Supportive transfusion therapy in cancer patients with acquired defects of hemostasis.

Bleeding occurs in approximately 10% of patients with cancer: supportive transfusion therapy with Platelets Concentrates (PC), Fresh Frozen Plasma (FFP) and plasma-derived or recombinant concentrates is often required for the cessation and prevention of the bleeding episodes. The most frequent causes of bleeding in cancer is thrombocytopenia followed by liver insufficiency with or without vitamin K deficiency, disseminated intravascular coagulation (DIC) and the inappropriate or excessive use of anticoagulants. Other acquired hemostatic defects such as acquired hemophilia (AHA) and acquired von Willebrand syndrome (AVWS) are rare but they can be life-threatening. Thrombocytopenia in cancer patients may be the consequence of marrow invasion, chemotherapy or platelet auto-antibodies; patients with severe hypoproliferative thrombocytopenia, must be treated with PC and carefully followed to assess refractoriness to PC. The management of the other acquired defects of hemostasis usually requires the use of FFP and specific plasma-derived or recombinant concentrates. PC, FFP and plasma-derived concentrates can induce complications and/or adverse events in cancer patients: these include mainly allergic (ALR) or anaphylactic reactions (ANR), Transfusion-Associated Graft-Versus-Host Disease (TA-GVHD), Trasfusion-transmitted bacteriemia (TTB), Transfusion-Related Acute Lung Injury (TRALI), Acute Hemolytic Transfusion Reactions (AHTR), Febrile Non Hemolytic Transfusion Reactions (FNHTR). Therefore, modifications such as leukocyte-reduction and irradiation of the blood components to be transfused in cancer patients are recommended to reduce the risk of these complications.

Treatment of periodontal disease results in improvements in endothelial dysfunction and reduction of the carotid intima-media thickness.

Several cohort studies reported a relation of cardiovascular events and periodontal disease. In particular, Porphyromonas gingivalis is associated with the development of atherosclerotic plaques. We verified in a longitudinal study whether inflammation biomarkers, endothelial adhesion molecules, leukocyte activation markers, and intima-media thickness could be beneficially modified by periodontal treatment alone. Thirty-five otherwise healthy individuals affected by mild to moderate parodontopathy were enrolled in the study. Echo-Doppler cardiography of the carotid artery, fluorescence-activated cell sorting analyses on lymphocytes and monocytes, and plasma inflammatory indices were evaluated at baseline and at multiple time points after the periodontal treatment. Results showed that inflammation biomarkers were abnormally increased at baseline. Periodontal treatment resulted in a significant reduction of the total oral bacterial load that was associated with a significant amelioration of inflammation biomarkers and of adhesion and activation proteins. Notably, intima-media thickness was significantly diminished after treatment. Inflammatory alterations associated with the genesis of atherosclerotic plaques are detected in otherwise healthy individuals affected by parodontopathy and are positively influenced by periodontal treatment. Reduction of oral bacterial load results in a modification of an anatomical parameter directly responsible for atherosclerosis. These results shed light on the pathogenesis of atherosclerosis and could have practical implications for public health.

A rapid assay for ristocetin cofactor activity using an automated coagulometer (ACL 9000).

We have set up a rapid assay for measuring the activity of the von Willebrand factor ristocetin cofactor (VWF : RCo) using an automated coagulometer (ACL 9000; Instrumentation Laboratory, Lexington, Massachusetts, USA) and commercially available lyophilized platelet reagents (Dade-Behring, Marburg, Germany). Since VWF : RCo tested with the coagulometer (ACL-VWF : RCo) did not require loading, calculation of von Willebrand factor (VWF) activity or pretreatment of samples (calibration standard and tested plasmas), we thought it might be useful for rapid, automatic screening of VWF activity. To assess the precision and the potency of this ACL-VWF : RCo, we tested the assay in this laboratory's internal normal and abnormal controls, in a group of 67 healthy individuals and in 28 patients with different types of von Willebrand disease (VWD). We compared the ACL-VWF : RCo findings with those of the standard agglutination test (Agg-VWF : RCo), normalizing both assays against VWF antigen (VWF : Ag) measured by 'automatic' and standard enzyme-linked immunosorbent assay 'in-house' methods, to calculate the VWF : RCo/VWF Ag ratios. The within-assay and between-assay repeatability of the automatic ACL-VWF : RCo gave coefficients of variation < 5%, and reproducibility in normal and abnormal laboratory controls gave coefficients of variation of 7.9 and 9.3%, respectively. In VWD patients the results were equivalent to those of the standard Agg-VWF : RCo assay but, because of the good sensitivity, the ACL-VWF : RCo was more accurate in evaluating the VWF : RCo and establishing the VWF : RCo/VWF : Ag ratios in VWD patients with low VWF levels. Moreover, this ACL-VWF : RCo is faster than Agg-VWF : RCo, providing results of calibration curves and of 10 patient samples within 15 min. We can conclude that this automatic ACL-VWF : RCo gives a reliable and useful measure of VWF activity and can be proposed as a screening test for rapid diagnosis of VWD even in patients with low VWF levels in plasma.

Mild to moderate reduction of a von Willebrand factor cleaving protease (ADAMTS-13) in pregnant women with HELLP microangiopathic syndrome.

BACKGROUND AND OBJECTIVES: Among the array of microangiopathies that may occur during pregnancy, HELLP syndrome and thrombotic thrombocytopenic purpura (TTP) produce similar laboratory findings (hemolytic anemia and thrombocytopenia), although neurological symptoms prevail in TTP and abnormal liver function in HELLP syndrome. It is clinically important to distinguish the two entities given that their managements differ (prompt induction of delivery in HELLP syndrome, plasma exchange in TTP). The purpose of this study was to evaluate whether or not ADAMTS-13, the metalloprotease that disposes ultralarge, highly thrombogenic multimers of von Willebrand factor (VWF) and is severely deficient or undetectable in many patients with TTP, is deficient in HELLP syndrome. DESIGN AND METHODS: We measured ADAMTS-13 and VWF (antigen, ristocetin cofactor activity, collagen binding, multimeric structure) in 17 pregnant women during HELLP syndrome and after 6 months during clinical remission. Controls were 25 healthy pregnant women and 50 healthy non-pregnant women. RESULTS: All the women with HELLP syndrome had lower plasma levels of ADAMTS-13 activity (median and range: 31%, 12-43) than did the healthy pregnant (71%, 48-105) and non-pregnant women (101%, 45-152); the reduced levels returned to normal on remission (115%, 90-170). Reduced levels were not due to the presence of inactivating autoantibodies and in no case was the protease undetectable in plasma. Ultralarge VWF multimers were not present in plasma, the levels of VWF were higher than in normal pregnancy. INTERPRETATION AND CONCLUSIONS: Because none of the pregnant women diagnosed with HELLP syndrome had undetectable ADAMTS-13 levels in pregnancy-associated thrombotic microangiopathies, the finding of severe ADAMTS-13 deficiency would argue against a diagnosis of HELLP syndrome and for a diagnosis of TTP.

Von Willebrand factor in Italian centenarians.

BACKGROUND AND OBJECTIVES: Subjects with blood type O have lower concentration of von Willebrand factor (VWF) than those with type A, B or AB. Since we recently observed that laboratory signs of marked hypercoagulability are compatible with health and longevity in Italian centenarians, we determined VWF and blood groups in healthy centenarians to see whether levels of this marker of endothelial perturbation were altered and whether its correlation with blood groups was similar to that among the general population. DESIGN AND METHODS: In 74 centenarians and in 110 controls (55<45 years old; 55>45 years old), we studied VWF antigen (VWF:Ag), ristocetin co-factor activity (VWF:Rco), multimeric pattern of VWF and cleaving protease (VWF:CP), and plasmin-antiplasmin complexes (PAP). RESULTS: The levels of VWF:Ag and VWF:Rco in centenarians were significantly higher than in controls without significant difference between blood group O or non-O. Fifty-one percent of centenarians have a reduction of the relative proportion of high molecular weight multimers (HMV); furthermore VWF:CP was lower and PAP significantly higher than in young controls. INTERPRETATION AND CONCLUSIONS: The loss of large VWF multimers in 51% of centenarians could depend on degradation protease(s) in the circulation. VWF, a well-known independent predictor of atherothrombotic disease, was increased in centenarians, independently of the blood group, confirming the previous results of a state of hypercoagulability. The finding that the VWF:CP levels are low when VWF levels are high in centenarians could be a corollary of the previous described paradox of successful aging, adding another marker of increased risk of atherothrombosis to the scenario.