteine (NAC), fresh frozen plasma (FFP) infusions, and plasma exchange (PLEX). METHODS: We retrospectively analyzed prospectively collected data. Hepatotoxicity was classified as uncomplicated acute hepatitis (UAH), acute liver injury (ALI), and ALF. ALF patients, if not opting for liver transplantation, had PLEX and NAC; ALI patients received NAC ± FFP (PLEX, if worsening); UAH patients had NAC. Plasma VWF antigen was measured (normal, 50% to 150%). In-hospital survival was analyzed as discharged alive or died/discharged in a terminal condition (poor outcome). RESULTS: Twenty-four consecutive rodenticide-induced hepatotoxicity patients (UAH in 1, ALI in 20, ALF in 3) from December 2017 to January 2019 were studied. Baseline VWF levels were 153%, 423 (146-890)% median (range), and 448 (414-555)% in UAH, ALI, ALF patients; model for end-stage liver disease (MELD) scores were 11, 24 (12-38), 36 (32-37) and in-hospital survival rates were 100%, 85%, 67%, respectively. VWF levels were higher in patients with poor outcome (555 [512-890]%) than in those discharged alive (414 [146-617]%) (p-value = 0.04). The area under the receiver operating curve of the VWF level, MELD score, and sequential organ failure assessment score to predict survival was 0.92, 0.84, and 0.66, respectively. Of 4 patients meeting criteria for liver transplantation (none had transplantation), 3 (75%) survived. CONCLUSIONS: High VWF levels predict poor outcome in rodenticide-induced hepatotoxicity. VWF reduction may be useful in such patients.

Causes, etiology and diagnosis of acquired von Willebrand disease: a prospective diagnostic workup to establish the most effective therapeutic strategies.

Acquired von Willebrand disease (aVWD) occurs in association with a variety of underlying disorders, most frequently in lymphoproliferative and myeloproliferative disorders, other malignancies, and cardiovascular disease. aVWD is a complex and heterogeneous defect with a multifactorial etiology and the pathophysiologic mechanisms remain unclear in many cases. Assays for anti-factor VIII (FVIII)/von Willebrand factor (VWF) activities often yield negative results although antibodies may be present in autoimmune disease and some lymphoproliferative disorders. Functional assays of VWF in patients' plasma and particularly in heart valve disease, VWF multimer analysis are important for aVWD diagnosis. In patients with normal partial thromboplastin times and normal VWF activity, the diagnosis of aVWD is based on clinical suspicion and a careful bleeding history, which should prompt the clinician to initiate further laboratory investigations. Management of bleeding in aVWD relies mainly on desmopressin, FVIII/VWF concentrates and high-dose intravenous immunoglobulin. The half-life of VWF may be very short, and in bleeding episodes high doses of FVIII/VWF concentrates at short intervals may be necessary even when high-dose intravenous immunoglobulin was applied before. Since the optimal treatment strategy has not yet been defined for aVWD of different etiology, controlled multicenter trials aiming at the development of standardized treatment protocols are urgently needed.

Acquired von Willebrand syndrome as side effect of valproic acid therapy in children is rare.

To determine the frequency and clinical relevance of acquired von Willebrand syndrome (aVWS) due to antiepileptic therapy by valproic acid, we investigated 50 consecutive children in three neuropediatric institutions. Coagulation factors were determined in local laboratories before and three times after starting therapy with valproic acid. Parameters of von Willebrand factor (VWF) were additionally investigated in a reference laboratory including multimeric analysis. Significant changes in the coagulation system were found concerning fibrinogen (decreased from 287 +/- 70 mg/dl to 222 +/- 67 mg/dl; p < 0.001) and platelet count. Changes of VWF parameters were also found but no patient developed laboratory defined aVWS. We conclude that the bleeding tendency observed in some children undergoing antiepileptic therapy with valproic acid is not due to aVWS.

High incidence of vaproate-induced coagulation disorders in children receiving valproic acid: a prospective study.

Reports have been published on blood coagulation disturbances by valproate therapy. In the present prospective trial, blood samples were drawn before valproate therapy, after 6 weeks of therapy, after more than 6 weeks and after longer than 6 months of valproate therapy from 23 children newly treated with valproate. Two children developed thrombocytopenia, and six children with initial normal von Willebrand factor showed acquired von Willebrand's disease. Fibrinogen levels dropped below the lower limit in 12 patients and subnormal factor XIII plasma levels were observed in 17% of patients. No patient developed signs of hemorrhage. Eight percent of patients developed valproate-induced thrombocytopenia. Reduction in platelets did not reach statistic significance. Thrombelastography showed a 47% incidence of altered platelet function. We found a statistically significant, positive correlation between clotting time of collagen extrinsic pathway inhibitor and, accordingly, adenosindiphosphate and valproate level. Plasmatic coagulation investigations showed a significant decrease of prothrombin time. Activated partial thromboplastin time measurements also showed significant prolongation with valproate. Activity of von Willebrand factor antigen and von Willebrand factor ristocetin cofactor significantly decreased. Factor XIII activity significantly decreased after valproate therapy for longer than 6 months (17% of children). Fibrinogen was significantly reduced. In the coagulatory system a decrease in the main antiprotease antithrombin III activity was observed. Blood coagulation disturbances are common in patients with valproate, but rarely become clinically symptomatic. Acquired von Willebrand's disease and hypofibrinogenemia may become relevant in patients with surgery or trauma. Particular attention should be paid to factor-XIII deficiency, which is especially seen with valproate therapy.

Acquired von Willebrand syndrome: an update.

Acquired von Willebrand syndrome (aVWS) is a rare bleeding disorder with laboratory findings similar to those for congenital von Willebrand disease (VWD). However, unlike congenital VWD, it arises in individuals with no personal or family history of bleeding. aVWS occurs in association with a variety of underlying disorders, most frequently in lymphoproliferative disorders, myeloproliferative disorders, and cardiovascular diseases. Through an analysis of the more recent literature data, the pathophysiology and the clinical, laboratory, and therapeutic aspects of this syndrome are concisely reported in this review.

Valproate-associated coagulopathies are frequent and variable in children.

PURPOSE: Valproic acid (VPA) is an antiepileptic drug (AED) commonly used for generalized and focal epilepsies. The clinical relevance of coagulopathies, known as side effects of VPA therapy, especially thrombocytopenia, von Willebrand disease, and a decrease of factor XIII, is still unclear. METHODS: In our institute, we noticed a high incidence of clinically relevant coagulation problems related to VPA in eight patients within 1 year only and a further seven children with significant coagulopathy were identified in the context of planned surgery. RESULTS: We provide an overview of these patients and all six VPA-induced coagulopathies. CONCLUSIONS: At this time, it cannot be recommended to control all hemostatic parameters in every patient. Whenever an increased bleeding tendency is observed, or before surgical procedures, a platelet count, thrombelastography, prothrombin time, activated partial thromboplastin time, TT, fibrinogen, von Willebrand factor, and factor XIII should be examined. With 385 VPA-treated patients per year and 15 cases of coagulation disorders in this period, we estimate the incidence of coagulation disorders related to VPA in children to be nearly 4%.

Cefotaxime as the potential cause of transient acquired von Willebrand syndrome.

Acquired von Willebrand syndrome (AvWS) is a relatively rare bleeding disorder. It has been reported in association with myeloproliferative disorders, autoimmune diseases, plasma cell dyscrasias and certain drugs. Cefotaxime is a third generation cephalosporin widely used for surgical prophylaxis and as empirical treatment of bacterial meningitis. We report a case of a transient AvWS in association with cefotaxime therapy.

Acquired von Willebrand syndrome in a myeloproliferative disorder. Case 6.

We present a woman (age: 57 years) with an excessive bleeding episode under acetylsalicylic acid after bone marrow puncture due to an acquired von Willebrand syndrome (avWS) in the context of a myeloproliferative disorder. The laboratory features showed a high platelet concentration and a qualitative defect of von Willebrand factor (vWF) with a low normal vWF ristocetin cofactor activity, a normal vWF antigen and a decrease of the larger vWF multimers in plasma. The exact mechanism of avWS is still incompletely resolved. Myeloproliferative diseases are one of several underlying disorders that may cause avWS. The diagnosis of the underlying disease is important because its treatment may lead to an improvement of the vWF abnormality. For symptomatic treatment of bleeding, desmopressin, vWF concentrate infusion, intravenous immunoglobulin and/or fibrinolysis inhibitors can be tried.

Coagulation abnormalities and acquired von Willebrand's disease type 1 in children receiving valproic acid.

Valproic acid is commonly used in the management of childhood epilepsy. The known hematologic side effects of the drug are hemorrhagic diatheses, thrombocytopenia, and hypofibrinogenemia. We studied coagulation parameters in 29 epileptic children receiving valproic acid for at least 6 months. Their ages ranged between 2 and 18 years (10.2 +/- 4.9 years). The total valproic acid dose was 250 to 1000 mg/day equivalent to 20 to 30 mg/kg/day. Treatment duration ranged from 6 to 57 months. These children had not previously had a hemostatic defect and had no family history of bleeding disorders. Platelet count, prothrombin time, activated partial thromboplastin time, bleeding time, fibrinogen, platelet aggregation assays, and ristocetin cofactor activity levels were determined in all of the patients, but von Willebrand's factor antigen levels could be determined in only 14 patients. The values of von Willebrand's factor antigen ranged from 53 to 218% (104.1 +/- 42.3), and ristocetin cofactor activity levels ranged from 11.5 to 218% (94.5 +/- 43.1). Six of the 29 children (20.7%) had decreased values of ristocetin and cofactor activity and were considered to have acquired von Willebrand's disease. The decreases in coagulation parameters were not dependent on either valproic acid dose or treatment duration. Two patients with low ristocetin cofactor activity values had mild epistaxis, which did not require discontinuation of therapy. In patients receiving valproic acid therapy, this side effect must be considered, especially before surgical intervention and serious traumatic conditions.

Highly substituted hydroxyethyl starch (HES200/0.62) leads to Type-I von Willebrand syndrome after repeated administration.

Hydroxyethyl starch (HES) is a frequently used plasma substitute that is popular due to a high degree of therapeutic safety. However, the administration of large volumes of highly substituted, high-molecular-weight starch often leads to iatrogenic von Willebrand syndrome (vWS) with hemorrhagic complications. In patients with cerebral circulatory disturbances we carried out hemodilution therapy during 9-10 days, infusing HES 200/0.62. A von Willebrand factor (vWF) multimeric analysis was carried out in 6 patients using a modified western blot according to the sodium dodecyl sulfate agarose gel electrophoresis method. The vWF multimeric analysis showed that all multimers decreased to the same degree, corresponding to type-I vWS.

The effect of 6% hydroxyethyl starch and desmopressin infusion on von Willebrand factor: ristocetin cofactor activity.

Hydroxyethyl starch is commonly used as a plasma volume expander in the surgical patient. Although it is generally considered a safe plasma substitution, some reports of an acquired von Willebrand's disease-like syndrome have been documented. To examine this further, von Willebrand factor: ristocetin cofactor activity (RCoF) was measured in two groups of patients perioperatively, following hydroxyethyl starch infusion and at 30, 60, and 240 minutes following either deamino-8-D-arginine vasopressin (DDAVP) (group I, n = 12) or saline (group II, n = 11). Following hydroxyethyl starch infusion, ristocetin cofactor activity decreased to 58 percent (group I) and 55 percent (group II) of their respective baseline values. After infusion of DDAVP, mean ristocetin cofactor activity in group I increased significantly to 95 percent at 30 minutes and 100 percent of baseline at 60 minutes. Mean ristocetin cofactor activity levels in group II, however, remained decreased, 69 percent and 57 percent of baseline at the same time points. There was no statistical difference between groups before or immediately after hydroxyethyl starch administration or at 240 minutes post-DDAVP or saline infusion. It is our conclusion that DDAVP is a safe therapy for the mild coagulapathy infrequently associated with hydroxyethyl starch administration.

Characterization of two cases of acquired transitory von Willebrand syndrome with ciprofloxacin: evidence for heightened proteolysis of von Willebrand factor.

We characterized the cause of two cases of transitory acquired von Willebrand syndrome associated with the administration of ciprofloxacin. Purified Ig from the two patients did not inhibit Ristocetin Cofactor activity or binding to collagen of normal plasma, ruling out the possibility of an inhibitor. The analysis of multimeric pattern of plasma von Willebrand Factor (vWF) showed the lack of larger multimers in both patients, with a relative decrease of all the remaining forms in the first patient. The subunit composition of plasma vWF showed a marked reduction of the native 225 Kd subunit (31.9% and 32.9%; normal range 74-86%) and an increased proportion of the 189, 176, and 140 Kd fragments. These abnormalities disappeared during the follow-up, without any specific therapy. In conclusion, a common pathophysiological basis is demonstrated in both patients, with a heightened proteolysis of plasma vWF by an unknown mechanism.

Hydroxyethyl starch induced acquired von Willebrand's disease.

Hydroxyethyl starch (HES) (Hespan, DuPont) is a widely used synthetic volume expander which in standard doses of up to 1.5l in 24 h has no significant effect on coagulation (Munsch et al. 1988). However, the data sheet states that in large volumes HES may alter the coagulation mechanism. We now report a case of HES induced acquired von Willebrand's disease (vWD) in which severe bleeding occurred.

Valproate therapy induces von Willebrand disease type I.

To investigate the increased tendency of hemorrhage in patients receiving valproate (VPA) therapy, we studied coagulation parameters in 30 randomized children of a group of 83 children receiving antiepileptic drug (AED) therapy. Besides a reduction in fibrinogen concentration and platelet count, we observed a significant decrease in factor VIII-complex. A decrease in factor VIII:C was noted in 33%, a decrease in von Willebrand factor (vWF:Ag) was noted in 83% and a decrease in ristocetin-cofactor activity (vWF:Rcof) was noted in 66% of the children. We classified a von Willebrand syndrome type I in 67% of our patients receiving VPA therapy. Sixty-three percent of patients had a history of bleeding, and 23% had a prolonged bleeding time. We compared our results with those of a control group and of a group of patients with congenital von Willebrand disease (vWD), from which patients with multimer types II and III were excluded. Because coagulation parameters in patients with congenital vWD are similar to those receiving AED therapy, we designated the increased tendency to hemorrhage as VPA-induced vWD. The decrease in coagulation parameters were not dependent on either VPA dose or period of administration. In patients receiving VPA therapy, this result must be considered, especially during surgical intervention and after traumatic events.

Development of a von Willebrand-like syndrome after prolonged use of hydroxyethyl starch.

A 29-year-old female with no prior history of bleeding tendencies had gingival bleeding develop after 10 days of treatment with hydroxyethyl starch (HES), 1,000 mL/day. Laboratory studies revealed a marked reduction in Factor VIII coagulant activity (VIII:C), von Willebrand's factor antigen (vWF:Agn), and (VIII R:RCo), resembling severe type I von Willebrand's disease. The HES was stopped and the bleeding subsided. The levels of Factor VIII:C, vWF:Agn, and Factor VIII R:RCo gradually increased to normal over the following 17 days.