Those with hemophilia or von Willebrand disease do not have increased perioperative complications following anterior cruciate ligament reconstruction: Results of a case-control large-database study

BackgroundThere is a lack of information on anterior cruciate ligament (ACL) reconstruction outcomes and complications for patients with congenital hypocoagulable conditions. The specific aim of this retrospective study was to report operative outcomes and complications for patients with congenital hypocoagulable disorders who underwent ACL reconstruction.MethodsWe performed a retrospective review of all patients who underwent an ACL reconstruction within Truven MarketScan Commercial Claims and Encounter Database from 2010 to 2014. Hemophilia A, hemophilia B and patients were identified. Patient demographics, cost of surgery, blood product use, concomitant injuries, repeat ACL injury, complications and various operative variables were collected. Statistical tests were conducted on SAS 9.4 2013.ResultsThirty-three hemophilia A, three hemophilia B, 63 von Willebrand factor patients, and 103,478 controls underwent ACL reconstruction. There is a statistically significant difference for hemarthrosis 1 year leading up to injury for hemophilia A compared with control (P = 0.0083). Total healthcare utilization 90 days after surgery was statistically significant for hemophilia A ($30,310 ± 52,745, P < 0.001) and von Willebrand factor ($20,355 ± 23,570, P < 0.001) compared with control ($14,564 ± 9512). Length of hospital stay, postoperative hemorrhage, concomitant injuries to the knee, additional ACL injury, infection rate, deep-vein thrombosis, and pulmonary embolism were not statistically significant. None of the hemophilia A or von Willebrand factor patients received blood products intraoperatively or postoperatively.ConclusionHemophilia A and von Willebrand factor patients had rates of postoperative complications and ACL re-injuries that were not statistically significant. Cost of healthcare utilization was identified as dramatically greater for hemophilia A and von Willebrand factor patients.     

The subcutaneous administration of the vasopressin analogue 1-desamino-8-D-arginine vasopressin in patients with von Willebrand's disease and hemophilia

Summary Twenty-one patients suffering from mild von Willebrand's disease (vWd) and patients suffering from mild or moderate hemophilia A received 1-desamino-8-D-arginine vasopressin (DDAVP) (Minirin^®, Ferring AG) s.c. at a dose of 0.4 µg/kg body weight. Additionally, two hemophiliacs and 22 patients with vWd received DDAVP i.v. Within the observation period of 3 h Factor (F) VIII:C levels increased 2.4 × baseline levels in hemophiliacs, and the maximal effect was observed 3 h post DDAVP s.c. In patients with vWd post DDAVP s.c. (i.v.) a 2.7 (3.4), 2.1 (1.9) and 2.2 (2.8) fold increase for F VIII: C, F VIIIR:Ag and F VIII:Rcof was observed. In eight patients suffering from vWd with additional F XII deficiency a small and transitory but significant increase of F XII levels was detected post DDAVP s.c. No local or systemic side effects were observed. In five patients with vWd tooth extractions were performed without bleeding complications under DDAVP s.c. treatment. Two patients practiced self-treatment by injecting the drug s.c. at home. We thus conclude that s.c. DDAVP is an effective, reliable, and cost-reducing form of treatment that does not bring with it the risk of transmitting infectious diseases in patients with vWd and hemophilia and that can be administered at home.Abbreviations F VIII:C factor VIII procoagulant activity - F VIIIR:Ag factor VIII related antigen - F VIII:Rcof ristocetin cofactor - aPTT activated partial thromboplastin time     

Immune coagulation disorders (excluding antiphospholipid syndrome]

During the course of replacement therapy, 22-30% of patients with severe hemophilia A develop alloantibody to factor VIII. Autoantibodies to coagulation factors rarely occur in elder individuals with previously normal hemostatic mechanisms or in patients with various underlying disorders. Although the great majority of the acquired inhibitors are directed to factor VIII, the antibodies may arise to every coagulation factor. The inhibitor antibodies directly inactivate specific clotting factor, or occasionally, they bind to a nonfunctional site, resulting in increased plasma clearance. In the last decade, we experienced 12 hemophilia A and 3 hemophilia B patients who developed factor VIII and factor VIII and factor IX inhibitor, respectively, 9 patients with autoantibody to factor VIII (acquired hemophilia), and 4 patients with acquired von Willebrand syndrome. Among 12 factor VIII inhibitors, 4 patients were identified to have inversion in the factor VIII gene, 1 with 4 bases deletion, and 1 with missense mutation resulting in G479R. Four of 9 patients with acquired hemophilia had underlying disorders of autoimmune hemolytic anemia, macroglobulinemia, urticaria, and pharyngeal cancer at the development of factor VIII inhibitor. Antibody to von willebrand factor was detected in 3 of 4 patients with acquired von Willebrand syndrome.     

The use of high-dose intravenous gamma-globulin in acquired von Willebrand syndrome

Acquired von Willebrand syndrome has been reported in patients with a variety of primary diseases, many immunologic in nature. Usually, an autoantibody to von Willebrand factor can be identified. These patients often experience severe hemorrhages requiring large doses of cryoprecipitate or factor VIII concentrates, thus exposing them to viral and allergic complications. The success of intravenous gamma-globulin in the treatment of other autoimmune diseases prompted us to treat two patients with acquired von Willebrand syndrome with high-dose intravenous gamma-globulin. Two days after initiation of therapy, von Willebrand factor and factor VIII rose to normal levels in both patients. Patient 1 underwent dental surgery, and patient 2 underwent a splenectomy without increased bleeding and without additional factor coverage or desmopressin acetate therapy. Thus, intravenous gamma-globulin is efficacious for acquired von Willebrand syndrome and obviates the need for replacement therapy with its attendant complications.     

血友病B基因突变的研究

目的　为了研究血友病B因子Ⅸ (FⅨ )分子缺陷的发生机制。方法　应用多聚酶链反应 (PCR)、单链构型多态性 (SSCP)和双链DNA直接荧光测序等技术对 1例重度血友病B患者FⅨ基因进行研究。结果　发现该患者FⅨ基因外显子Ⅷ的 36 3bpDNA片段上 ,在第 30 790位核苷酸发生碱基替换T(GTT)→A(GTA) ,形成编码缬氨酸的同义点突变。此外 ,还发现在第 310 6 4位的胞苷 (C)缺失。该缺失突变 ,导致阅读框架改变 ,并导致在第 310 83～ 310 85位提前形成终止密码子TAG。结论　由于FⅨ基因外显子Ⅷ编码FⅨ催化结构区域 ,该基因缺失突变可严重引起催化结构区域的异常 ,导致FⅨ的分子缺陷和凝血功能障碍 ,从而导致严重的血友病B。     

Potential laboratory misdiagnosis of hemophilia and von Willebrand disorder owing to cold activation of blood samples for testing

To assess the potential for misdiagnosis of von Willebrand disorder (vWD) and hemophilia A while following current National Committee for Clinical Laboratory Standards (NCCLS) guidelines and consequent to a poorly recognized cold-activation phenomenon, we processed 39 normal citrate-anticoagulated samples by standard procedures (reference) or stored at low (approximately 4 degrees C) or ambient (approximately 22 degrees C) temperature for 3.5 hours before centrifugation and processing. Samples were tested in parallel for several hemostasis factors, including von Willebrand factor (vWF). Similar results were obtained for all samples for factors II, V, VII, IX, X, XI, and XII. For factor VIII (FVIII) and vWF, only samples stored at ambient temperature had results comparable to reference sample results. In most cases, low temperature storage led to much lower results. Taking the lower reference limit as 50%, most would have been defined as "abnormal," and a misdiagnosis of vWD or hemophilia A could easily arise. ABO classification and age were associated with FVIII and vWF levels, but neither was associated conclusively with relative loss of plasma FVIII coagulant and vWF caused by the cold-activation phenomenon. We advise laboratories following current NCCLS guidelines not to store or transport whole blood samples for FVIII and vWF testing at 2 degrees C to 4 degrees C because of the risk of misdiagnosing vWD or hemophilia A. Storage and transport at ambient temperature seem acceptable and provide results comparable to freshly centrifuged samples.     

Molecular etiology of factor VIII deficiency in hemophilia A

Hemophilia is a common X-linked coagulation disorder due to deficiency of factor VIII. The factor VIII gene has been cloned in 1984 and a large number of mutations that cause hemophilia A have been identified in the last decade. The most common of the mutations is an inversion of factor VIII that accounts for nearly 45% of patients vvith severe hemophilia A. This review lists all the factor VIII mutations identified to date and briefly discusses their functional significance. © 1995 Wiley-Liss, Inc.     

Treatment with desmopressin acetate to reduce blood loss after cardiac surgery. A double-blind randomized trial

Bleeding after cardiopulmonary bypass remains a cause for concern, requiring reexploration of the chest in approximately 3 percent of patients who have had operations on the heart. We examined the possibility that this problem might be alleviated by desmopressin acetate (DDAVP), which increases the plasma level of von Willebrand factor and improves hemostasis in mild hemophilia and other conditions associated with defective platelet function. In a double-blind, prospective, randomized trial, we studied the effect of intraoperative desmopressin acetate in 70 patients undergoing various cardiac operations requiring cardiopulmonary bypass. Patients undergoing uncomplicated primary coronary-artery bypass grafting were not included. The drug significantly reduced mean operative and early postoperative blood loss (1317 +/- 486 ml in the treated group vs. 2210 +/- 1415 ml in the placebo group); of the 14 patients whose 24-hour blood loss exceeded 2000 ml, 11 had received the placebo. Plasma levels of von Willebrand factor were higher after desmopressin acetate than after placebo. Patients with the most bleeding had relatively low levels of von Willebrand factor before operation, suggesting a role for this factor in the hemorrhagic tendency induced by extracorporeal circulation. There were no untoward side effects of desmopressin acetate. We conclude that the administration of desmopressin acetate can be recommended to reduce blood loss in patients undergoing complex cardiac operations. The beneficial effect of the drug on hemostasis after cardiopulmonary bypass may be related to its effect on von Willebrand factor.     

Hemophilia and von Willebrand's disease: genetic considerations

Recent progress in the biochemical characterization of coagulation factors VIII and IX has greatly contributed to our understanding of the inheritance of hemophilia and von Willebrand's disease and facilitated the recognition of carriers of these disorders. Factor VIII is a molecular complex which may be quantitated immunologically as factor VIII-related antigen. Within this complex reside the von Willebrand factor, absent in von Willebrand's disease, and factor VIII procoagulant activity and antigen. Hemophilia is an x-linked disorder; female carriers may be recognized by a disproportionate increase in factor VIII-related antigen or procoagulant antigens in relation to procoagulant activity. Prenatal diagnosis of hemophilia has been accomplished by measurements of clotting activity and antigens in fetal blood. Von Willebrand's disease has been classified on the basis of laboratory abnormalities, the biochemical characteristics of the von Willebrand factor, and its patterns of inheritance. In the most commonly observed form, there is autosomal dominant inheritance, and most patients are heterozygotes. These individuals manifest variably prolonged bleeding times and concordantly reduced activities associated with factor VIII. Rarely, there is an autosomal recessive pattern in which the homozygotes have much more severe clinical disease, including hemathroses. However, the biochemical defects in the von Willebrand factor appear to be quite diverse, defying any simple classification of this disorder.     

Relation of socioeconomic levels and life style to fibrinogen and von Willebrand factor in healthy Venezuelans and those with ischemic cardiopathy

Previous studies in Europe, U.S.A and Japan have revealed an inverse relationship between socioeconomic levels and fibrinogen concentration. Similar results have been reported in a smaller number of studies for concentrations of von Willebrand factor. In this opportunity we present results on the relationship between smoking, drinking, physical activity, age and socioeconomic level on fibrinogen and von Willebrand factor concentrations in a Venezuelan sample. The control population consisted of 978 men and 968 women. Patients with coronary heart disease were 172 males and 78 females. The presence of one or more of the following conditions: smoking or less than 5 years of having quit, non drinkers or drinking in excess, and a reduced physical activity, was considered a health related risk factor for high levels of these two haemostatic variables. Our results indicate that in Controls, the socioeconomic level had a significant effect on fibrinogen and von Willebrand factor levels, only in women: those of lower socioeconomic levels had the highest concentrations. This difference was maintained when age was taken into account. Health related behaviors had no significant effect on either variable. In patients, age had no effect on either variable. The health behavior risk factor had a significant effect only on fibrinogen of male patients, and socioeconomic level had a significant effect only on the fibrinogen of female patients. More studies in Venezuela are recommended, in order to increase our knowledge on the relationship between socioeconomic levels, haemostatic markers and the occurrence of coronary heart disease.     

Low cost industrial production of coagulation factor IX bioencapsulated in lettuce cells for oral tolerance induction in hemophilia B

Antibodies (inhibitors) developed by hemophilia B patients against coagulation factor IX (FIX) are challenging to eliminate because of anaphylaxis or nephrotic syndrome after continued infusion. To address this urgent unmet medical need, FIX fused with a transmucosal carrier (CTB) was produced in a commercial lettuce (Simpson Elite) cultivar using species specific chloroplast vectors regulated by endogenous psbA sequences. CTB-FIX (∼1 mg/g) in lyophilized cells was stable with proper folding, disulfide bonds and pentamer assembly when stored ∼2 years at ambient temperature. Feeding lettuce cells to hemophilia B mice delivered CTB-FIX efficiently to the gut immune system, induced LAP⁺ regulatory T cells and suppressed inhibitor/IgE formation and anaphylaxis against FIX. Lyophilized cells enabled 10-fold dose escalation studies and successful induction of oral tolerance was observed in all tested doses. Induction of tolerance in such a broad dose range should enable oral delivery to patients of different age groups and diverse genetic background. Using Fraunhofer cGMP hydroponic system, ∼870 kg fresh or 43.5 kg dry weight can be harvested per 1000 ft² per annum yielding 24,000–36,000 doses for 20-kg pediatric patients, enabling first commercial development of an oral drug, addressing prohibitively expensive purification, cold storage/transportation and short shelf life of current protein drugs.     

Molecular pathology and immunology of factor VIII (hemophilia A and factor VIII inhibitors)

Factor VIII is a large procoagulant glycoprotein that circulates in plasma in a noncovalent complex with von Willebrand factor. It is essential for the efficient cleavage of coagulation factor X by factor IXa, and its absence causes a severe bleeding disorder. Plasma factor VIII is reduced from the normal range of approximately 100 to 200 ng/ml in patients with the hereditary coagulation defect, hemophilia A, as well as in patients who develop autoantibodies that inactivate factor VIII. The understanding of factor VIII structure has been enhanced by recent studies that have characterized the X chromosome gene responsible for its synthesis, and preliminary information is now available about specific genetic defects. The basis for antibody formation in approximately 15 per cent of repeatedly transfused hemophilic patients is less clear at this time, however, for these individuals appear to have a variety of genetic defects that are not characteristically different from the patients who do not develop inhibitors. Although the antibodies cause a serious problem for affected individuals, they have been very useful in characterizing normal factor VIII and nonfunctional factor VIII-like protein that is found in the plasmas of 10 per cent of patients with mild hemophilia. Moreover, they are very useful reagents that can be used for immunoassay of factor VIII that has been modified in ways that have destroyed its procoagulant function.     

Homozygous splice site variant affecting the first von Willebrand factor A domain of COL12A1 in a patient with myopathic Ehlers-Danlos syndrome

Myopathic Ehlers-Danlos syndrome (mEDS) is a subtype of EDS that is caused by abnormalities in COL12A1. Up-to-date, 24 patients from 15 families with mEDS have been reported, with 14 families showing inheritance in an autosomal dominant manner and one family in an autosomal recessive manner. We encountered an additional patient with autosomal recessive mEDS. The patient is a 47-year-old Japanese man, born to consanguineous parents with no related features of mEDS. After birth, he presented with hypotonia, weak spontaneous movements, scoliosis, and torticollis. He had soft palms but no skin hyperextensibility or fragility. Progressive scoliosis, undescended testes, and muscular torticollis required surgery. During adulthood, he worked normally and had no physical concerns. Clinical exome analysis revealed a novel homozygous variant in COL12A1 (NM_004370.6:c.395-1G > A) at the splice acceptor site of exon 6, leading to in-frame skipping of exon 6. The patient was diagnosed with mEDS. The milder manifestations in the current patient compared with previously reported patients with mEDS might be related to the site of the variant. The variant is located in the genomic region encoding the first von Willebrand factor A domain, which affects only the long isoform of collagen XII, in contrast to the variants in previously reported mEDS patients that affected both the long and short isoforms. Further studies are needed to delineate comprehensive genotype–phenotype correlation of the disorder.     

Variations of plasma Willebrand factor and fibrinogen in coronary pathology]

In order to determine a marker of prethrombotic states, reliable and easy to measure, we studied 200 patients under 60 years of age admitted to hospital for a precordial chest pain. Four groups were established: transmural myocardial infarction, acute infarction without Q wave, unstable angina and atypical chest pain. Fibrinogen, von Willebrand factor, cholesterol, and triglyceride levels were measured as well as the white cell and platelet counts. There was a statistically significant correlation between transmural myocardial infarction and increased levels of fibrinogen, von Willebrand factor and white blood cells. Von Willebrand factor was already increased in the acute phase of transmural infarction, reached a maximum on the fifth day and then decreased slowly during the following ten days. This study suggests that plasma von Willebrand factor could be a reliable marker of transmural myocardial infarction in the acute phase or during the two weeks following the thrombotic event.     

Recombinant factor VIIa in the treatment of bleeding

Recombinant factor VIIa (rFVIIa) has become available for treating people with hemophilia with inhibitors who experience bleeding or require surgery. It has become apparent that rFVIIa is useful in controlling bleeding in a variety of clinical situations. This review attempts to collate and summarize the nonhemophilia applications of rFVIIa. The theoretical mechanism for the coagulation and hemostatic effects of rFVIIa are discussed. The dosage and clinical administration are described. The potential uses for patients with liver disease, anticoagulation-induced bleeding, surgery, thrombocytopenia, thrombasthenia, von Willebrand disease, and other bleeding disorders are reviewed. The use of rFVIIa is evolving, and the indications, dosage, and precautions or contraindications need to be further described and defined. It is an expensive therapy and needs to be prescribed judiciously. This review is meant to be an introduction to this new hemostatic reagent. The uses for rFVIIa will evolve as more studies are published.     

Abnormality of von Willebrand factor in patients with hemoglobin E-beta (0) thalassemia

The authors have identified six Southeast Asian patients ranging in age from 14 to 21 years with hemoglobin E-beta(0) thalassemia and a coagulopathy involving von Willebrand factor (vWF). These patients had normal or only slightly decreased plasma clotting factor levels. The activated partial thromboplastin time was prolonged in four of the patients. The abnormal feature common to all patients was a qualitative loss of high molecular weight multimers of vWF by crossed immunoelectrophoresis (vWF:CIE). Plasma vWF antigen concentration (vWF:Ag) and ristocetin cofactor activity (vWF:RCo) also were decreased and bleeding time prolonged in three patients. Epistaxis was present in two. No family history of increased bleeding tendency was present in any patient. Coagulation parameters and vWF:CIE were normal in two first-degree relatives without this hemoglobinopathy. vWF abnormalities and clinical manifestations were greatest in those patients with the most severe anemia and hepatosplenomegaly. These six patients appear to have an acquired abnormality of vWF, although they lack the clinical characteristics of acquired von Willebrand disease. While the etiology of this abnormality is unclear, the authors speculate that proteolysis of vWF secondary to extramedullary hematopoiesis or loss through high cardiac output shear stress in these anemic patients may be involved.     

Binding of von Willebrand factor to collagen by flow cytometry

We developed a new method for the detection of large von Willebrand factor (vWf) multimers binding to collagen and for the determination of vWf antigen (vWf:Ag) using flow cytometry. Collagen is coated on to polystyrene beads, allowing detection of found large vWf multimers. In addition, rabbit antibody against vWf is coated on to the beads allowing detection of all vWf:Ag. In plasma samples from healthy persons and patients (with type 1, 2A, 2N, or severe von Willebrand disease or hemophilia), 4 different assays were performed: vWf:Ag by immunoelectrophoresis; vWf ristocetin cofactor (vWf:RCof); CBA; and vWf:Ag based on an enzyme-linked immunosorbent assay using polystyrene beads. We assayed the flow cytometric method using 2 bead sizes. The optimal bead size was 3.136 microns. The results of CBA and vWf:Ag closely correlated with those of vWf:RCof and vWf:Ag (immunoelectrophoresis), respectively, and showed a low limit of detection. Interassay variance of cytometric methods was lower than interassay variance of traditional assays. In addition, we used the new assays to monitor desmopressin therapy.     

Amino acid substitutions in conserved domains of factor VIII and related proteins: study of patients with mild and moderately severe hemophilia A.

Mutations leading to hemophilia A by substitution of amino acids in coagulation factor VIII may provide important clues to the structure and function of this large and enigmatic protein. To efficiently find missense mutations, hemophiliacs with mild and moderately severe forms of the disease were surveyed. DNA samples from affected individuals were assayed for mutations by denaturing gradient gel electrophoresis following DNA amplification of target regions, which included all coding regions except for that of the dispensable B domain. Missense mutations were observed in 20 of the 34 patients examined, with identical mutations found in five pairs of patients. All mutations were found in the repetitive A and C domains. By aligning these domains in factor VIII with homologous domains in factor V, ceruloplasmin, and the mouse milk fat globule membrane protein, it was determined that most mutations change amino acids in areas of strong sequence conservation. Three additional mutations were detected, including a point mutation in an intron, a stop codon mutation, and a silent base change. Ten of the 18 different mutations discovered in this patient population are reported here for the first time.     

Use of intravenous immunoglobulin in patients with acquired von Willebrand syndrome

Acquired von Willebrand syndrome (AVWS) is a rare bleeding disorder with laboratory findings similar to those for congenital von Willebrand disease. Unlike the congenital form, AVWS usually occurs in individuals with no personal or family history of bleeding disorders. According to an international registry, AVWS is mainly associated with lymphomyeloproliferative, immunologic, and cardiovascular disorders, as well as with solid tumors and other miscellaneous conditions; however, the prevalence of AVWS in these underlying disorders is still unknown. von Willebrand factor (VWF) is synthesized normally in most AVWS patients, and the low plasma VWF levels are from its accelerated removal from plasma by five different mechanisms, including autoantibodies. Because of the reduced half-life of endogenous-exogenous plasma VWF, bleeding of AVWS cannot be managed with desmopressin or factor VIII/VWF concentrates. Clinical use of intravenous immunoglobulin (IVIg) in AVWS has been reported since 1988. IVIg is most effective in AVWS with type immunoglobulin (Ig) G monoclonal gammopathies of undetermined significance and in other cases with IgG autoantibodies. IVIg can correct factor VIII and von Willebrand factor complex activities for about 15-20 days, and repeated injections induce remission of AVWS in these patients. Prospective studies are required to evaluate the efficacy and safety of IVIg in AVWS.     

Von Willebrand factor and platelet adhesiveness

A modification of Salzman's method has been used in an attempt to provide an assay in vitro for the von Willebrand factor. Platelet adhesiveness was increased in von Willebrand's disease by previously coating the beads with normal or haemophilic plasma or cryoprecipitate, whereas von Willebrand plasma had no corrective effect. Antihaemophilic factor (AHF) concentrates were studied in the same way and results compared with experiments in vivo.