Compromised activity of natural killer cells in diffuse large b-cell lymphoma is related to lymphoma-induced modification of their surface receptor expression.

While natural killer (NK) cells are essential players in detection and elimination of malignant cells, these surveillance properties can be compromised by cancer cells. Since NK cell education primarily occurs in the bone marrow and lymphoid tissue, this process might be particularly affected by their infiltration with lymphoma cells. This study aimed to explore functional properties of diffuse large B-cell lymphoma (DLBCL) patient NK cells, which could potentially promote tumour immune evasion and disease propagation.NK cells isolated from the peripheral blood (PB) of 26 DLBCL patients and 13 age-matched healthy controls (HC) were analysed. The cytotoxic CD56dim subtype was the only one identified in patients. Compared to HC, patient cells demonstrated low levels of inhibitory CD158a/b along with decreased expression of activating NKG2D and CD161 and increased inhibitory NKG2A levels. Patient NK cell cytotoxic activity was impaired, as were their degranulation and inflammatory cytokine production, which partially recovered following non-receptor-dependant stimulation.The phenotypically skewed and restricted population of patient NK cells, along with their blunted cytotoxic and immune-regulatory activity, appear to be driven by exposure to lymphoma environment. These NK cell functional aberrations could support lymphoma immune evasion and should be considered in the era of cellular therapy.

Protein C global assay evaluation in naturally conceived vs. assisted reproduction-achieved twin pregnancies: a prospective longitudinal study.

PURPOSE: Protein C global assay tests the global function of the protein C pathway, the most clinically significant anticoagulant pathway in humans. The objective of this study is to assess the difference in protein C global assay levels, throughout twin gestation, in naturally conceiving and ART-treated women. METHODS: This is a prospective cohort longitudinal study of pregnant women with twin gestation. Protein C Global evaluation was performed on frozen blood samples. Ninety-eight women with twin pregnancy, thirty-eight naturally conceived and sixty following ART, were evaluated on four occasions: during the first, second, and third trimesters, and 6 weeks or later after delivery (baseline). RESULTS: Protein C global assay levels were lower throughout pregnancy as compared to basal levels in both the naturally conceived and ART-conceived groups. However, protein C global assay levels were similar between the ART-conceived and naturally conceived twin pregnancies in all three trimesters. Perinatal complications were associated with decreased protein C global assay levels during the third trimester, although no difference was encountered between naturally conceived and ART-complicated twin pregnancies. CONCLUSION: While protein C global assay levels drop during twin pregnancy, there is no difference between ART-conceived and naturally conceived gestations. Decreased levels of protein C global assay during the third trimester were similarly associated with perinatal complications in both groups. Our results imply that twin pregnancy of itself is a more dominant factor for perinatal complications as compared to other factors, such as subfertility or the exposure to ART per se.

Pregnancy and non-pregnancy related immune thrombotic thrombocytopenic purpura in women of reproductive age.

Pregnancy is a precipitating factor for immune thrombotic thrombocytopenic purpura (iTTP). We compared the clinical course and outcomes of iTTP in women of reproductive age, between those with pregnancy- and non-pregnancy-related iTTP. A review of all reproductive-aged women diagnosed with iTTP during 2010-2019 in seven university hospitals in Israel. Of 42 cases of iTTP, 12 (28.6%) were pregnancy-related. At presentation, the laboratory profiles did not differ significantly between those with pregnancy- and non-pregnancy-related iTTP, including hemoglobin (median 8.4 vs 8.0 g/dL), platelet count (12.5 vs. 11.5 X 109/L); and levels of bilirubin (1.23 vs. 1.82 mg/dL), lactate dehydrogenase (1615 vs. 1701 U/L), creatinine (0.61 vs. 0.79 mg/dL) and anti-ADAMTS13 antibodies titer (75 vs. 82 U/mL). The proportions of women with renal, neurologic, or hepatic involvement were similar between the groups. Cardiac involvement was more common among those with pregnancy-related disease (25.0% vs. 3.3%, P = 0.06). The median number of courses of plasma-exchange therapy was 11 for both groups. All the women were treated with parenteral corticosteroids and the rate of adjunctive treatments did not differ between the groups (P = 0.30). Four women (one-third) with pregnancy-related disease had preeclampsia. Two women (16.7%) with pregnancy-related iTTP died during the acute episode (P = 0.07); no deaths were observed in the non-pregnancy-related group. Among reproductive-aged women with iTTP, most clinical and laboratory profiles were similar between those with pregnancy- and non-pregnancy-related disease. However, the higher rates of cardiac involvement and mortality among women with pregnancy-related iTTP highlight its challenging management.

[EXPERIENCE IN DIAGNOSTIC ASSAYS FOR HEPARIN-INDUCED THROMBOCYTOPENIA - EXPERIENCE OF A TERTIARY HOSPITAL IN ISRAEL].

AIMS: To analyze the experience of a tertiary medical center in clinical and laboratory diagnosis of suspected HIT. BACKGROUND: The diagnosis of heparin-induced thrombocytopenia (HIT) requires clinical data and laboratory detection of platelet activating factor 4/heparin (PF4/H) antibodies by immunological or functional assays. Although antigen screening assays are widely used, the functional assays are performed only by several expert labs. METHODS: A retrospective review of the Hematology Laboratory database on patients evaluated between the years 2008-2016 at Rambam, identified 412 individuals with clinical suspicion of HIT. Till 2011, 135 cases were screened using particle gel PaGIA (Biorad) and between the years 2012-2016, a total of 277 cases were screened by lateral flow Milenia (Biotec GmbH). All patients diagnosed with HIT were treated with Fondaparinux (Arixtra). Functional assay with heparin/LMWH induced platelet aggregation was performed using light transmission aggregometry (Helena AggRAM) to validate borderline or positive results in indistinct cases. RESULTS: From the tested samples, 63% vs. 75% were negative in PaGIA and Milenia, respectively (P=0.03), and were considered negative for HIT. During 2008-2011, only 38% of cases with non-negative immunoassay results underwent functional aggregation, whereas, in 2012-2016, 83% of such cases were further evaluated. None of the borderline PaGIA samples was positive in the functional assay compared to 13.3% borderline Milenia results; 25% of positive PaGIA and 51.7% of positive Milenia were confirmed by a positive functional HIT assay (P=N.S.). The survival rate among 14 patients with a positive functional assay was 42.7 % (6 patients). CONCLUSIONS: The Milenia assay introduced at our lab in 2012, has improved the screening process. The functional assay provides a more accurate HIT diagnosis. The combined approach of an optimal laboratory and clinical investigation is crucial to obtain a precise HIT diagnosis.

Effects of Acute Stress on Thrombosis.

Stress, the nonspecific response to any demand for change, is an adaptive response of the human body to various stimulants. As such, stress-induced hypercoagulation may represent an adaptive response to bleeding. Numerous epidemiological studies have revealed that a correlation exists between stress and thrombotic risk and biochemically, links of the relationship between psychological stress and coagulation pathways have been made. The stress reaction is coupled with neurohormonal changes mediated mainly by the sympathetic neural system and the hypothalamic-pituitary-adrenal axis. Singling out the specific pathways affecting coagulation in this complex response is hampered by many confounders. The mediators of the stress reaction (neurotransmitters and hormones) can directly affect platelets and the coagulation cascade and indirectly affect hemostasis via changes in hemodynamics. In this review, the authors will delineate the distinct neurobiological mechanisms that govern the effects of stress on coagulation, and report their recent findings.

Inhalation of a Short-Acting ß2-Adrenoreceptor Agonist Induces a Hypercoagulable State in Healthy Subjects.

BACKGROUND: Catecholamine infusion elicits an increase in clotting factors and this increase has been attributed to stimulation of ß2-adrenorecptors (ß2AR). Accordingly, we tested the hypothesis that inhalation of a short-acting selective ß2AR agonist can induce a procoagulant state in healthy individuals. METHODS: We recruited 23 healthy volunteers (nine females; mean age: 26±0.8 years; body mass index: 24.7±0.5 kg/m2) and randomly allocated them into two groups, the ß2AR arm (seventeen subjects) and the saline arm (six subjects). Hemodynamics, plasma norepinephrine concentration, and procoagulant, anticoagulant, and fibrinolytic profiles of each participant were determined using specific assays before and after inhalation of either 2 mL nebulized normal saline or a mixture of 1 mL saline and 1 mL of salbutamol (5 mg salbutamol sulfate), a selective ß2AR agonist, which were delivered by a nebulizer over ten minutes. RESULTS: Saline inhalation had no effect on the procoagulant, anticoagulant and fibrinolytic profiles of the six healthy volunteer in the study's saline arm. Salbutamol inhalation caused (a) a significant increase in the activity or levels of the procoagulant factors; FVIII increased by 11±3% (p = 0.04), von Willebrand factor increased by 7±1% (p = 0.03), and (b) a significant decrease in the activated partial prothrombin time from 27.4±0.4 seconds to 25.5 ±0.5 seconds (p<0.001) in the 17 volunteers in the study's ß2AR arm. D-dimer and prothrombin fragments F1+2 were elevated by 200 ±90% and 505.0 ±300.0%, respectively. In addition, the activity of the anticoagulant protein C pathway (demonstrated by the protein C Global assay) decreased from 1.0±0.08 to 0.82±0.06 (p<0.001). Although plasma levels of tissue plasminogen activator decreased, all other indices of the fibrinolytic system did not change following salbutamol inhalation. CONCLUSION: We found that a single inhalation of salbutamol, a short-acting ß2AR agonist, activates the clotting system without affecting the fibrinolytic system. This induction of a procoagulant state in healthy subjects warrants further investigation in patients treated with these agents.

A 14-Year Experience in the Management of Patients with Acquired Immune Thrombotic Thrombocytopenic Purpura in Northern Israel.

Acquired idiopathic thrombotic thrombocytopenic purpura (I-TTP) is a life-threatening microangiopathic disorder usually treated with therapeutic plasma exchange (TPE). The current study assessed the role of rituximab in the treatment of complicated I-TTP. The sequence of TTP events was compared in a group of I-TTP patients treated with TPE and a cohort of refractory or relapsed patients who also received rituximab. This retrospective evaluation included 45 I-TTP patients, treated between January 2000 and October 2013, who underwent at least 3 TPE procedures and were followed up until December 2013 or death. Thirty-one patients with an uncomplicated course received TPE only. Fourteen patients had a complicated course due to either a primary refractory/exacerbated disease (n = 5) or relapse (n = 9) and received rituximab together with TPE. The median number of TPE procedures performed in the first TTP episode in the uncomplicated cohort and groups with primary refractory or relapsed TTP was 11, 27 and 45, respectively. The relapse rates per follow-up year in the uncomplicated I-TTP, primary refractory and relapsed I-TTP groups were 0.18, 0.2 and 0.6 episodes, respectively. After rituximab therapy this rate dropped to 0.2 per year in the relapsed subgroup. In conclusion, about a quarter of patients with I-TTP had a complicated course and experienced a major benefit from rituximab in terms of effectiveness and safety.

ADAMTS-13 in the Diagnosis and Management of Thrombotic Microangiopathies.

Thrombotic microangiopathies (TMAs) comprise a group of distinct disorders characterized by microangiopathic hemolytic anemia, thrombocytopenia, and microvascular thrombosis. For many years distinction between these TMAs, especially between thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), remained purely clinical and hard to make. Recent discoveries shed light on different pathogenesis of TTP and HUS. Ultra-large von Willebrand factor (UL-VWF) platelet thrombi, resulting from the deficiency of cleavage protease which is now known as ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), were found to cause TTP pathology, while Shiga toxins or abnormalities in regulation of the complement system cause microangiopathy and thrombosis in HUS. TMAs may appear in various conditions such as pregnancy, inflammation, malignancy, or exposure to drugs. These conditions might cause acquired TTP, HUS, or other TMAs, or might be a trigger in individuals with genetic predisposition to ADAMTS-13 or complement factor H deficiency. Differentiation between these TMAs is highly important for urgent initiation of appropriate therapy. Measurement of ADAMTS-13 activity and anti-ADAMTS-13 antibody levels may advance this differentiation resulting in accurate diagnosis. Additionally, assessment of ADAMTS-13 levels can be a tool for monitoring treatment efficacy and relapse risk, allowing consideration of therapy addition or change. In the past few years, great improvements in ADAMTS-13 assays have been made, and tests with increased sensitivity, specificity, reproducibility, and shorter turnaround time are now available. These new assays enable ADAMTS-13 measurement in routine clinical diagnostic laboratories, which may ultimately result in improvement of TMA management.

The coagulation profile of preterm delivery.

INTRODUCTION: Hypercoagulation was suggested to be involved in preterm birth etiology; however, the coagulation state of preterm parturients remains unelucidated. The study aim was to evaluate the haemostatic system of pregnant women with premature uterine contractions (PUC). MATERIALS AND METHODS: The cohort study population consisted of 76 healthy pregnant women admitted with regular PUC. The study group included 38 women who experienced preterm birth; 14 of them had preterm premature rupture of membranes (PPROM). The control group included 38 women who eventually had term delivery. Groups were matched for maternal age, number of births and gestational age at admission. Blood samples were tested for haemostatic parameters and coagulation activation markers. RESULTS: Significantly shorter PT and aPTT were documented in the study compared to control group (25.7±2 vs. 27.4±2.7seconds, P=0.003, and 9.96±0.5 vs. 10.1±0.4seconds, P=0.05, respectively), although differences in absolute values were small. There was no significant difference between the two groups in levels of: fibrinogen, D-dimer, protein C-global, free protein S antigen, factor VIII activity, Von Willebrand factor, plasminogen activator inhibitor-1, prothrombin fragments F1+2 (PT F1+2), tissue factor and tissue factor pathway inhibitor. Women with PPROM had significantly lower PT F1+2 levels compared to those who had preterm delivery with intact membranes (351±99 vs. 561±242pmol/L, P=0.003). CONCLUSIONS: Shortened PT and aPTT, reflecting increased thrombotic activity in maternal plasma, could serve as a marker of real preterm labor in women with premature uterine contractions. Further prospective studies in a larger cohort are warranted to validate these findings.

Identification of a novel mutation in the PNLIP gene in two brothers with congenital pancreatic lipase deficiency.

Congenital pancreatic lipase (PNLIP) deficiency is a rare monoenzymatic form of exocrine pancreatic failure characterized by decreased absorption of dietary fat and greasy voluminous stools, but apparent normal development and an overall good state of health. While considered to be an autosomal recessive state affecting a few dozens of individuals world-wide and involving the PNLIP gene, no causative mutations for this phenotype were so far reported. Here, we report the identification of the homozygote missense mutation, Thr221Met [c.662C>T], in two brothers from a consanguineous family of Arab ancestry. The observed genotypes among the family members were concordant with an autosomal recessive mode of inheritance but moreover a clear segregation between the genotype state and the serum PNLIP activity was evident. Based on biophysical computational tools, we suggest the mutation disrupts the protein's stability and impairs its normal function. Although the role of PNLIP is well established, our observations provide genetic evidence that PNLIP mutations are causative for this phenotype.

Reduced protein C Global assay level in infertile women prior to IVF-ET treatment.

PURPOSE: In the last few years more robust evidence is emerging to point out at an increased rate of prematurity and low birth weight in singleton pregnancies following ART. Whether this increased rate is related to ART practice or to infertility per se, is still an open question. Our aim in this study was to explore this question by evaluating Protein C (ProC) Global assay in infertile women before ART treatment. METHODS: A cohort of 95 unselected and consecutive infertile women, eligible for ART, was prospectively recruited for the study. The control group included 77 matched healthy fertile women with a history of spontaneous conceptions. Pro C Global assay was evaluated in both groups. A full thrombophilic work-up was performed in the study group. RESULTS: ProC Global assay level was found to be significantly lower in the study as compared to the control group, corresponding to 0.78 ± 0.16 and 0.88 ± 0.16, respectively (P < 0.01). As well, abnormal ProC Global assay level of ≤ 0.8 was significantly higher in the study as compared to control group corresponding to 53 % and 29 %, respectively. ProC Global assay level was significantly lower in women within the study group found to have APCR, factor V Leiden and high factor VIII level, any thrombophilia or combined thrombophilia when compared to women without these thrombophilic risk factors. CONCLUSIONS: Reduced ProC Global assay level is encountered in infertile women prior to ART treatment. This finding may suggest a unique anticoagulation Protein C pathway in infertile as compared to fertile women. Further studies are encouraged to explore this finding.

The association between poor ovarian response and thrombophilia in assisted reproduction.

OBJECTIVE: To investigate the association between thrombophilic risk factors and poor ovarian response in an assisted reproductive technologies (ART) setting. STUDY DESIGN: This is a preliminary prospective cohort study in a university affiliated reproductive medicine unit. Eighty-nine infertile women undergoing IVF-ET treatment were recruited. Following IVF-ET treatment, the 28 women that had ≤ 3 oocytes on retrieval were the study group, and the 61 women that had ≥ 4 oocytes on retrieval were the control group. All women underwent ovarian reserve testing and thrombophilia work-up prior to treatment. RESULTS: Patients' characteristics, except for chronological age, were similar between the two groups. Women in the study group had clear manifestations of low ovarian reserve, evident by ovarian reserve testing, controlled ovarian hyper-stimulation and IVF-ET treatment results, as compared to the control group. The incidence of all thrombophilias tested was similar between the study and control group. Moreover, the incidence of any single or combined thrombophilia was also similar between the two groups. Logistic regression model analysis and Pearson correlation tests did not show significant correlation between number of oocytes retrieved and thrombophilia. Furthermore, basal ovarian reserve tests did not differ between women with and without thrombophilia. When only the 48 women ≤ 35 years of were analyzed, the five women in the study group had significantly higher incidence of a single as well as combined thrombophilia as compared to the 43 controls. CONCLUSIONS: Thrombophilic risk factors have no correlation with poor ovarian response in the general infertile population undergoing ART. Whether premature low ovarian reserve is linked to thrombophilia remains to be established.

[New scoring system for estimating the risk for pregnancy complications and venous thromboembolism in women with thrombophilia].

Pregnancy is an acquired state of hypercoagulation. An association has been found between various pregnancy complications and thrombophilia. Among those complications are: preeclampsia, intrauterine fetal death, intrauterine growth retardation and placentaL abruption. This article will present a novel scoring system estimating pregnancy complications in women with thrombophilia. The biological and epidemiological background of the association between pregnancy complications and thrombophilia will be discussed and the therapeutic options will be evaluated. Finally, for illustrative purposes, a patient presenting with combined thrombophilia--both genetic and acquired--will be discussed. This patient had suffered severe gestational complications that led to devastating obstetrical outcome.

Hypercoagulation in chronic post-traumatic stress disorder.

BACKGROUND: Whereas procoagulation abnormalities in acute stress are well established, little is known about the mechanism of hypercoagulation in chronic stress, such as post-traumatic stress disorder (PTSD). This is crucial, given the fact that chronic coagulation disturbances have been associated with increased morbidity and premature mortality due to thromboembolism and cardiovascular disorders, complications recently described in PTSD patients. OBJECTIVES: To explore the mechanisms of hypercoagulation in chronic PTSD. METHODS: Thirty patients diagnosed with chronic PTSD were enrolled and compared with a control group matched for age, gender and ethnicity. Hypercoagulation state was evaluated by levels of fibrinogen, D-dimer, prothrombin fragment F 1+2, von Willebrand factor (vWF) antigen, factor VIII activity, activated protein C resistance, ProC Global assay, and tissue factor antigen. Psychiatric evaluation was performed using the Mini-International Neuropsychiatric Interview and Clinician Administered PTSD Scale (CAPS). RESULTS: vWF antigen levels were significantly higher in patients with chronic PTSD compared with the controls (121.3 +/- 42 vs. 99.7 +/- 23, respectively, P = 0.034). Higher levels of vWF antigen and factor VIII activity were found in patients with severe chronic PTSD (CAPS > 80), compared to controls and patients with chronic PTSD and less severe symptoms (CAPS < or = 80). However, no differences were observed in any other studied coagulation parameters between patients and controls. CONCLUSIONS: Increased levels of vWF antigen and factor VIII activity were documented in severe chronic PTSD. These findings suggest that the higher risk of arterial and venous thromboembolic events in PTSD patients could be related to endothelial damage or endothelial activation.

Long-term response to rituximab in patients with relapsing thrombotic thrombocytopenic purpura.

Acquired thrombotic thrombocytopenic purpura (TTP) is an uncommon disease in adults, characterized by fever, neurological manifestations, microangiopathic hemolytic anemia, thrombocytopenia, renal dysfunction, and the presence of antibodies against the enzyme ADAMTS13. Treatment with plasmapheresis has increased the survival from 10% to more than 90%. Still, there is a subset of patients with resistant TTP who fail to respond to plasmapheresis or remain dependent on this procedure. There is mounting evidence that rituximab may play an important role in remission induction of resistant/relapsing TTP, but the extent of the remission is unknown. We present here four patients with chronic-relapsing TTP who responded favorably to rituximab. All four patients achieved prolonged remission of 23 to 82 months after the treatment. One patient relapsed 6 years afterthe initial treatment with rituximab and re-entered remission following retreatment.

Activation of coagulation in amniotic fluid during normal human pregnancy.

INTRODUCTION: Amniotic fluid (AF) is an important medium for fetal development which exhibits high procoagulant activities; however, the role of these procoagulants during pregnancy has not been elucidated and might be associated with pregnancy complications. The current study aimed to evaluate factor X (FX) activation and its association with tissue factor (TF), tissue factor pathway inhibitor (TFPI) and coagulation activation markers in AF during normal human pregnancy. METHODS: Activation of FX and concentration of TF, free TFPI, D-dimer and prothrombin fragments (F1+2) were evaluated in AF samples obtained for chromosome analysis from 91 women with normal pregnancy: 65 samples were taken from patients at 16-20 weeks of gestation, 9 samples were drawn at 21-30 weeks and 17 samples--after 30 weeks of gestation. RESULTS: Activation of FX in AF significantly increased during normal pregnancy (from 65±41 to 205±80 equivalent RVV ng/mg total protein, P<0.0001). TF and TFPI levels in AF also rose with gestational age. In contrast, the AF concentration of D-dimer and F1+2, markers of coagulation activation significantly decreased when expressed per mg total protein. Levels of free TFPI correlated with TF (r=0.5, P<0.001), and were 8-fold higher than those of TF during pregnancy. CONCLUSION: High levels of TFPI might be associated with the inhibition of procoagulant activity in amniotic fluid during normal pregnancy, which may account for the rarity of clinical amniotic fluid embolism.

[Laboratory evaluation of lupus anticoagulant in Israel].

Lupus anticoagulants (LAC) are antibodies which are detected by a prolongation of phospholipid-dependent coagulation assays, and are associated with thrombotic events and pregnancy complications in patients with the antiphospholipid syndrome. The antiphospholipid syndrome is defined by arterial or venous thrombosis and/or pregnancy morbidity and by laboratory diagnosis of antiphospholipid antibodies. The laboratory diagnosis is based on LAC and/or anticardiolipin and/or anti-beta2-glycoprotein I antibodies present in plasma, on two or more occasions at least 12 weeks apart. ALthough the presence of LAC correlates best with thrombosis, the Laboratory testing of LAC is not well standardized. In this article, the Laboratory evaluation of LAC will be explained, including the different tests that are recommended by the Israeli Sub-committee of Thrombosis and Hemostasis Laboratories, the possibility to evaluate LAC in patients treated with antithrombotic therapy, and how to report and interpret the results.

Prophylactic therapy with enoxaparin in children with acute lymphoblastic leukemia and inherited thrombophilia during L-asparaginase treatment.

INTRODUCTION: Thrombotic events (TE) are well documented in patients with acute lymphoblastic leukemia (ALL). They occur due to a combination of disease, host and treatment-related risk factors. Low molecular weight heparin (LMWH) has been found to be effective and safe in children with ALL during L-asparaginase treatment. At present, whether or not to give primary anticoagulant prophylaxis for TE during induction or reinduction courses to children with ALL is controversial. Our group investigated the use of LMWH as a prophylactic treatment for ALL children with a genetic prothrombotic predisposition. METHODS: Eighty consecutive children with ALL treated between the years 1999 and 2008 were studied. Genetic analysis of factor V Leiden (G1691A) and prothrombin (G20210A) gene mutations were done at diagnosis. LMWH was given once daily subcutaneously at a dose of 1mg/kg, starting with the first dose of L-asparaginase (day 12 of induction, day 8 of consolidation) until one week after the last dose (day 40 of induction, day 25 of consolidation), to patients with inherited thrombophilia stemming from either factor V Leiden or prothrombin gene mutation. RESULTS: Eighteen patients were found to have a genetic predisposition for TE, all of them received prophylactic LMWH. Six of the 80 (7.5%) patients developed thromboembolic events. Three of these six had a prothrombin (PT) gene mutation and received prophylactic LMWH. No TE event occurred in patients with factor V Leiden mutation receiving prophylactic LMWH. CONCLUSION: It is suggested that patients with ALL and PT gene mutation may have a higher risk of clotting complications in comparison to patients with factor V Leiden mutation. A randomized trial of LMWH should be performed to assess its safety and efficacy in preventing venous TE.

Asymptomatic deep vein thrombosis in advanced cancer patients: the value of venous sonography.

PURPOSE: Although guidelines for venous thromboembolism prevention are available, the implementation of anticoagulant prophylaxis in patients with advanced cancer has yet to be more clearly defined. We aim to determine the incidence of lower extremity deep vein thrombosis (DVT) diagnosed by Doppler sonography (USD) in asymptomatic nonambulatory patients with advanced cancer. METHOD: In a prospective study, 44 nonambulatory cancer patients with grade 3-4 World Health Organization performance status, asymptomatic for lower extremity DVT, underwent bilateral venous USD studies of the lower extremities. Different risk factors and laboratory data were registered and correlated with the incidence of DVT. RESULT: Asymptomatic DVT was detected in 15 of 44 patients (34%, 95% CI, 0.21-0.49). Twenty-three percent of all patients had isolated deep calf vein thrombi and 11% of all patients had thrombi in the proximal veins. The only significant risk factor was the number of metastatic sites. DVT was found in 4 of 23 (17.4%) patients with one metastatic site as opposed to 11 of 21 (52.3%) with two or more sites (p < 0.01). CONCLUSION: USD of the lower extremities detected asymptomatic DVT in 34% of advanced nonambulatory cancer patients and may serve as an additional decision-making tool in the consideration of anticoagulant therapy for this specific population.

Evaluation of the protein C global assay during normal pregnancy and after assisted reproduction.

OBJECTIVE: To prospectively compare the Protein C Global assay results in a cohort of infertile women who conceived after assisted reproductive technology (ART) with results from women who conceived spontaneously. METHODS: Sixty-four infertile women who conceived after ART and 47 fertile women who conceived spontaneously were prospectively evaluated. All women in the study and control groups had singleton pregnancies. The Protein C Global assay was performed in the two groups on four occasions: during the first, second, and third trimesters, as well as 6 weeks or later after delivery (baseline). RESULTS: Protein C Global assay results declined gradually during pregnancy in both groups. However, basal as well as first- and second-trimester Protein C Global assay results were significantly lower in the infertile group compared with the fertile group, corresponding to 0.89+/-0.22 and 1.06+/-0.33 (P=.025), 0.79+/-0.15 and 0.87+/-0.19 (P=.036), and 0.73+/-0.10 0.79+/-0.13 (P=.012), respectively. CONCLUSION: These findings support the notion that infertile women conceiving singleton pregnancies after ART are a priori at an increased hypercoagulation state. Protein C Global assay levels decline gradually during pregnancy in women who conceived naturally, as well as in infertile women who conceived after ART treatment.