Clearance of fibrinogen and von Willebrand factor in serial double-filtration plasmapheresis

Double filtration plasmapheresis (DFP) is a widely used and effective way to clear autoantibodies from plasma. It can, however, transiently alter the hemostatic system and cause a bleeding tendency in some patients. There is limited data on the consecutive effect of serial DFP on the hemostatic system, especially on fibrinogen and von Willebrand factor (vWF) levels. This study measured fibrinogen and vWF serially before and after each session of DFP in 8 patients who received one course of DFP treatment for 3 to 5 consecutive sessions on an alternate-day basis. In each session of DFP, the clearance rate of fibrinogen and vWF exceeded 63 and 45%, respectively. The final levels of fibrinogen and vWF after a full course of DFP were reduced to 14.3 and 51.2% of baseline level, respectively. No bleeding tendency was observed in any of the 34 DFP sessions. In conclusion, although an obvious decrease in fibrinogen level and the modest decrease in vWF were observed after an intensive course of DFP treatment, the low incidence of clinically important bleeding confirms the hemostasis-related safety of DFP.     

Anticoagulation,bleeding, and clotting at donor plasmapheresis

This article is based on a question of a colleague from North America how coagulation could be triggered between a donor's arm and a fistula needle during plasma donation (synonymous with donor plasmapheresis). The technique of venipuncture and citrate anticoagulation are described. Uncommon and rare problems such as prolonged bleeding, scarring, and thrombosis in plasma donors are discussed. If venous puncture and citrate: blood flow ratio at 1:16 are correctly performed, however, there will be no anticoagulation abnormalities due to plasma donation.     

A monoclonal antibody directed against human von Willebrand factor induces type 2B-like alterations.

We have previously described a monoclonal antibody (mAb), 1C1E7, against von Willebrand factor (VWF), that increases ristocetin-induced platelet aggregation (RIPA) and induces a preferential binding of the high-molecular-weight multimers of VWF to platelet GPIb. Further investigations using a rotational viscometer at a shear rate of 4000 s(-1) could now demonstrate that shear-induced platelet aggregation (SIPA) is significantly increased with 1C1E7 and that this could be completely inhibited by the anti-GPIb mAb 6D1. In contrast, platelet adhesion to a collagen surface at a shear rate of 2600 s(-1), using a rectangular perfusion chamber, was significantly inhibited in the presence of 1C1E7. When citrated whole blood was incubated with 1C1E7, a spontaneous binding of VWF to the platelet GPIb could be demonstrated by flow cytometric analysis. Parallel to this, a decrease of the highest molecular weight multimers of VWF in the plasma was found. Platelets with bound VWF on their surface were able to form macroaggregates but were no longer able to adhere. These phenomena are very similar to the alterations described in von Willebrand's disease type 2B. The epitope of this mAb could be localized to the N-terminal part of the subunit; therefore a distant conformational change in the A1 domain of VWF is suggested.     

Pathogenesis,Clinical Picture and Treatment of von Willebrand's Disease

Von Willebrand's disease Is probably the most common congenital bleeding disorder, with a prevalence close to 1% in some epidemiological studies. The disease is caused by a quantitative deficiency or a qualitative defect of the von Willebrand factor, which is a multimeric glycoprotein consisting of subunits of 2050 amino acids. The size of multimers ranges from approximately 500 kDa to 20 MDa. Each subunit consist of repeated domain structures. Several functional domains have been identified which can bind such structures as platelet receptors glycoprotein lb or llb/IIIA, heparin, collagen or factor VIII. The von Willebrand factor has two main functions in haemostasis, to promote normal platelet adhesion and to be a carrier protein for factor VIII. Von Willebrand's disease is divided into three major types and several subtypes depending on the quantity and quality of the von Willebrand factor in plasma and platelets. A new classification has recently been proposed. Typical symptoms are mucosal bleeding, easy bruising and increased bleeding tendency in connection with tooth extractions and other invasive procedures. Severe cases may have joint bleeding and other haemophilia-like bleeding. Desmopressin is the treatment of choice in mild cases, whereas more severe cases need treatment with factor VIII concentrates.     

Prethymectomy plasmapheresis in myasthenia gravis

Plasma exchange before thymectomy may decrease the time on mechanical ventilation (MV) and shorten the stay in the intensive care unit (ICU) for patients with myasthenia gravis (MG). This study evaluated the effects of prethymectomy plasmapheresis. A total of 29 myasthenic patients, 18 women and 11 men aged 20-73 years, were treated with double filtration plasmapheresis (DFP) for two to five consecutive sessions over a period between 2 and 21 days (mean 8.1 days) before transsternal thymectomy. Acetylcholine receptor antibody (AchRAb) titers, vital capacity (VC), maximal inspiratory pressure (Pimax), and MG score were measured before and after the course of DFP. Three outcome measures including duration of postoperative hospital stay, duration of ICU stay, and duration of MV were analyzed for correlation with clinical variables. The duration of MV ranged from 6 to 93 h, with a median of 21 h. The median ICU stay was one day and the median postoperative hospital stay was 10 days. A higher removal rate of AchRAb was associated with a shorter duration of ICU and postoperative hospital stay (P = 0.001 and 0.019, respectively). Postoperative hospital stay was strongly correlated with post-DFP Pimax (P = 0.010), and marginally correlated with pre-DFP VC (P = 0.047) and to a lesser extent with pre-DFP Pimax (P = 0.063). Univariate analysis using the log rank test revealed that removal rate of AchRAb <30% (P = 0.043) and pre-DFP Pimax <-60 cmH2O (P = 0.024) were significantly associated with prolonged ICU stay. Risk factors for prolonged postoperative stay included post-DFP Pimax <-60 cmH2O (P = 0.017), pre-DFP Pimax <-60 cmH2O (P = 0.031), and post-DFP VC < 1.0 L (P = 0.046). Our results confirmed the efficacy and safety of DFP in prethymectomy preparation for myasthenic patients.     

Experience of double filtration plasmapheresis in the treatment of Guillain-Barré syndrome

Therapeutic plasma exchange (TPE) is a standard treatment in Guillain-Barré syndrome. TPE may require exogenous fluid for replacement of plasma and, depending on the equipment used, varying extracorporeal volumes. Potential adverse effects include allergic reaction, infection, and hypotension. From September 1993 to December 1997, we treated 16 patients with Guillain-Barré syndrome by a newly developed method of automated double filtration plasmapheresis (DFPP). Patients (ten males and six females, age ranged from 16 to 73) suffering from acute ascending motor weakness and fulfilling the diagnostic criteria for GBS were chosen for DFPP. Each patient received at least five sessions of apheresis in 7 to 10 days and approximately 2.5 to 3.0 L of plasma was treated in each session. Patients were evaluated by disability grade according to a Hughes scale. The mean grade of disability was 3.62 at treatment and improved to 2.37 four weeks after the start of DFPP. The median time to grade 2 (walk without support) was 19 days. There were five patients (41.6%) in need of respirator support. The median time to weaning off the respirator was 9 days. Only two patients (12.5%) could not reach grade 2 at the end of 6 months. Our results were comparable to previously published results of TPE. We conclude that DFPP may be as effective as TPE in the treatment of GBS. J. Clin. Apheresis 14:126–129, 1999. © 1999 Wiley-Liss, Inc.     

双重滤过血浆置换与血浆置换治疗重症自身免疫性疾病的比较研究

目的比较双重滤过血浆置换(DFPP)和血浆置换(PE)治疗重症自身免疫性疾病(SAID)的差异。方法 27例SAID患者分为两组,分别采用DFPP和PE进行治疗,对疗效、并发症、费用、住院时间、实验室指标等进行比较。结果 PE组平均治疗2.2次、住院时间42.5d、治疗费用3.95万元,DFPP组平均治疗2.88次、住院时间41.94d、治疗费用4.99万元。PE组显效50%,好转30%,无效20%;DFPP组显效52.94%,好转35.29%,无效11.76%;两组疗效相当。PE组并发症发生率45.45%,DFPP组并发症发生率8.16%,DFPP组并发症明显少于PE组(P0.05)。PE后白细胞、血红蛋白、血小板、血钾、血肌酐、尿素氮、谷丙转氨酶、白蛋白、球蛋白、免疫球蛋白A(IgA)、IgG、IgM、C3没有差异(P均0.05),只有血钠略有上升(P0.05)。DFPP后白细胞、血红蛋白明显升高,白蛋白、球蛋白、IgA、IgG、IgM、C3明显降低(P均0.05),血小板、血钾、血钠、血肌酐、尿素氮、谷丙转氨酶变化不大(P均0.05)。结论 DFPP在治疗SAID中的作用与PE相当,并发症和风险较小,治疗更有保障。     

Therapeutic plasma exchange for fulminant hepatic failure secondary to Wilson's disease

Wilson's disease (WD) is an autosomal‐recessive disorder of impaired copper metabolism resulting in accumulation of copper primarily in the liver but ultimately in many organs and tissues. A small number of patients with WD initially present with fulminant hepatic failure (FHF), hypercupremia, and intravascular hemolysis. The therapeutic goals for these patients include quickly removing the copper and preparing the patient for liver transplantation. Here, we report on a 6‐year‐old male with WD in FHF with anemia, renal insufficiency, and coagulopathy. The patient received a series of therapeutic plasma exchanges (TPE) as adjunctive therapy to remove copper and stabilize his coagulopathy and anemia until a transplant was possible. A total of five single plasma volume (1500 mL) TPE were performed over the course of 11 days with plasma as the replacement fluid. Laboratory results demonstrated temporary improvement after each procedure. Liver transplantation was performed 12 days after beginning TPE and 35 days after admission to the hospital. TPE was a successful adjunctive therapy to bridge this patient with WD to transplantation. J. Clin. Apheresis 27:282–286, 2012. © 2012 Wiley Periodicals, Inc.     

Successful preoperative treatment of a Graves' disease patient with agranulocytosis and hemophagocytosis using double filtration plasmapheresis

Agranulocytosis is an uncommon but serious complication of Graves' disease under thionamide therapy. In some patients removal of circulating thyroid hormones and thyroid antibodies by plasmapheresis is an effective adjunctive therapeutic option. In perioperative settings, however, plasmapheresis may cause excess bleeding intraoperatively due to coagulation factor depletion unless fresh frozen plasma (FFP) products are used in the replacement fluid mix. Double filtration plasmapheresis (DFPP) in which only a small amount of albumin supplementation is used may be a potential alternative to conventional apheresis interventions where clotting factor depletion is problematic. We report a case of a patient with Graves' disease complicated with intravenous immunoglobulin responsive methimazole-induced agranulocytosis/hemophagocytosis who underwent successful preoperative DFPP treatment in preparation for thyriodectomy. In addition to conventional apheresis using FFP replacement, DFPP may offer an effective adjunct option in the management of hyperthyroid patients needing emergent surgical interventions.     

Serum hyperviscosity syndrome responding to therapeutic plasmapheresis in a patient with primary Sjögren's syndrome

Hyperviscosity syndrome is a disorder first described in patients with Waldenstr?m's macroglobulinemia and is not commonly seen in rheumatic diseases. Its association with Sj?gren's syndrome is very rare and it has been reported in very few patients. We report the case of a patient with primary Sj?gren's syndrome presenting as hyperviscosity syndrome who was successfully treated with therapeutic plasma exchange.     

Role of plasmapheresis in acute disseminated (postinfectious) encephalomyelitis

Acute disseminated encephalomyelitis (ADEM) is a demyelinating central nervous system disease that is associated with high morbidity and mortality. Although the recognition of ADEM may be facilitated by newer imaging techniques, the optimal treatment of this disease remains uncertain. We describe 4 patients with severe ADEM who responded to treatment that included intensive plasmapheresis. Two of the patients were in coma at the time that plasmapheresis was instituted, and all 4 patients made an excellent recovery. Immunologic studies revealed increased serum IgA levels, increased circulating immune complex levels as measured by the Raji cell assay, and decreased numbers of T and B cells prior to treatment of ADEM. These abnormalities improved following plasma exchange. Plasmapheresis appears to be effective in reversing the neuropathologic process in ADEM. The role of this treatment modality in ADEM requires further evaluation in controlled clinical trials. © 1992 Wiley-Liss, Inc.     

Seeing is believing: A review of apheresis therapy in the treatment of ophthalmologic disease

Apheresis procedures have a role in treatment of disparate diseases involving many different organ systems. Often the disease processes where apheresis plays a role in treatment are considered “orphan diseases”—relatively rare disease processes that lack specific pharmaceutical agents or established treatment protocols. Many of these disease processes can affect the eye with devastating results for the eyesight of these patients. The unique ability of apheresis to affect disease by modifying blood plasma and modulating disease‐causing agents therein renders apheresis procedures valuable tools in the treatment of certain ophthalmologic diseases. This review comprehensively evaluates the role of apheresis in the treatment of ophthalmologic diseases of the eye and surrounding orbit including age‐related macular degeneration, bilateral diffuse uveal melanocytic proliferation, paraneoplastic retinopathy, atopic keratoconjunctivitis, sympathetic ophthalmia, and endocrine‐associated ophthalmopathy. Apheresis procedure parameters are provided for the apheresis practitioner based on review of the relevant literature.     

Canine models of inherited bleeding disorders in the development of coagulation assays,novel protein replacement and gene therapies

Animal models of inherited bleeding disorders are important for understanding disease pathophysiology and are required for preclinical assessment of safety prior to testing of novel therapeutics in human and veterinary medicine. Experiments in these animals represent important translational research aimed at developing safer and better treatments, such as plasma‐derived and recombinant protein replacement therapies, gene therapies and immune tolerance protocols for antidrug inhibitory antibodies. Ideally, testing is done in animals with the analogous human disease to provide essential safety information, estimates of the correct starting dose and dose response (pharmacokinetics) and measures of efficacy (pharmacodynamics) that guide the design of human trials. For nearly seven decades, canine models of hemophilia, von Willebrand disease and other inherited bleeding disorders have not only informed our understanding of the natural history and pathophysiology of these disorders but also guided the development of novel therapeutics for use in humans and dogs. This has been especially important for the development of gene therapy, in which unique toxicities such as insertional mutagenesis, germ line gene transfer and viral toxicities must be assessed. There are several issues regarding comparative medicine in these species that have a bearing on these studies, including immune reactions to xenoproteins, varied metabolism or clearance of wild‐type and modified proteins, and unique tissue tropism of viral vectors. This review focuses on the results of studies that have been performed in dogs with inherited bleeding disorders that closely mirror the human condition to develop safe and effective protein and gene‐based therapies that benefit both species.     

Use of autologous pregnancy plasma to treat a flare of juvenile rheumatoid arthritis: case report and literature review

A patient with juvenile rheumatoid arthritis whose disease was in remission during pregnancy underwent third-trimester plasmaphereses. The stored plasma was returned to her 1 year postpartum, when the disease flared, without beneficial results. The literature on the use of blood products in rheumatoid arthritis and pregnancy is reviewed.