Bruce C. McLeod

Frequency of immediate adverse effects associated with therapeutic apheresis.

BACKGROUND: Therapeutic apheresis was found to be reasonably safe in prior studies using instruments that are now largely obsolete. The incidence of adverse effects with current instruments and techniques has not been assessed in a large multicenter study.

Frequency of immediate adverse effects associated with apheresis donation

BACKGROUND: Apheresis donation is considered safe, but the incidence of adverse effects has not been determined in a large multicenter series of donations with modern instruments.

ACCELERATED PROSTACYCLIN DEGRADATION IN THROMBOTIC THROMBOCYTOPENIC PURPURA

Plasma prostacyclin (PGI2) degradation rate was measured in a 39-year-old man with chronic thrombotic thrombocytopenic purpura (TTP). His disease responded to plasma exchange, or plasma infusion alone, given at 3-4 week intervals. Plasmapheresis with albumin replacement had an adverse effect. PGI2 degradation rate was measured by incubation of exogenous PGI2 with plasma at 37 degrees C and recording of PGI2 activity after one, five, and fifteen min incubation by measurement of inhibition of platelet aggregation. The PGI2 degradation rate of the patient was significantly higher than that of normal subjects. The degradation rate improved after each plasma treatment and correlated well with clinical improvement. Moreover, the degradation rate of PGI2 could be corrected in vitro by the addition of normal plasma. When the patients plasma was incubated with aortic rings, PGI2 activity was reduced but the level of its inactive end product, 6-keto-PGF1 alpha, was normal. These findings indicate that our patient had normal PGI2 stimulating activity but had an abnormal rate of PGI2 degradation. Accelerated PGI2 degradation which leads to PGI2 deficiency may be important in the pathogenesis of microvascular thrombosis.

Alloimmunization to RhD by platelet transfusions in autologous bone marrow transplant recipients

Abstract. Platelet transfusions from RhD‐positive (D‐positive) donors are often given to RhD‐negative (D‐negative) cancer patients. The low observed rate of alloimmunization has been attributed to disease and therapy‐related immunosuppression. We have studied the occurrence of alloimmunization in 16 D‐negative patients who did not have detectable anti‐D prior to autologous bone marrow transplantation for malignant disease. All received D‐positive platelets, but no other D‐positive blood product. Three patients (19%) developed anti‐D at 13, 24 and 83 days, respectively, after first receiving D‐positive platelets, and after a total dose of 53, 65 and 119 D‐positive platelet unit equivalents, respectively. Two of them also developed anti‐C. The 13 patients in whom anti‐D was not detected were also heavily transfused with D‐positive platelets (mean ± SD = 136 ± 82 platelet unit equivalents). In 6 of them, the last recorded antibody screen was less than 3 months after the first D‐positive platelets, and may not exclude a primary immune response. Thus, despite profound immunosuppression associated with autologous marrow transplantation, alloimmune responses to D‐positive red cells in platelet concentrates can occur in some D‐negative recipients.

Therapeutic apheresis: history, clinical application, and lingering uncertainties

Undertaking a review article to commemorate a 50th anniversary engenders an appreciation of history. Since therapeutic apheresis (TA) is a field that is completely dependent on an underlying technology, it seems appropriate to begin this article with a brief overview of the history of apheresis technology. As it happens, many seminal events occurred within a 20-year period that nicely brackets the publication of the first issue of TRANSFUSION. One line of development began in Boston in the early 1950s. Dr Edwin Cohn, a Harvard biochemist, had devised a large-scale method for purification of albumin from pooled human plasma. Albumin would tolerate pasteurization and was expected to be a safer agent for resuscitation of wounded soldiers than lyophilized pooled plasma, which had proven in World War II to carry an appalling risk of hepatitis transmission. As an offshoot of this effort, Dr Cohn envisioned a device that would separate donor plasma—the desired component—immediately and “online” during the whole blood donation process. The resulting “Cohn centrifuge,” a huge apparatus with a “reusable” metal centrifugal element, was never really practical for its intended purpose, although it proved useful for deglycerolizing frozen red blood cells (RBCs). Fortunately a young engineer named Alan Latham was commissioned to improve it. When others’ enthusiasm for the instrument flagged, he obtained control of the relevant patents, improved the design of the centrifugal element, and found a way to fabricate a single-use version from plastic at a modest cost. The resulting “Latham bowl” was first marketed in a device for washing or deglycerolizing RBCs (Haemonetics Model 10). It was later adapted for “intermittent-flow” platelet (PLT) donation and TA procedures in the Haemonetics Model 30, which was the first apheresis instrument to be widely available on a commercial basis. A second “bloodline” of technology for TA had its inception at the National Cancer Institute (NCI) in the mid-1960s. George Judson, an IBM engineer whose son was being treated for chronic myelocytic leukemia (CML), asked Dr Emil Freireich if he could use his engineering skills to enhance his son’s treatment. Dr Freireich envisioned a device that would remove some of the excess white blood cells (WBCs) from the blood of CML patients for transfusion to neutropenic patients. A cooperative effort ensued, supported jointly by Mr Judson’s employer and the NCI. The result was a continuous-flow centrifugal blood separator, also with a “reusable” metal bowl and capable not only of meaningful WBC collection and depletion but also of exchanging plasma or RBCs. Subsequent refinements by IBM and by Cobe Laboratories, a dialysis equipment manufacturer that eventually bought IBM’s blood processor division, led to the versatile and more automated Cobe Spectra that became a mainstay of TA in the United States after its introduction in the late 1980s. A third family of apheresis instruments originated at Fenwal in the 1970s. These devices were the first to employ a sealless centrifuge mechanism devised independently by both Herbert Cullis at Fenwal and Yoichiro Ito at the National Institutes of Health. The sealless system ABBREVIATIONS: AQP-4 = aquaporin-4; ASFA = American Society for Apheresis; CML = chronic myelocytic leukemia; CNS = central nervous system; DSA = donor-specific antibody; HUS = hemolytic uremic syndrome; LDL(s) = low-density lipoprotein(s); MAHA = microangiopathic hemolytic anemia; MS = multiple sclerosis; NCI = National Cancer Institute; NMO = neuromyelitis optica; RBCX = red blood cell exchange; SLE = systemic lupus erythematosus; TA = therapeutic apheresis; TPE = therapeutic plasma exchange; TTP = thrombotic thrombocytopenic purpura; XM = crossmatch.

Treatment of metastatic breast cancer with a split-course high-dose chemotherapy regimen and autologous bone marrow transplantation.

PURPOSE We investigated the role of high-dose chemotherapy and autologous bone marrow transplantation (ABMT) as the initial systemic treatment in patients with hormone-unresponsive metastatic breast cancer. We studied a regimen involving a split-course schedule using sequential administration of two pairs of alkylating agents separated by 5 days of rest. The rest period was intended to provide time for recovery from the treatment-immediate adverse effects, thereby allowing further dose escalation. PATIENTS AND METHODS The treatment consisted of thiotepa 225 to 300 mg/m2/d (days - 11 to -9), cisplatin 50 to 100 mg/m2/d (days - 11 and -3), and cyclophosphamide 60 mg/kg/d (days - 3 and -2). Dose escalation was performed in the initial 15 patients before reaching dose-limiting toxicities. When feasible, responding patients received posttransplant irradiation to sites of residual or prior bulky disease. Patients with bone marrow or CNS involvement, prior pelvic irradiation, or age greater than 55 years were excluded. RESULTS Thirty-nine patients with measurable or assessable tumor were enrolled: 23 with visceral metastases, 11 with only soft tissue disease, and five with skeletal involvement. Twenty-five patients had received no chemotherapy for metastatic disease before transplantation. The dose-limiting toxicities of this therapy were renal and gastrointestinal. Six patients died from complications: four of a fungal infection and two of hemorrhage. A complete response was achieved in 14 patients (36%), three of whom are free of disease at 79+, 55+, and 40+ months after transplantation. Ten of 25 patients not treated with standard-dose chemotherapy for metastatic disease achieved a complete response (40%). The three patients in continuous remission were in the untreated relapse group. CONCLUSION This single high-dose treatment achieved a relatively high complete response rate in patients with metastatic breast cancer and may have cured some of them. On the other hand, the split-course dose schedule as tested here did not permit significant dose-intensification.

Complement activation by plasma separator membranes

Because of their structural similarity to dialysis membranes, six plasma separator membranes were evaluated for the ability to activate complement, as judged by immunoconversion of the third component of complement in crossed Immunoelectro‐phoresis. A polysulfone and two cellulose acetate membranes were relatively strong alternative pathway activators. Polypropylene, poly[vinylidine fluoride] and polyvinyl‐chloride derivative membranes were weak activators in some sera. Membrane activation was inhibited in citrate‐anticoagulated but not in heparin‐anticoagulated plasma. The results of such in vitro screening should be of value in selecting materials and anticoagulation regimens for membrane plasma separators.

Plasma and plasma derivatives in therapeutic plasmapheresis.

In therapeutic plasmapheresis, patient plasma is withdrawn and a colloid replacement solution is infused in its place. A 4% to 5% human serum albumin solution in saline is the preferred replacement solution in most instances, even though this practice causes transient mild deficiencies of most plasma proteins. Albumin solutions are pasteurized for viral inactivation, are very unlikely to cause a febrile or allergic reaction, and are convenient to store and administer. Single‐donor plasma must be type specific, which requires advance knowledge of patient blood type, and must be ordered and usually thawed before use. It also carries a higher risk of reactions. On the plus side, it replaces all plasma constituents and is appropriate for patients with thrombotic thrombocytopenic purpura or an existing coagulopathy. Neither cryosupernatant plasma, which is relatively deficient in the proteins in cryoprecipitate, nor plasma derived from pools that have been virally inactivated with detergents and organic solvents has been shown to produce better outcomes than fresh frozen plasma for any indication.

Long-term frequent plasma exchange donation of cryoprecipitate

Plasma exchange donation accomplishes the selective donation of cryoprecipitate. It facilitates the repeated donation of large quantities of factor VIII by individual donors and reduces donor exposure for recipients. A highly motivated donor is described who has undergone 103 donations between May 1983 and March 1987, producing 359,460 IU of factor VIII and supplying all the factor VIII needed since August 1983 by his severely affected hemophiliac son, now age 14. The donor has remained in good health, and no significant abnormalities have been noted in hematologic, biochemical, immunologic, coagulation, and serum protein testing. Extensive experience with this donor suggests that repeated plasma‐exchange donation is safe and can sometimes allow single‐donor support of severe hemophiliacs.

A High-Potency, Single-Donor Cryoprecipitate of Known Factor VIII Content Dispensed in Vials

Current factor VIII products expose recipients to many donors and hence to a high risk of acquiring blood-borne infections. Plasma-exchange donation of cryoprecipitate can reduce donor exposure by repeatedly obtaining large yields of factor VIII from individual donors. In this study, donor factor VIII levels were stimulated with desmopressin before donation. Mean yield per donation increased from 1399 +/- 425 IU in controls to 3818 +/- 1350 IU in stimulated donations (p less than 0.001), and mean factor VIII concentration in the cryoprecipitate increased from 8.2 +/- 3 IU/mL to 24 +/- 12 IU/mL (p less than 0.001). A new packaging system dispenses assayed aliquots of stimulated cryoprecipitate in plastic vials. The direct cost of production for this material is