Ron Hoffman

Thrombohemorrhagic complications of myeloproliferative disorders

Myeloproliferative disorders are commonly associated with thrombohemorrhagic manifestations. The current review highlights recent advances in understanding the epidemiology and pathogenetic mechanisms of thrombotic and bleeding complications. Therapeutic modalities and prophylactic interventions corresponding to the specific disease states are also discussed.

Emerging options in the treatment of deep vein thrombosis and pulmonary embolism

The incidence of venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism, is increasing and the disease has been found to account for over 500,000 annual deaths in the European Union. VTE is associated with increased mortality and may lead to serious long-term complications. Unfractionated heparin (UFH), low molecular weight heparin (LMWH) and vitamin K antagonists (VKA) have remained standard of care for many years. Recent trials of novel anticoagulants have indicated that new therapeutical options may soon become available. Studies on the role of new agents in VTE prevention in patients undergoing orthopaedic surgery have provided the evidence suggesting potential value of these drugs for the management of acute events. At present, investigation of new anticoagulants has reached the stage when phase III clinical studies on some novel agents have been completed and others are in progress. Of those furthest along are the direct Factor Xa inhibitors, rivaroxaban and apixaban, and the direct thrombin inhibitor, dabigatran. Findings of ongoing trials are expected to determine potential impact of these agents on current clinical practice.

Corpus luteum hemorrhage in women with bleeding disorders.

Bleeding into the corpus luteum following ovulation rarely has clinical significance in healthy women, but may lead to life-threatening hemorrhage in women with congenital or acquired bleeding disorders. Women who are at an increased risk for corpus luteum hemorrhage (CLH) can be divided in two categories; first, those taking anticoagulants because of a thrombotic disorder; and second, women with congenital bleeding disorders. The management and prevention of CLH is still unsettled and the literature dealing with this problem is based on case reports only. This review focuses on the pathophysiology, clinical presentation, diagnosis and treatment options of an acute bleeding event and prevention modalities of CLH in women with bleeding disorders.

Dehydration as a Possible Cause of Monthly Variation in the Incidence of Venous Thromboembolism

Background: Monthly or seasonal changes in the incidence of venous thromboembolism (VTE) were previously reported; however, the mechanism of such variability is not completely understood. Methods: In the present retrospective single-center analysis, consecutive patients with proximal deep vein thrombosis and/or pulmonary embolism (PE) diagnosed between January 2009 and December 2013 were evaluated. Results: The study population included 1496 patients, 48% men, mean age 63 ± 18 years. Most (82%) cases with VTE were provoked and 39% of patients had active cancer. Four months of peak incidence (3, 7, 10 and 11) were compared with 4 months of the lowest incidence (4, 5, 6, and 12), showing a significant difference in VTE numbers (597 vs 405 cases/year, P = 0.001). In all subgroup analyses, including gender, provoked or unprovoked event and presence or absence of cancer, significant differences between the months of peak and lowest incidence remained. Blood urea nitrogen (BUN)–creatinine ratio was significantly higher in all cases in the peak incidence group compared to the lowest incidence group (24 ± 1.5 vs 21 ± 1.6, P = 0.03). In patients with unprovoked VTE (n = 269), levels of BUN and hematocrit were significantly increased in the peak incidence group compared to lowest incidence group (19.5 ± 0.8 mg/dL vs 16 ± 1.1 mg/dL, P = 0.03; 39.2 ± 0.3% vs 37.4 ± 0.5%, P = 0.01, respectively). Conclusions: The current study demonstrates that occurrence of VTE exhibits monthly variation also existing in patients with provoked events and even in those with cancer. Dehydration is suggested as a potential explanation to the month-related variation in incidence of VTE.

Heparanase procoagulant activity, factor Xa, and plasminogen activator inhibitor 1 are increased in shift work female nurses.

Epidemiologic studies indicate on an increased risk of cardiovascular disease and cancer in shift workers, although the underling mechanism is obscure. Heparanase directly enhances tissue factor (TF) activity leading to increased factor Xa production and subsequent activation of the coagulation system. In the present study, a comparison of coagulation markers among healthy shift working (SW) vs. healthy daytime working (DW) female nurses was performed. Thirty SW and 30 DW female nurses were enrolled. For each of the 60 participants, blood was drawn between 7:00 and 8:00xa0a.m. and at least 8xa0h after the last work shift. Plasma was studied for coagulation marker that included TF/heparanase procoagulant activity, TF activity, heparanase procoagulant activity, heparanase level, factor Xa level, plasminogen activator inhibitor 1 (PAI-1), plasminogen, α2-antiplasmin, fibrinogen, global protein C, von Willebrand factor, and D-dimer by chromogenic assays and enzyme-linked immunosorbent assays (ELISAs). Sleep quality was assessed by self-report according to the Pittsburgh Sleep Quality Index. The heparanase procoagulant activity increased by 2-fold and the TF/heparanase procoagulant activity increased by 1.5-fold in SW nurses compared to DW nurses (Pu2009<u20090.05). Factor Xa levels and PAI-1 levels were significantly higher among SW nurses compared to the DW group (22 vs. 18xa0ng/ml, Pu2009<u20090.05, and 32 vs. 22xa0ng/ml, Pu2009<u20090.005, respectively). No significant differences were found in the other tested coagulation markers between the study groups. Heparanase procoagulant activity, factor Xa level, and PAI-1 level were significantly higher in SW nurses compared to the DW group. These alterations of blood coagulation activation may potentially contribute to cardiovascular and cancer morbidity.

Does molecular analysis increase the efficacy of bronchoalveolar lavage in the diagnosis and management of respiratory infections in hemato-oncological patients?

OBJECTIVESnThe identification of the specific pathogen responsible for a respiratory infection in patients with hematological malignancies (HM) would ensure relevant treatment and prevent toxicity associated with anti-infective therapy. This large-scale study aimed to explore the clinical impact of fiberoptic bronchoscopy with bronchoalveolar lavage (FOB-BAL) in conjunction with molecular analysis on the diagnosis and management of respiratory infections in hemato-oncological patients.nnnMETHODSnAll consecutive patients with HM and pulmonary infiltrates, who underwent FOB-BAL between January 2008 and January 2013, were included in the analysis. Clinical characteristics, FOB-BAL results, and treatment adjustments were recorded, and factors predicting a positive BAL were assessed.nnnRESULTSnFour hundred and twenty-five FOB-BAL procedures were analyzed. BAL revealed a specific diagnosis in 219 (51.5%) patients, 208 of them with a pulmonary infection. Infectious etiological agents found were mainly Aspergillus spp (n=142), bacterial species (n=44), and Pneumocystis jirovecii (n=34). Multivariate analysis showed that a lymphoproliferative disease, ≥2 symptoms (dyspnea/cough/hemoptysis/pleuritic pain), and less than 4 days between symptom appearance and FOB-BAL, predicted a positive FOB-BAL result. BAL results prompted a treatment modification in 48% of subjects.nnnCONCLUSIONSnFOB-BAL in conjunction with molecular assays is efficient in the rapid detection of life-threatening infections, allowing for adjustment of anti-infective therapy, which may result in better outcomes and reduce treatment-related toxicity.

Hemostasis and Thrombosis in the Oldest Old

Abstract There is a growing proportion of the elderly population in the Western world, and these individuals require special considerations regarding a broad variety of aspects, including treatment approaches to illnesses that affect all age groups. The hemostatic system in individuals changes considerably with aging. Specifically, changes in levels of procoagulant and natural anticoagulant factors along with thrombopathy simultaneously create a hypercoagulable state and hemostatic difficulties. Underlying morbidities, such as congestive heart failure, chronic obstructive pulmonary disease, diabetes mellitus, and cancer, increase the risk for venous and arterial thrombosis. This population is also increasingly affected by acquired bleeding disorders, including acquired hemophilia and acquired von Willebrand syndrome, as well as mild congenital bleeding disorders. Real‐life data demonstrate that recurrent and fatal venous thromboembolism is the major hemostatic concern in the elderly. The fact that treatment of thrombotic complications increases the bleeding risk also has to be taken into consideration, particularly in the older age group. This remains true in the era of direct oral anticoagulants. In conclusion, maintaining a delicate balance between thrombosis and bleeding risks is the key issue in providing qualified treatment to elderly patients.

Can we program VTE prevention in pregnancy

Venous thromboembolism (VTE) is a leading cause of morbidity and mortality in women of fertile age [1, 2]. The incidence of obstetric VTE in the Western world is estimated at 1:800–1,000 pregnancies, half of them being diagnosed during puerperium, although the risk of VTE is spread over all three trimesters [3]. The risk factors for VTE development in pregnancy and puerperium include: obesity, personal and family history of VTE, parity, thrombophilia and others. Low molecular weight heparin (LMWH) is the drug of choice used for thromboprophylaxis, which may lead to a decrease in VTE incidence [4]. Risk assessment tools become crucial in helping treating physicians to address the vital and challenging questions related to the management of VTE in medical and surgical patients. During pregnancy and the postpartum period, the need for thromboprophylaxis should be determined using the risk scoring approach, but prospective randomized studies examining this issue are still not available. Hence, nowadays, decision-making regarding the appropriateness of thromboprophylaxis is based on case–control studies and expert opinion only. The major questions during gestation are: who is the right patient for therapy, when to start thromboprophylaxis, what kind of prophylaxis is preferable, and at what dosage? The article by Testa et al. [5] reports on a cohort study designed to assess whether the stratification of pregnant women into different risk categories based on the VTE risk score would translate into a lower rate of VTE than that observed in the general population. For this purpose, the pregnancy health care program (PHP) was launched at the hospital of Cremona, Italy aiming to tailor thromboprophylactic regimens for pregnant women according to this score. The risk model included known risk factors for pregnancy-related VTE converted into a severity score ranging between 0.5 and 3. Based on the scoring results, women were divided into three categories (I–III) and the thromboprophylaxis regimen was decided upon. The regimens included observation alone, mechanical means or LMWH. One thousand seven hundred and eighty-seven pregnant women entered the PHP, 70 % were in risk category I and 5 % in category III. No VTE episodes were recorded in the study participants, which is four times lower than in the general population. This program was designed 7 years ago when only one VTE scoring system was available. Meanwhile, a number of attempts have been made to develop risk scoring systems for the evaluation of pregnant women [6–9]. Nearly all of them are based on major risk factors defining women at high risk for thrombotic events or gestational vascular complications. The PHP is an essential and timely effort to improve the outcome of pregnant women from different VTE risk categories, allowing tailoring modes of thromboprophylaxis. As stated by the authors, the study has several limitations, the most important of which is the lack of a control group. Nevertheless, this article contributes to the paucity of data regarding VTE management in pregnancy. Randomized controlled studies are warranted to develop the optimal risk scoring system allowing personalized management of pregnant women at VTE risk. R. Hoffman B. Brenner (&) Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, P.O. Box 9602, Haifa 31096, Israel e-mail: b_brenner@rambam.health.gov.il