Persistence of recipient plasma cells and anti-donor isohaemagglutinins in patients with delayed donor erythropoiesis after major ABO incompatible non-myeloablative haematopoietic cell transplantation.

Delayed donor erythropoiesis and pure red-cell aplasia (PRCA) complicate major-ABO mismatched non-myeloablative allogeneic stem-cell transplantation. To characterize these events, we analysed red-cell serology and chimaerism in lymphohaematopoietic lineages, including plasma cells and B cells, in 12 consecutive major-ABO incompatible transplants following cyclophosphamide/fludarabine-based conditioning. Donor erythropoiesis was delayed to more than 100 days in nine (75%) patients including six (50%) who developed PRCA. During PRCA, all patients had persistent anti-donor isohaemagglutinins and recipient plasma cells (5-42%), while myeloid and T cells were completely donor in origin. In contrast, B-cell chimaerism was frequently full-donor when significant anti-donor isohaemagglutinins persisted. Four patients with early mixed haematopoietic chimaerism and the prolonged presence of anti-donor isohaemagglutinins and recipient plasma cells developed delayed-onset (>100 days post-transplant) red cell transfusion dependence and PRCA after myeloid chimaerism converted from mixed to full donor. These findings confirm that donor-erythropoiesis is impacted by temporal disparities in donor immune-mediated eradication of recipient lymphohaematopoietic cells during major-ABO incompatibility and suggest that plasma cells are relatively resistant to graft-versus-host haematopoietic effects.

Transfusion medicine management for reconstructive spinal repair in a patient with von Willebrand's disease and a history of heavy surgical bleeding.

STUDY DESIGN: A case report of a multidisciplinary approach to a second reconstructive back surgery in a patient with von Willebrand's disease, flatback syndrome, and a history of heavy surgical bleeding is presented. OBJECTIVE: To review the perioperative planning and assessment of hemostasis and transfusion medicine management, including administration of Humate P, a Factor VIII preparation with high von Willebrand factor content. SUMMARY OF BACKGROUND DATA: Reconstructive spinal procedures may require significant transfusion support even in patients with normal preoperative hemostasis. In addition to the hemostatic problem caused by von Willebrand's disease, the reported patient requested minimal exposure to allogeneic blood products because of hepatitis C infection acquired from previous transfusions. METHODS: The multidisciplinary team included the patient, hematologist, blood bank medical director, anesthesiologist, and operating surgeon. Preoperative assessment showed a Type 2A von Willebrand's disease variant. A careful planning process included a test infusion of desmopressin and extensive autologous donations of red cells, plasma, and platelets, which were collected before the procedure. RESULTS: Anterior and posterior spine fusions were performed during a 14-hour procedure. Hemostasis and clinical response were excellent. Humate P was administered perioperatively as assessed by the baseline Factor VIII and von Willebrand's disease levels, the plasma volume, the half-life of infused Humate P, and the anticipated risk and tolerance for bleeding. The estimated blood loss was 5 L. Replacement included 9 units of autologous red cells, 6 units of autologous plasma, 2 autologous plateletpheresis collections, a single allogeneic plateletpheresis product, and 17,000 units of Humate P administered over the perioperative period. CONCLUSIONS: Using a careful multidisciplinary approach, excellent hemostasis can be achieved with minimal exposure to untreated allogeneic blood products during aggressive spinal surgery in a patient with a clinically significant congenital coagulopathy.

Comprehensive analysis of citrate effects during plateletpheresis in normal donors.

BACKGROUND: Although plateletpheresis procedures are generally well tolerated, the clinical and metabolic consequences associated with rapid infusion of up to 10 g of citrate are underappreciated, and a comprehensive description of these events is not available. STUDY DESIGN AND METHODS: Clinical and laboratory changes were studied in seven healthy donors undergoing three 90-minute plateletpheresis procedures each, at continuous, fixed citrate infusion rates of 1.1, 1.4, and 1.6 mg per kg per minute. RESULTS: Serum citrate levels increased markedly with increasing citrate infusion rates and did not achieve a stable plateau. As citrate infusion rates increased, the total volume processed and platelet yields also increased, but donor symptoms became more severe. Ionized calcium (iCa) and ionized magnesium (iMg) concentrations decreased markedly, by 33 and 39 percent below baseline, respectively, at a citrate rate of 1.6 mg per kg per minute. Intact parathyroid hormone levels were higher at 30 minutes than at later time points, despite progressive decreases in iCa and iMg. Urine citrate, calcium, magnesium, sodium, and potassium concentrations and urine pH values increased markedly during all procedures. CONCLUSION: Marked, progressive increases in serum citrate levels occur during plateletpheresis, accompanied by symptomatic decreases in iCa and iMg, with significantly increased renal excretion of calcium, magnesium, and citrate.

Delayed donor red cell chimerism and pure red cell aplasia following major ABO-incompatible nonmyeloablative hematopoietic stem cell transplantation.

Delayed donor red cell engraftment and pure red cell aplasia (PRCA) are well-recognized complications of major ABO-incompatible hematopoietic stem cell transplantation (SCT) performed by means of myeloablative conditioning. To evaluate these events following reduced-intensity nonmyeloablative SCT (NST), consecutive series of patients with major ABO incompatibility undergoing either NST (fludarabine/cyclophosphamide conditioning) or myeloablative SCT (cyclophosphamide/high-dose total body irradiation) were compared. Donor red blood cell (RBC) chimerism (initial detection of donor RBCs in peripheral blood) was markedly delayed following NST versus myeloablative SCT (median, 114 versus 40 days; P <.0001) and strongly correlated with decreasing host antidonor isohemagglutinin levels. Antidonor isohemagglutinins declined to clinically insignificant levels more slowly following NST than myeloablative SCT (median, 83 versus 44 days; P =.03). Donor RBC chimerism was delayed more than 100 days in 9 of 14 (64%) and PRCA occurred in 4 of 14 (29%) patients following NST, while neither event occurred in 12 patients following myeloablative SCT. Conversion to full donor myeloid chimerism following NST occurred significantly sooner in cases with, compared with cases without, PRCA (30 versus 98 days; P =.008). Cyclosporine withdrawal appeared to induce graft-mediated immune effects against recipient isohemagglutinin-producing cells, resulting in decreased antidonor isohemagglutinin levels and resolution of PRCA following NST. These data indicate that significantly delayed donor erythropoiesis is (1) common following major ABO-incompatible NST and (2) associated with prolonged persistence of host antidonor isohemagglutinins. The clinical manifestations of these events are affected by the degree and duration of residual host hematopoiesis.

MCV as a guide to phlebotomy therapy for hemochromatosis.

BACKGROUND: A multitude of recommendations exist for laboratory assays to monitor the pace and endpoints of phlebotomy therapy for hemochromatosis. All of these recommendations rely on an assessment of storage iron to guide treatment, and none have been prospectively evaluated. STUDY DESIGN AND METHODS: Nine consecutive patients underwent serial monitoring of Hb, MCV, transferrin saturation, and ferritin during weekly phlebotomy to deplete iron stores (induction therapy) and less frequent sessions to prevent iron reaccumulation (maintenance therapy). Changes in MCV and Hb were used to guide the pace of phlebotomy over a median of 7 years of follow-up. RESULTS: During induction therapy, the MCV increased transiently because of reticulocytosis and then stabilized for a prolonged period before decreasing more sharply, which reflected iron-limited erythropoiesis. Iron depletion was achieved after a median of 38 phlebotomies and removal of 9.0 g of iron. Maintenance phlebotomy was targeted to maintain the MCV at 5 to 10 percent below prephlebotomy values and the Hb at >13 g per dL. Transferrin saturation fluctuated considerably during treatment, but remained below 35 percent during MCV-guided maintenance therapy. Ferritin values were not useful guides to the pace of phlebotomy. The median maintenance therapy phlebotomy interval was 7.5 weeks (range, 6-16), which corresponded to an average daily iron removal of 35 to 67 microg per kg. Most patients showed evidence of iron reaccumulation at phlebotomy intervals of 8 weeks or more. CONCLUSION: The MCV is an inexpensive, precise, physiologic indicator of erythropoietic iron availability. When used in conjunction with the Hb, it is a clinically useful guide to the pace of phlebotomy therapy for hemochromatosis.

Massive immune haemolysis after allogeneic peripheral blood stem cell transplantation with minor ABO incompatibility.

Immune haemolysis as a result of minor ABO incompatibility is an underappreciated complication of haematopoietic transplantation. The increased lymphoid content of peripheral blood stem cell (PBSC) transplants may increase the incidence and severity of this event. We observed massive immune haemolysis in 3 out of 10 consecutive patients undergoing HLA-identical, related-donor PBSC transplants with minor ABO incompatibility. Non-ablative conditioning had been given in 9 of these 10 cases, including two with haemolysis. Cyclosporin alone was used as prophylaxis against graft-vs.-host disease (GVHD). Catastrophic haemolysis of 78% of the circulating red cell mass led to anoxic death in the first case seen, but severe consequences were avoided by early, vigorous donor-compatible red cell transfusions in the subsequent two cases. Haemolysis began 7-11 d after PBSC infusion and all patients with haemolysis had a positive direct antiglobulin test (DAT), with eluate reactivity against the relevant recipient antigen. However, neither the intensity of the DAT, the donor isohaemagglutinin titre, nor other factors could reliably be used to predict the occurrence of haemolysis. Our data indicate that haemolysis may be frequent and severe after transplantation of minor ABO-incompatible PBSCs when utilizing cyclosporin alone to prevent GVHD. Meticulous clinical monitoring and early, vigorous donor-compatible red cell transfusions should be practiced in all instances.

Operational medicine experience integrated into a military internal medicine residency curriculum.

The optimal training of physicians should prepare them for the environment in which they will practice. During the past several years, the practice of internal medicine has shifted from a focus on the inpatient setting to one that includes an emphasis on the ambulatory clinic. Military internists must be further prepared to practice medicine with forward units, at field hospitals, and in other operational settings. Community-based teaching programs that reflect present and future practice are increasingly recognized as essential, yet details on the structure and implementation of such programs, especially those designed to teach field and operational medicine, are lacking. The Internal Medicine Residency Program at Walter Reed Army Medical Center has developed and implemented an operational medicine curriculum that includes a field medical training exercise. The program is driven by the residents and chief resident and requires little additional funding. Resident research continues to increase, morale remains high, and the first class to complete the 3-year operational curriculum achieved a 100% pass rate on the American Board of Internal Medicine certification examination. We describe our 3-year experience of implementing this program, with an emphasis on curriculum design and execution, qualitative assessment, and initial lessons learned.

Operational experiences during medical residency: perspectives from the Walter Reed Army Medical Center Department of Medicine.

The preparation of military primary care physicians for practice in operational environments has taken on greater importance during the past decade. The Department of Defense military-unique curriculum identifies the elements that should be incorporated into residency training programs to accomplish comprehensive training in operational matters. We describe efforts to integrate the military-unique curriculum into internal medicine residency, including obstacles encountered, so that other programs may learn from our experience.

Association of protein S deficiency with thrombosis in a kindred with increased levels of plasminogen activator inhibitor-1.

OBJECTIVE: A single kindred in North America with venous thrombosis was described as having defective fibrinolysis because of increased levels of plasminogen activator inhibitor-1 (PAI-1). Our study describes the discovery of protein S deficiency in this kindred and its association with venous thromboembolism. DESIGN: A family study. SETTING: Community. PARTICIPANTS: Twenty-eight adults (ages 21 to 71 years) from three generations of the kindred; seven had a history of venous thromboembolism. MEASUREMENTS: Plasma levels of total and free protein S antigen, as well as the activities of protein S, protein C, PAI-1, and antithrombin III. RESULTS: Six of 7 persons (86%) with a history of venous thromboembolism were deficient in total and free protein S; of 21 asymptomatic members, 9 were deficient in protein S (P = 0.08). When compared with these 9 asymptomatic family members, the 6 persons with protein S deficiency and a history of thrombosis tended to smoke (P = 0.01) and to have higher triglyceride levels (P = 0.001). Overall, the mean PAI-1 activity in the 7 persons who had thrombosis was 7.9 kAU/L (AU/mL) and was 9.3 kAU/L (AU/mL) in the 21 persons who did not have thrombosis (95% CI, -9.9 to 7.0). CONCLUSIONS: In this kindred, a deficiency of total and free or functional protein S is the cause of thrombosis. Measurement of PAI-1 activity was not useful in the evaluation of familial thrombosis. The utility of the routine measurement of PAI-1 activity in the evaluation of familial thrombosis has not been established.

Human ehrlichiosis: a newly recognized tick-borne disease.

Human ehrlichiosis was first described in the United States in 1986. Since then, more than 215 cases have been reported, including some fatalities. Ehrlichia species belong to the same family as the organism that causes Rocky Mountain spotted fever. Human ehrlichiosis occurs most frequently in the southern mid-Atlantic and south-central states, during spring and summer months. The clinical presentation is similar to that seen in Rocky Mountain spotted fever although, with ehrlichiosis, leukopenia is more often found and skin rash is less often noted. Definitive diagnosis is based on acute and convalescent serum antibody titers. Ehrlichiosis cannot reliably be distinguished from other common febrile illnesses on the basis of clinical, epidemiologic or laboratory features. Therapy must be initiated empirically in suspected cases. Both ehrlichiosis and Rocky Mountain spotted fever respond well to tetracycline and chloramphenicol, but not to penicillins or cephalosporins.

Recurrent venous thrombosis and hypercoagulable states.

Patients with recurrent venous thrombosis, or those with thrombosis at a young age (less than 45 years) and a family history of thrombotic disorders, may have an inherited hypercoagulable disorder. The most common disorders are deficiencies of protein S, protein C and antithrombin III, inhibitors of the coagulation cascade. These deficiencies may be found in approximately 10 percent of patients who are under age 45 and have venous thrombosis. Acquired disorders associated with recurrent venous thrombosis include carcinoma and antiphospholipid antibody syndrome. Appropriate anticoagulation can reduce the risk of recurrent thrombosis in patients with inherited and acquired abnormalities.

Synchronous diffuse well-differentiated lymphocytic lymphoma and gastric adenocarcinoma presenting as splenomegaly and iron deficiency anemia.

Diffuse well-differentiated lymphocytic lymphoma (D-WDLL) and chronic lymphocytic lymphoma (CLL) represent closely related neoplasms which may have indolent courses. Dating back more than one century, reports of associated second primary malignancies continue to intrigue clinicians. A case of synchronous D-WDLL and gastric adenocarcinoma, presenting as splenomegaly and iron deficiency anemia, is presented. The case and literature are reviewed.

Oxygen consumption and temperature control of premature infants in a double-wall incubator.

The effects of a double wall in a forced convection-heated incubator were studied on ten naked, nondistressed, premature infants by measuring their mean skin temperature, esophageal temperature, and oxygen consumption when they were in thermal steady state, with, and without, the double wall in place. The incubator air temperature was maintained within the recommended thermoneutral zone during the consecutive paired experiments. Ambient room temperature and relative humidity were constant and the infant's activity (quiet sleep) and postprandial state were the same in both conditions. Together with a significant rise in operative temperature (P less than .05) induced by the double wall (accounted for by a 0.9 C mean increased in incubator wall temperature nearest the baby), their mean skin temperature and esophageal temperatures increased (P less than .025), while a decrease in oxygen consumption occurred in nine of the ten infants (P less than .05). These findings suggest that the double wall reduced radiant and total heat loss from the baby by diminishing the temperature gradient between the skin and incubator surfaces and that metabolic heat production (oxygen consumption) was reduced when the double wall was in place.