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Biomedical subjects

Louis Fink

Publications and source records attributed to Louis Fink.

7 recordsLinked to original sources
PubMed2006

Acquired resistance to activated protein C (aAPCR) in multiple myeloma is a transitory abnormality associated with an increased risk of venous thromboembolism.

Acquired activated protein C resistance (aAPCR), not associated with factor V Leiden, has been described in cancer patients with an increased risk of venous thromboembolism (VTE). APCR was determined in 1178 myeloma patients using an activated partial thromboplastin time-based resistance assay in the presence of excess of factor V-deficient plasma; polymerase chain reaction amplification of genomic DNA was used to detect factor V Leiden mutation. A total of 109 patients were found to have abnormal APCR and one-third of them were carriers for the mutation. With a median follow-up of 40 months, the presence of aAPCR was associated with a significantly increased risk of thrombosis (P < or = 0.001). APCR was measured again after treatment in 31 patients with abnormal baseline values and had normalised in 30 of them. This study indicates that aAPCR is the most common single transitory baseline coagulation abnormality associated with VTE in myeloma patients.

Activated Protein C Resistance↗
PubMed2004

Deep vein thrombosis in patients with multiple myeloma treated with thalidomide and chemotherapy: effects of prophylactic and therapeutic anticoagulation.

A group of 256 newly diagnosed myeloma patients were enrolled in a phase III study that included 4 monthly cycles of induction chemotherapy and tandem transplant. All patients were randomized to either receive or not receive thalidomide. A total of 221 patients (86%) received no prophylactic anticoagulation (cohort I); 35 patients received low dose coumadin (cohort II). The incidence of deep vein thrombosis (DVT) was significantly higher in the thalidomide arm hazard ratio: 4.5; P < 0.0001). As low dose coumadin (1 mg/d) failed to decrease thrombotic complications in 35 patients (cohort II), low molecular weight heparin (LMWH, enoxaparin 40 mg s.c. q.d.) was instituted as DVT prophylaxis in the thalidomide-treated patients (n = 68) of the subsequent cohort (n = 130, cohort III). This intervention eliminated the difference in DVT incidence between the two arms (thalidomide and no thalidomide). Within cohorts I and II, 36 patients, in whom thalidomide was discontinued after experiencing a thrombotic episode during chemotherapy, subsequently resumed the drug on full anticoagulation; with a median follow-up of 22 months, DVT recurred in four patients (11%). After completing induction and tandem transplantation, 55 patients were re-exposed to thalidomide and chemotherapy during consolidation treatment. Thrombotic complications were observed in 4%. Our experience, although not based on a randomized study, suggests that the excess frequency of thrombosis in patients treated with chemotherapy and thalidomide can be safely reduced by the prophylactic use of LMWH. The rate of DVT recurrence observed in our study upon thalidomide resumption was sufficiently low to allow its continuation in patients who may benefit from this therapeutic intervention.

Adult↗
PubMed2003

The blood coagulation mechanism in multiple myeloma.

Many cancers are associated with hypercoagulability, including multiple myeloma. At least four possible reasons for hypercoagulability have been described in myeloma patients: interference of immunoglobulins on fibrin structure, procoagulant autoantibody production, effects of inflammatory cytokines on endothelium, and acquired activated protein C (APC) resistance. Moreover, injury to endothelium, either by tumor cells or by chemotherapy, may predispose to thrombosis by causing upregulation of adhesion molecules, allowing adhesion of blood cellular elements (platelets, lymphocyte, neutrophils, and tumor cells, which secrete thrombogenic as well as angiogenic substances). In most cases, the pathogenesis of a thrombotic complication in myeloma patients remains unexplained. Administration of chemotherapy may play a larger role in the thrombotic process than a specific abnormality does because thrombotic complications become more prominent after the start of treatment. The recently reported evidence of a non-factor V Leiden APC resistance has increased our understanding of the pathophysiology of this hypercoagulable state.

Activated Protein C Resistance↗
PubMed2003

Thalidomide and deep vein thrombosis in multiple myeloma: risk factors and effect on survival.

Thalidomide has antiangiogenic properties and was found to be effective in patients with multiple myeloma (MM) when used in the setting of posttransplantation relapse. We have now analyzed risk factors associated with development of deep vein thrombosis (DVT) in a cohort of 535 patients treated with thalidomide with cytotoxic chemotherapy (VAD [vincristine/doxorubicin/dexamethasone], CAD [cyclophosphamide/doxorubicin/dexamethasone], DCEP [dexamethasone/cyclophosphamide/etoposide/cisplatin], or DT-PACE [dexamethasone/thalidomide/cisplatin/doxorubicin/cyclophosphamide/etoposide] or without cytotoxic chemotherapy (thalidomide and dexamethasone only). A total of 82 patients developed DVT, and the frequency was affected by a number of baseline characteristics. On multivariate analysis, the combination of thalidomide with chemotherapy including doxorubicin was associated with the highest odds ratio (OR) for DVT (4.3; P < or = 0.001); in addition, newly diagnosed disease (OR, 2.5; P = 0.001) and chromosome 11 abnormality (OR, 1.8; P = 0.048) were also independent predictors for DVT. With a median follow-up of 2.9 years, survival was inferior in patients with chromosome 13 abnormalities (P = 0.001), age > 60 years (P = 0.001), lactate dehydrogenase level > or = 190 IU/L (P = 0.002), and creatinine level > or = 2 mg/dL (P < 0.001). However, the development of DVT did not adversely affect survival when examined as a time-dependent variable and adjusted for standard risk features (hazard ratio, 0.8; P = 0.162).

Aged↗
PubMed2002

Increased serum homocysteine and sudden death resulting from coronary atherosclerosis with fibrous plaques.

INTRODUCTION: Modest elevations of total homocysteine have been associated with increased risk for coronary atherosclerosis but correlation between elevated homocysteine and plaque morphology has not been described in humans. METHODS: We determined serum homocysteine at postmortem from 87 men with coronary thrombus (62 of whom were diagnosed as acute), from 35 men with severe coronary disease without thrombus, and from 46 controls. In coronary deaths, atherosclerotic plaques at the sites of maximal luminal narrowing of the four epicardial coronary arteries were classified as fibrous plaques, fibrous cap atheromas, thin-cap atheromas, and healed ruptures, and macrophage infiltration was assessed semiquantitatively. RESULTS: Median serum homocysteine postmortem as a result of acute thrombus was 10.4 micro mol/L (P=0.4 versus controls), 12.1 micro mol/L in men with organized thrombi (P=0.1 versus controls), 15.6 micro mol/L in men without thrombus (P=0.007 versus controls), and 9.8 micro mol/L in controls. The median homocysteine was 12.1 micro mol/L in 65 men with healed infarcts (P=0.03 versus controls). The number of fibrous plaques was associated with log-normalized homocysteine (P=0.004), independent of age, albumin, smoking, hypertension, and serum cholesterol. Homocysteine levels in the upper tertile (>15 micromol/L) were associated with sudden death without acute or organized thrombus (odds ratio 3.8, P=0.03) independent of age and other risk factors; the coexistence of diabetes increased the association (odds ratio 25.1, P=0.009, versus lowest tertile < or =8.5 micromol/L). CONCLUSIONS: Increased serum homocysteine is associated with sudden death in the absence of acute coronary thrombosis, especially with concomitant diabetes, and with the presence of lipid-poor, fibrous plaques.

Adult↗
PubMed2002

Thrombogenic activity of doxorubicin in myeloma patients receiving thalidomide: implications for therapy.

Ten percent of newly diagnosed myeloma patients treated with any type of chemotherapy develop deep venous thrombosis (DVT). Thalidomide has proven activity in refractory multiple myeloma (MM), and although single-agent thalidomide has minimal prothrombogenic activity, its combination with cytotoxic chemotherapy is associated with a significantly increased risk of DVT. We analyzed the incidence of DVT in 232 MM patients who received a combination of chemotherapy and thalidomide on 2 protocols that differed only by the inclusion of doxorubicin in one. DT-PACE (dexamethasone/thalidomide/cisplatin/doxorubicin/cyclophosphamide/etoposide) was offered to patients with preceding standard dose therapy, but no prior autotransplantation, while DCEP-T (dexamethasone/cyclophosphamide/etoposide/cisplatin/thalidomide) was administered for relapse after transplantation. If there were signs or symptoms suggestive of DVT, patients received additional investigations, including Doppler ultrasonography, followed by venography if indicated. Only patients on DT-PACE but not DCEP-T experienced an increased incidence of DVT. A statistical association between the incidence of DVT and combination chemotherapy including doxorubicin (P =.02) was observed; this association was confirmed on multivariate analysis. MM patients treated with thalidomide and doxorubicin have a high risk of developing DVT.

Adult↗