Posterior reversible encephalopathy syndrome in infection, sepsis, and shock.

BACKGROUND AND PURPOSE: The cause of "posterior reversible encephalopathy syndrome" (PRES) is not established. We recently encountered several patients who developed PRES in the setting of severe infection. In this study, we comprehensively reviewed the clinical and imaging features in a large cohort of patients who developed PRES, with particular attention to those with isolated infection, sepsis, or shock (I/S/S). METHODS: The clinical/imaging features of 106 patients who developed PRES were comprehensively evaluated. In 25 of these patients, PRES occurred in association with severe I/S/S separate from transplantation. The clinical/imaging features (computer tomography, MR imaging, and MR angiography [MRA]) of the patients with I/S/S were further evaluated, including organ/tissue/blood culture results, mean arterial blood pressure (MAP) at toxicity, extent of cerebral edema, and presence of vasospasm. RESULTS: PRES occurred in association with I/S/S in 25 of 106 patients (23.6%), in addition to 4 other major clinical settings, including cyclosporine/FK-506 (post-transplant) neurotoxicity (46.2%), autoimmune disease (10.4%), postchemotherapy (3.7%), and eclampsia (10.4%). In the 25 patients with I/S/S, available cultures demonstrated a predominance of gram-positive organisms (84%). Blood pressure was "normal" at toxicity in 10 patients (MAP, 95 mm Hg); "severe" hypertension was present in 15 patients (MAP, 137 mm Hg). Extent of brain edema graded on imaging studies was greater in the normal MAP group compared with the severe hypertension group (P < .05). MRA demonstrated vasospasm in patients with severe hypertension and vessel "pruning" in the normal MAP group. CONCLUSION: Infection/sepsis/shock may be an important cause of PRES, particularly in relation to infection with gram-positive organisms.

Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is an immune-mediated syndrome caused by heparin. Complications range from thrombocytopenia to thrombocytopenia with thrombosis. We report a prospective, historical- controlled study evaluating the efficacy and safety of argatroban, a direct thrombin inhibitor, as anticoagulant therapy in patients with HIT or HIT with thrombosis syndrome (HITTS). METHODS AND RESULTS: Patients with HIT (isolated thrombocytopenia, n=160) or HITTS (n=144) received 2 microgram. kg(-1). min(-1) IV argatroban, adjusted to maintain the activated partial thromboplastin time 1.5 to 3.0 times baseline value. Treatment was maintained for 6 days, on average. Clinical outcomes over 37 days were compared with those of 193 historical control subjects with HIT (n=147) or HITTS (n=46). The incidence of the primary efficacy end point, a composite of all-cause death, all-cause amputation, or new thrombosis, was reduced significantly in argatroban-treated patients versus control subjects with HIT (25.6% versus 38.8%, P=0.014). In HITTS, the composite incidence in argatroban-treated patients was 43.8% versus 56.5% in control subjects (P=0.13). Significant between-group differences by time-to-event analysis of the composite end point favored argatroban treatment in HIT (P=0.010) and HITTS (P=0.014). Argatroban therapy, relative to control subjects, also significantly reduced new thrombosis and death caused by thrombosis (P<0.05). Argatroban-treated patients achieved therapeutic activated partial thromboplastin times generally within 4 to 5 hours of starting therapy and, compared with control subjects, had a significantly more rapid rise in platelet counts (P=0.0001). Bleeding events were similar between groups. CONCLUSIONS: Argatroban anticoagulation, compared with historical control subjects, improves clinical outcomes in patients who have heparin-induced thrombocytopenia, without increasing bleeding risk.

Potentiation of carmustine-cranial irradiation-induced myelosuppression by cimetidine.

In nine patients with glioblastomas, the histamine H2-receptor antagonist cimetidine was found to augment the myelosuppressive activities of carmustine and cranial irradiation. The nadir in neutrophil cell counts in this group averaged 650 +/- 220/microL. In a comparable series of 31 patients who did not receive cimetidine, the lowest neutrophil cell count averaged 2,160 +/0 240/microL. Further, marked suppression of these cells in the patients receiving cimetidine extended through day 42 of the treatment cycle. By contrast, the patients treated with carmustine and cranial irradiation alone did not experience significant neutropenia. This suggests that cimetidine may enhance the myelosuppressive effects of cytotoxic therapy.

Engraftment with peripheral blood stem cells using noncontrolled-rate cryopreservation: comparison with autologous bone marrow transplantation.

Peripheral blood stem cells (PBSC) are used increasingly as a source of stem cell support following myeloablative therapy. In this report, the results of 33 patients undergoing PBSC transplantation were compared to 17 concurrent patients undergoing autologous bone marrow transplantation (ABMT). PBSC were cryopreserved using 6% pentastarch and 5% dimethyl sulfoxide (DMSO) with noncontrolled-rate freezing. Many patients in the PBSC group were selected because they were excluded as candidates for ABMT due to prior pelvic irradiation, marrow tumor involvement, or other factors. PBSC were mobilized with high-dose cyclophosphamide (CY), CY+granulocyte-macrophage colony-stimulating factor (GM-CSF), or GM-CSF alone. Colony-stimulating factors were not administered after transplantation. A median of 7.4 x 10(8) mononuclear cells (MNC)/kg were collected containing a median of 3.2 x 10(4) granulocyte-macrophage colony-forming units (CFU-GM)/kg and 5.7 x 10(4) burst-forming units (BFU-E)/kg. After thawing, CFU-GM recovery was 67% and BFU-E recovery was 59%. The thawed, pooled PBSC contained 6.4 x 10(6) CD34+ cells/kg. The entire PBSC volume (median 870 mL) was infused over a median of 157 minutes. PBSC patients required a median of 15 days to achieve an ANC of 500/microL and 22 days for a platelet count of 50,000/microL. Neutrophil recovery was inversely correlated with the number of harvested progenitor cells (p = 0.014); the time to achieve a platelet count of 50,000/microL was inversely associated with CD34+ cells/kg (p = 0.005). PBSC transplant patients achieved an ANC of 500/microL 6 days faster (p < 0.05) and had a 10-day shorter hospitalization (p < 0.05) than ABMT patients. Use of noncontrolled-rate cryopreserved PBSC is associated with faster engraftment and shorter hospital duration than ABMT.

Ex vivo purging of allogeneic marrow with L-Leucyl-L-leucine methyl ester. A phase I study.

L-Leucyl-L-leucine methyl ester (LLME) is a lysosomatropic compound that is converted by dipeptidyl peptidase I to metabolites that are membranolytic for cytotoxic T cells, NK cells, and LAK cells. Ex vivo treatment of murine marrow with LLME ameliorates acute graft-versus-host-disease (GVHD), which led to consideration of a clinical study. A phase I study design was initiated to evaluate the effects of ex vivo purging of allogeneic marrow on engraftment, since LLME also suppresses human progenitor cells. All patients received a preparative regimen of cyclophosphamide plus total body irradiation. GVHD prophylaxis consisted of cyclosporine +/- corticosteroids. This study included 19 patients with high risk disease undergoing allogeneic transplantation from an HLA-identical sibling (n = 12) or a partially HLA-matched family donor (n = 7). Marrow mononuclear cells were treated ex vivo in a dosage escalation study with LLME concentrations of 0.25 mM, 0.375 mM, and 0.5 mM. Marrow NK and LAK activities were essentially eliminated at concentrations > or = 0.375 mM LLME. CD8+ cells were also reduced. Granulocyte macrophage colony-forming unit recovery was 3% at 0.5 mM LLME. The median time to an absolute neutrophil count of 500/microliters was 17 days after transplantation (95% confidence interval = 14-18 days). One patient that received marrow treated with 0.5 mM LLME died of secondary graft failure. Complete donor chimerism was documented in each evaluable case. NK recovery was delayed at LLME concentrations > or = 0.375 mM LLME. Grade II/IV GVHD occurred in 4/18 evaluable patients. Ex vivo treatment of human marrow with LLME diminishes NK activity, LAK activity, CD8+ cells, and granulocyte macrophage colony-forming units, but does not totally prevent acute GVHD.

Non-occlusive bleeding times may improve the value of Ivy bleeding times.

The present studies measured bleeding times, without venous occlusion, in a series of patients, whose bleeding times (+ venostasis) consistently exceeded 20 min. During these tests, the amount of blood loss (expressed as mg/min) was also quantitated. To allow comparison, normal controls were studied before and following aspirin ingestion. In normal controls, the mean standard Ivy bleeding time was 5.0 with a range of 2.5 to 7.5 min. Two hours after aspirin (650 mg), this increased to 7.3 min (range 4.0-12.0). For comparison, the non-occlusive bleeding time averaged 3.8 min (1.0-6.5) and after aspirin 5.3 min (2.5-11.5). The measured amount of blood loss was 5.0 mg/min (0-10.5 mg/min) under all of the above conditions. At the other extreme, patients with severe bone marrow failure had occluded and non-occluded bleeding times in excess of 20 min. Moreover, these were often associated with excess blood loss. By contrast, patients with "Ivy" values greater than 20 min in association with platelet counts greater than 10,000/microliters had unpredictable bleeding parameters. In the latter group, the non-occluded values ranged from 1 to greater than 20 min. Of particular note, the non-occlusive times appeared to correlate with spontaneous bleeding manifestations. Only a rare patient (1/37), whose non-occluded value was less than 20 min, had worrisome bleeding. By contrast, serious bleeding manifestations were observed in 39% whose non-occluded value exceeded 20 min. This was even higher (64%) in those with a non-occluded value greater than 20 min and excess blood loss.(ABSTRACT TRUNCATED AT 250 WORDS)

Pilot study of combined cryosupernatant and protein A immunoadsorption exchange in the treatment of grade 3-4 bone marrow transplant-associated thrombotic microangiopathy.

Bone marrow transplant-associated thrombotic microangiopathy (BMT-TM) ranges in severity from a self-limiting to a fatal disorder. There is no specific therapy for this condition to date. We have previously described a simple clinical grading system (grade 0-4) for BMT-TM; patients with grade 3-4 BMT-TM do poorly. A previous study in our institution suggested that a combination of exchange with cryosupernatant replacement and protein-A immunoadsorption (PAI) might be of benefit. Therefore we performed a pilot study to evaluate the effectiveness of cryosupernatant alternating with PAI exchange for 2 weeks in a series of 13 patients with grade 3-4 BMT-TM. Twelve of 13 patients had undergone allogeneic-BMT a median of 25 days (range of 5-458 days) prior to the onset of grade 3-4 BMT-TM. The thirteenth patient had undergone autologous peripheral stem cell transplant 11 days prior to grade 4 BMT-TM. Pre-therapy, 10 patients had grade 4 BMT-TM and three had grade 3. Eight (62%) showed a response to treatment. Post-therapy, four responders had grade 3, three had grade 2 and one had grade 0 BMT-TM. The median follow-up of the responders is 90 days (range 21 to 464). Three responders have died at 21, 44, and 226 days following the development of BMT-TM of interstitial pneumonia in one, aspergillus in one, and multiorgan failure syndrome (MOFS) in one. The remaining responders are alive 66-465 days post-TM. All non-responders died of MOFS at 6-31 days post-TM. These results suggest that combined exchange with cryosupernatant alternating with PAI is effective therapy for some patients with moderate to severe BMT-TM and may improve survival.

Cyclophosphamide-mobilized peripheral blood stem cells in patient with lymphoid malignancies.

Mobilization of peripheral blood stem cells (PBSC) can be accomplished with cytokines or rebound from myelo-suppressive chemotherapy. In this study, patients were mobilized with cyclophosphamide (CY) 4 g/m2 either alone or followed by GM-CSF 250 micrograms/m2 or G-CSF 600 micrograms. Colony-stimulating factors were administered subcutaneously. Eligibility included patients with non-Hodgkin's lymphoma (NHL; n = 29), Hodgkin's disease (n 4) and acute lymphoblastic leukemia (n = 2). One patient died from mobilization-related complications. Admission for neutropenic fevers and other complications occurred in 73% of patients receiving CY alone compared with 32% received CY + G-CSF or GM-CSF (P < 0.05). Apheresis was initiated when the white blood count approached 1 x 10(9)/l and continued until approximately 6 x 10(8) mononuclear cells/kg were collected. Mobilization with CY + GM-CSF led to significantly greater numbers of collected CFU-GM than with CY alone. Colony-stimulating factors were not administered after transplantation. collected progenitor cells correlated with the peak cell counts after mobilization. Following transplantation, an ANC > = 500 x 10(6)/l was achieved at 14.5 days and a platelet count > = 50 x 10(6)/l was achieved on day 20. Days to achieve an ANC > = 500 x 10(6)/l did not correlate with any of the analyzed variables. Platelet engraftment correlated with harvested BFU-E, thawed CD34+ cells and peak counts following mobilization. for patients with NHL, CR was obtained in 82% of evaluable cases. Median time to relapse was 343 days. Twenty five per cent of patients remain disease-free at 900+ days of follow-up.(ABSTRACT TRUNCATED AT 250 WORDS)

Bone marrow transplant-associated thrombotic microangiopathy: a case series.

Bone marrow transplant-associated thrombotic microangiopathy (BMT-TM) has been reported with widely varying frequencies and outcomes. Therefore a BMT-TM grading system (0-4) was developed based on the lactate dehydrogenase (LD) level and percentage (%) fragmented cells (FC) as follows: grade 0, normal or increases LD and FC < or = 1.2%; grade 1, normal LD and FC > or = 1.3%; grade 2, increases LD and FC = 1.3-4.8%; grade 3 increases LD and FC = 4.9-9.6%; and grade 4, increases LD and FC > or = 9.7%. Patients with grade 0 and grade 1 BMT-TM did not differ in clinical parameters. Twenty two patients had BMT-TM grade 2-4. These were observed for outcome. Seven of 10 with grade 2 BMT-TM had resolution of BMT-TM a median of 99 days (range 50-229 days) from diagnosis. This occurred spontaneously in five and following discontinuance of cyclosporine (CsA) in two. The remaining three had persistent BMT-TM at grade 2 (two patients) and grade 1 (one patient). In contrast, none with grade 3-4 BMT-TM had resolution. Seven with grades 3-4 BMT-TM underwent a variety of plasma exchange procedures; six had partial hematologic responses. Patients with grades 3-4 BMT-TM had a poorer survival (median survival = 60 days) than those with grade 2 BMT-TM where the median survival has not been reached (P = 0.018). These results indicate that BMT-TM is common following allogeneic-BMT and the outcome is dependent on the grade. Those with grade 1-2 BMT-TM generally do well.(ABSTRACT TRUNCATED AT 250 WORDS)

Calpain activity in bone marrow transplant-associated thrombotic thrombocytopenic purpura.

The pathophysiology of thrombotic thrombocytopenic purpura (TTP) is not well understood. Recent studies have described a platelet aggregating factor which has been characterized as a calcium-dependent cysteine protease (calpain) in patients with TTP. A type of TTP, sometimes called secondary TTP, has been associated with bone marrow transplantation (BMT). However, unlike primary adult TTP, BMT-TTP has important differences and often does not respond well to plasma exchange. We describe the measurement of calpain activity in a group of BMT patients (with and without the clinical syndrome of transplant-associated TTP). Calpain was measured using a functional assay (14C-serotonin platelet release with inhibition by the cysteine protease inhibitor, leupeptin) in the sera of patients following autologous (auto) or allogeneic (allo) BMT. We also independently diagnosed and graded the BMT-TTP on the day of blood sampling using a scale that related to the percentage schistocytes and lactic dehydrogenase level. Calpain activity was detected in 1/8 (13%) grade 0-1 (6 auto, 2 allo); 6/16 (38%) grade 2 (3 auto, 13 allo) 9/16 (56%) grade 3 (2 auto, 14 allo) and 8/8 (100%) grade 4 BMT-TTP. Pre-BMT samples were tested in 10 allo-BMT patients who had positive calpain results post-BMT. One patient gave positive results before the transplant. This patient developed grade 4 BMT-TTP (day 24 post-BMT) and died despite apheresis. Positive calpain results were highly associated with neurologic symptoms, P < 0.001. Nineteen of 24 (79%) patients with positive results had neurologic symptoms compared to three of 21 (14%) patients with negative results. In conclusion, calpain was detected in half of the BMT patients with mild to moderate BMT-TTP (grades 2-3) and was uniformly found in those with severe (grade 4) BMT-TTP. Typically the calpain activity develops as TTP complicates the transplant process. It is unknown whether calpain contributes to the pathogenesis of this disorder, or is a secondary event.

Reduction of allogeneic transplant morbidity by combining peripheral blood and bone marrow progenitor cells.

One case has been reported of a patient undergoing allogeneic transplantation with peripheral blood progenitor cells (PBPCs) rather than bone marrow. We now report the first case of a patient who underwent an allogeneic transplant with bone marrow combined with PBPCs.

Phase II study of roquinimex in myelodysplastic syndrome.

A Phase II clinical trial was undertaken using roquinimex (Linomide) in patients with myelodysplastic syndromes (MDS). Roquinimex is an orally active drug with immunostimulating activities demonstrated in vitro and clinically. Seventeen patients with MDS were enrolled in the study. Eligibility was limited to cytopenic patients with <20% marrow blasts. The drug was given orally twice weekly for 12 weeks with frequent monitoring of clinical, hematologic, and immunologic parameters. An increase in CD8+ and CD56+/CD3- cells was detected by 3 weeks. There was, however, no augmentation of natural killer or lymphokine-activated killer cell activity; progenitor cells were unchanged. Four patients had improvement in neutrophil counts, and two patients had improvement in platelet counts. Despite this improvement, the responses were transient or not maintained after discontinuation of therapy. One patient with RAEB, who was red cell transfusion dependent, experienced a complete remission that has persisted 14 months after completion of therapy. Adverse events developed in >25% of patients and included arthralgia, fever, headache, and myalgia. These side effects led to early withdrawal of therapy in five patients. These findings suggest that roquinimex may be of occasional benefit to patients with myelodysplastic syndromes.

Direct antithrombin agents ameliorate disseminated intravascular coagulation in suspected heparin-induced thrombocytopenia thrombosis syndrome.

This is a case series of 5 patients who were treated with the direct antithrombin agents (lepirudin or argatroban) for known or suspected heparin-induced thrombocytopenia thrombosis syndrome (HITTs). Coincidentally all had evidence of disseminated intravascular coagulation (DIC). The DIC parameters improved with treatment and each patient was successfully discharged from the hospital. These observations provide evidence that the direct antithrombin inhibitors, lepirudin and argatroban, can improve DIC. Moreover the presence of DIC in a patient with suspected HlTTs should not mitigate against the use of these agents.

Platelet glass bead retention is useful in monitoring response to 1-deamino-8-D-arginine-vasopressin (d-DAVP).

Seven patients with a suspected mild bleeding disorder had consistently abnormal glass bead platelet retention. This was the only coagulation abnormality detected in six of these patients; the seventh individual showed evidence of mild von Willebrand disease. Nevertheless, platelets from the six that were studied behaved in a similar fashion in the two-stage platelet retention assay of McPherson and Zucker. This indicated that their platelets were defective in maintaining repetitive platelet-platelet interaction in the second phase of this assay but functioned normally in the first phase. Their one-stage platelet retention defects consistently normalized following the infusion of 1-deamino-8-D-arginine-vasopressin (d-DAVP). The duration of response was variable and easily defined by monitoring this parameter. These findings suggest platelet retention analysis may be useful in identifying mild bleeding disorder patients, who may benefit from d-DAVP.

Effects of epsilon aminocaproic acid on primary hemostasis.

These studies examined the effect of an oral dose of epsilon-aminocaproic acid (EACA) on primary hemostasis. Bleeding time tests (with and without the use of a blood pressure cuff) were measured before and 2 h following EACA in 56 patients with mild bleeding disorders and/or thrombocytopenia. Preliminary studies evaluated the reproducibility of these tests in 13 patients who had bleeding times (cuff) ranging from 8.0 to greater than 20 min. Their replicate bleeding time values with cuff agreed within 2.5 min and those without cuff within 3 min. Therefore, the 56 study patients were considered to have had no change in their bleeding times after EACA, if their bleeding time with cuff was +/- 2.5 min and/or their nonoccluded value was +/- 3 min of their baseline values, respectively. An isolated increase in bleeding times was observed in 6 of 56 (11%) patients. All 6 had myelodysplasia associated with long bleeding times; their nonoccluded values increased by 5-14 min. Of the 56 study patients, 54% showed a decrease in their bleeding times following EACA. The changes were evident with venostasis in 18 of 30 (60%) and without venostasis in 12 (40%) patients. These studies suggest that EACA may improve primary hemostasis in some patients with prolonged bleeding times.

Evidence of an anti-A1 inhibited by EDTA.

EDTA is added to some commercial A and B cells as a means of preventing hemolysis in serum testing. Unexpected results in serum testing have been reported with EDTA-dependent agglutinins, but not with agglutinins inhibited by EDTA. A serum sample was found to contain an anti-A1 undetected by serum testing, but resulting in incompatible crossmatches. Studies indicated that reactivity was inhibited by the EDTA present in the diluent of the A reagent red cells.

Modulation of mild bleeding disorder during remissions and exacerbations of Graves' disease.

A patient with Graves' disease had a symptomatic thrombocytopathy during periods of remission. When euthyroid, she noticed bruising, petechiae, and epistaxis. Hemostatic abnormalities included prolongation of the bleeding time by aspirin, reduced platelet retention (a second-phase defect), and abnormal thrombin-induced aggregation and serotonin release. When hyperthyroid, bleeding symptoms resolved, and platelet function returned to normal. These observations suggest that mild bleeding disorders may be influenced either directly or indirectly by thyroid hormone levels.

Successful treatment of severe refractory aplastic anemia with 3-beta etiocholanolone and nandrolone decanoate.

A patient with aplastic anemia, who had been unresponsive to androgens, antithymocyte globulin, high-dose methylprednisolone, and cyclosporine, responded to treatment with 3-beta-etiocholanolone, nandrolone decanoate, and prednisolone acetate. Six months following initiation of therapy, she became red cell and platelet transfusion independent with neutrophils persistently over 1,000/microliters. A sustained partial remission has persisted for over 2 years. This observation suggests that a combined hematostimulatory approach may be of benefit, even in patients with long-standing refractory aplasia.

Desmopressin (d-DAVP) effects on platelet rheology and von Willebrand factor activities in uremia.

Bleeding times, von Willebrand activities, and platelet retentions were examined before and following d-DAVP in 13 uremic patients. Shortening of the bleeding time from 16.6 +/- 2.2 (SEM) to 6.8 +/- 0.7 min was seen in six patients. However, bleeding times remained greater than or equal to 20 min in the remaining seven individuals. The only baseline parameter that correlated with response to d-DAVP was the amount of blood loss (mg/min) during the bleeding time test. Responders had normal blood loss values averaging 6.2 +/- 1.5 mg/min. By contrast, these values were elevated in 6/7 of the non-responders and averaged 28.4 +/- 5.9 mg/min (P = 0.01). Von Willebrand activities increased following d-DAVP in the responders but not in the non-responders. Platelet retention was uniformly low in all patients and improved from 21.0 +/- 7.0% to 75.0 +/- 7.9% (P = less than 0.001) following d-DAVP in responders but not non-responders. To further define the retention abnormality in uremia, the two-stage platelet retention assay was performed prior to d-DAVP. Most of the patients (9/12) had both first- and second-phase abnormalities. Therefore, the retention defect in uremia appears to be more complex than that seen in von Willebrand's disease (2nd phase abnormality only). Nevertheless, d-DAVP seems to improve platelet rheology in uremic individuals whose von Willebrand activities increase with d-DAVP.