Joseph M. Baron

Randomized, pilot study of intermittent pneumatic compression devices plus dalteparin versus intermittent pneumatic compression devices plus heparin for prevention of venous thromboembolism in patients undergoing craniotomy

BACKGROUND Unfractionated heparin and the low molecular weight heparin, dalteparin, are used for prophylaxis against venous thromboembolism in patients undergoing craniotomy. These drugs were compared in a randomized, prospective pilot study comparing intermittent pneumatic compression devices plus dalteparin to intermittent pneumatic compression devices plus heparin. METHODS One hundred patients undergoing craniotomy were randomly allocated to receive perioperative prophylaxis with subcutaneous (SC heparin, 5000 units every 12 hours, or dalteparin, 2,500 units once a day, begun at induction of anesthesia and continued for 7 days or until the patient was ambulating. Entry criteria were age over 18 years, no deep vein thrombosis (DVT) preoperatively as judged by lower limb duplex ultrasound and no clinical evidence of pulmonary embolism preoperatively. Patients with hypersensitivity to heparin, penetrating head injury or who refused informed consent were excluded. Patients underwent a duplex study 1 week after surgery and 1 month clinical follow-up. All patients were treated with lower limb intermittent pneumatic compression devices. RESULTS There were no differences between groups in age, gender, and risk factors for venous thromboembolism. There were no differences between groups in intraoperative blood loss, transfusion requirements or postoperative platelet counts. Two patients receiving dalteparin developed DVT (one symptomatic and one asymptomatic). No patient treated with heparin developed DVT and no patient in either group developed pulmonary embolism. There were two hemorrhages that did not require repeat craniotomy in patients receiving dalteparin and one that did require surgical evacuation in a patient treated with heparin. Drug was stopped in two patients treated with dalteparin because of thrombocytopenia. None of these differences were statistically significant. CONCLUSION There was no significant difference in postoperative hemorrhage, venous thromboembolism or thrombocytopenia between heparin and dalteparin. The results suggest that, given the small sample size of this trial, both drugs appear to be safe and the incidence of venous thromboembolism by postoperative screening duplex ultrasound appears to be low when these agents are used in combination with intermittent pneumatic compression devices.

Safety of perioperative subcutaneous heparin for prophylaxis of venous thromboembolism in patients undergoing craniotomy

OBJECTIVE To determine whether perioperative subcutaneous heparin is safe to use for patients undergoing craniotomy and to determine the incidence of venous thromboembolism in patients undergoing craniotomy. METHODS Perioperative prophylaxis with subcutaneous heparin, 5000 U every 12 hours, was begun at induction of anesthesia for craniotomy and continued for 7 days postoperatively or until the patient was ambulating. Entry criteria to the study included patient age over 18 years and no evidence of deep vein thrombosis (DVT) preoperatively as judged by lower limb duplex ultrasound. Patients were excluded if they had duplex evidence of DVT or clinical evidence of pulmonary embolus (PE) preoperatively, had hypersensitivity to heparin or related products, had sustained a penetrating head injury, or refused informed consent. Any patient undergoing craniotomy was eligible, including patients with a ruptured aneurysm or arteriovenous malformation and those with spontaneous intracranial hemorrhage. Patients underwent duplex study 1 week after surgery and 1 month of clinical follow-up. Records were also kept on 68 nonstudy patients who refused consent. All patients were treated with lower limb pneumatic compression devices. RESULTS One hundred six patients were treated. No differences were noted between study and nonstudy patients in some individual risk factors for DVT or PE, such as obesity, smoking, paralysis, infection, pregnancy or postpartum state, varicose veins, heart failure, or previous DVT or PE. Significantly more (43 of 106) patients in the study group had a history of risk factors for DVT or PE, particularly malignancy, however, compared with nonstudy patients (20 of 68 patients; chi2, P < 0.01). There were no differences between groups in intraoperative blood loss, transfusion requirements, or postoperative platelet counts. Four clinically significant hemorrhages occurred during surgery in patients receiving heparin. Three resulted from intraoperative aneurysm rupture and one from intraventricular bleeding during resection of an arteriovenous malformation. These events were believed to be related to known complications of these operations, not to heparin. Of the study patients, two developed symptomatic DVT and one developed a nonfatal PE during the 1-month postoperative period. One additional study patient developed DVT below the popliteal veins, which was not treated. Four study patients developed DVT 1 to 2 months after surgery. In nonstudy patients, three developed DVT and two developed PE (one fatal, one nonfatal). CONCLUSION Perioperative heparin may be safe to administer to patients undergoing craniotomy, but a larger study is needed to demonstrate efficacy.

Study of three patients with thrombotic thrombocytopenic purpura exchanged with solvent/detergent-treated plasma : Is its decreased protein S activity clinically related to their development of deep venous thromboses ?

Solvent/detergent treated plasma (S/DP) has reduced protein S activity (about 0.5 units/mL) as compared with fresh frozen plasma (FFP). When used as replacement fluid for repetitive therapeutic plasma exchange (PEX), e.g., in patients with thrombotic thrombocytopenic purpura (TTP), S/DP could lead to lowered protein S levels and, possibly, risk of hypercoagulable complications. We describe three patients with TTP who had low functional protein S (FPS) levels during PEX for TTP. Each developed one or more deep vein thromboses (DVTs) while receiving 100% S/DP or 50% S/DP and 50% cryosupernatant plasma (CSP) as replacement fluid. FPS levels rose when 100% CSP was substituted for S/DP. Our observations suggest that use of S/DP alone or in 50% combination with CSP as replacement fluid in PEX for TTP may lead to difficulty in maintaining safe FPS levels. Determination of risk of resulting clinically significant thrombotic events requires further study. J. Clin. Apheresis 15:169–172, 2000.

Osteosclerosis in primary hyperparathyroidism

Osteosclerosis in adults with primary hyperparathyoidism is rare; the usual skeletal manifestation, when presented, is diffuse osteropenia. We describe a patient with generalized osteosclerosis in association with primary hyperparathyroidism. The findings are documented by conventional and fine-detail radiography, absorptiometric bone mineral analysis, quantitative microradiography and histologic examination of bone. The unique features are contrasted with the manifestations recorded in a recently studied group of 87 hyperparathyroid patients. The data presented here support a causal relationship in this patient between parathyroid hormone excess and the development of densely sclerotic bones.

Therapeutic plasma exchange for the acute management of the catastrophic antiphospholipid syndrome: β2-glycoprotein I antibodies as a marker of response to therapy

We describe two patients with the catastrophic antiphospholipid syndrome associated with elevation of β2‐glycoprotein I antibodies and fulminant thrombotic diatheses. Both patients were treated with therapeutic plasma exchange (TPE), which resulted in a marked decrease in antibody titer accompanied by an improved clinical outcome in one patient (IgG antibody). In the second patient, the outcome was poor despite TPE (IgA antibody). There were no significant complications of TPE in either case. Because of the fulminant nature of the catastrophic antiphospholipid syndrome, we conclude that a trial of TPE is warranted for the acute management. Further studies are needed to clarify which patients may benefit from this treatment. J. Clin. Apheresis 14:171–176, 1999.

IgA Anti-β2-Glycoprotein I Autoantibodies Are Associated with an Increased Risk of Thromboembolic Events in Patients with Systemic Lupus Erythematosus

Background The clinical utility of testing for antiphospholipid antibodies (aPL) of IgA isotype remains controversial. Methodology/Principal Findings To address this issue, we reasoned that if IgA aPL contribute to the clinical manifestations of the antiphospholipid syndrome, then an association with thromboembolic events should manifest in patients whose only aPL is of IgA isotype. We performed a retrospective chart review of 56 patients (31 with systemic lupus erythematosus [SLE] and 25 without SLE) whose only positive aPL was IgA anti-β2-glycoprotein I (isolated IgA anti-β2GPI) and compared their clinical features with 56 individually matched control patients without any aPL. Patients with isolated IgA anti-β2GPI had a significantly increased number of thromboembolic events, as compared to controls. When patients were stratified into those with and without SLE, the association between isolated IgA anti-β2GPI and thromboembolic events persisted for patients with SLE, but was lost for those without SLE. Titers of IgA anti-β2GPI were significantly higher in SLE patients who suffered a thromboembolic event. Among patients with isolated IgA anti-β2GPI, there was an increased prevalence of diseases or morbidities involving organs of mucosal immunity (i.e., gastrointestinal system, pulmonary system, and skin). Conclusions/Significance The presence of isolated IgA anti-β2GPI is associated with an increased risk of thromboembolic events, especially among patients with SLE. IgA anti-β2GPI is associated with an increased prevalence of morbidities involving organs of mucosal immunity.

Repression of the PDCD2 gene by BCL6 and the implications for the pathogenesis of human B and T cell lymphomas

The human BCL6 gene on chromosome 3 band q27, which encodes a transcriptional repressor, is implicated in the pathogenesis of human lymphomas, especially the diffuse large B-cell type. We previously identified the human PDCD2 (programmed cell death-2) gene as a target of BCL6 repression. PDCD2 encodes a protein that is expressed in many human tissues, including lymphocytes, and is known to interact with corepressor complexes. We now show that BCL6 can bind directly to the PDCD2 promoter, repressing its transcription. Knockdown of endogenous BCL6 in a human B cell lymphoma line by introduction of small interfering RNA duplexes increases PDCD2 protein expression. Furthermore, there is an inverse relationship between the expression levels of the BCL6 and PDCD2 proteins in the lymphoid tissues of mice overexpressing human BCL6 (high BCL6 levels, minimal PDCD2) and controls (minimal BCL6, high PDCD2) as well as in tissues examined from some human B and T cell lymphomas. These data confirm PDCD2 as a target of BCL6 and support the concept that repression of PDCD2 by BCL6 is likely important in the pathogenesis of certain human lymphomas.

PDCD2, a protein whose expression is repressed by BCL6, induces apoptosis in human cells by activation of the caspase cascade

We have previously reported that the human programmed cell death-2 gene (PDCD2), a target of BCL6 repression, is likely to be important in the pathogenesis of certain human lymphomas. We now demonstrate that transfection of a construct expressing PDCD2 induces apoptosis in human cell lines, that this occurs, at least in part, through activation of the caspase cascade, and, furthermore, that caspase inhibitors block this effect. Immunohistochemical studies in human benign lymphoid and lymphoma tissues support these findings. In addition, transfection of a VP16-BCL6 zinc fingers fusion protein, which competes with the binding of endogenous BCL6 in a Burkitt lymphoma cell line, increases PDCD2 protein expression and apoptosis, and knockdown of the PDCD2 protein in this cell line by PDCD2-specific small interfering RNA duplexes inhibits apoptosis. These studies indicate that one function of PDCD2 is to promote apoptosis in several human and mammalian cell lines and tissues, including lymphoma. Although the pathways involved in lymphomagenesis are likely to be multiple and complex, it is plausible that repression of PDCD2 expression by BCL6, which, in turn, leads to downregulation of apoptosis, is one mechanism involved in BCL6-associated lymphomatous transformation. The usefulness of increasing PDCD2 expression in the treatment of certain lymphomas merits further investigation.

Gastric adenocarcinoma after gastric lymphoma

Three men and one woman developed intestinal‐type moderately or poorly differentiated gastric adenocarcinoma 4 to 15 years after the diagnosis of gastric lymphoma. Treatment of the lymphomas had included partial gastrectomy and follow‐up radiotherapy and/or chemotherapy. Review of the literature reveals an additional 12 patients who developed adenocarcinoma 3.5 to 34 years (median, 14.5 years) after diagnosis of gastric lymphoma. In the total series of 16 patients, only four were women, who tended to be younger (median age, 36.5 years) than the men (median, 48.5 years) when lymphoma was diagnosed. Patients with gastric lymphoma seem to have an increased incidence of gastric adenocarcinoma. Carcinoma after gastric lymphoma often arises in the distal stomach and appears to occur irrespective of the type of therapy for the lymphoma.

PIM1 gene cooperates with human BCL6 gene to promote the development of lymphomas

Diffuse large B-cell lymphomas in humans are associated with chromosomal rearrangements (∼40%) and/or mutations disrupting autoregulation (∼16%) involving the BCL6 gene. Studies of lymphoma development in humans and mouse models have indicated that lymphomagenesis evolves through the accumulation of multiple genetic alterations. Based on our prior studies, which indicated that carcinogen-induced DNA mutations enhance the incidence of lymphomas in our mouse model expressing a human BCL6 transgene, we hypothesized that mutated genes are likely to play an important cooperative role in BCL6-associated lymphoma development. We used retroviral insertional mutagenesis in an effort to identify which genes cooperate with BCL6 in lymphomagenesis in our BCL6 transgenic mice. We identified PIM1 as the most frequently recurring cooperating gene in our murine BCL6-associated lymphomas (T- and B-cell types), and we observed elevated levels of PIM1 mRNA and protein expression in these neoplasms. Further, immunohistochemical staining, which was performed in 20 randomly selected BCL6-positive human B- and T-cell lymphomas, revealed concurrent expression of BCL6 and PIM1 in these neoplasms. As PIM1 encodes a serine/threonine kinase, PIM1 kinase inhibition may be a promising therapy for BCL6/PIM1-positive human lymphomas.