Robert G. Lerner

Subcutaneous Low-Molecular-Weight Heparin Compared with Continuous Intravenous Heparin in the Treatment of Proximal-Vein Thrombosis

Abstract Background. Low-molecular-weight heparin has a high bioavailability and a prolonged half-life in comparison with conventional unfractionated heparin. Limited data are available for low-molecular-weight heparin as compared with unfractionated heparin for the treatment of deep-vein thrombosis. Methods. In a multicenter, double-blind clinical trial, we compared fixed-dose subcutaneous low-molecular-weight heparin given once daily with adjusted-dose intravenous heparin given by continuous infusion for the initial treatment of patients with proximal-vein thrombosis, using objective documentation of clinical outcomes. Results. Six of 213 patients who received low-molecular-weight heparin (2.8 percent) and 15 of 219 patients who received intravenous heparin (6.9 percent) had new episodes of venous thromboembolism (P = 0.07; 95 percent confidence interval for the difference, 0.02 percent to 8.1 percent). Major bleeding associated with initial therapy occurred in 1 patient receiving low-molecular-weight h...

Stimulation of Human Leukocyte Thromboplastic Activity by Endotoxin

Summary Leukocytes incubated in vitro in plasma or serum, but not in saline, develop a potent procoagulant activity like tissue factor. This activity is not present in freshly collected leukocytes from normal individuals. The generation of activity is stimulated by gram-negative endotoxin.

Warfarin use and the risk of valvular calcification.

Summary.  Background: Warfarin affects the synthesis and function of the matrix Gla‐protein, a vitamin K‐dependent protein, which is a potent inhibitor of tissue calcification. Objectives: To investigate the incidence of mitral valve calcium (MVC), mitral annular calcium (MAC) and aortic valve calcium (AVC) in patients with non‐valvular atrial fibrillation (AF) treated with warfarin vs. no warfarin. Patients and methods: Of 1155 patients, mean age 74 years, with AF, 725 (63%) were treated with warfarin and 430 (37%) without warfarin. The incidence of MVC, MAC and AVC was investigated in these 1155 patients with two‐dimensional echocardiograms. Unadjusted logistic regression analysis was conducted to examine the association between the use of warfarin and the incidence of MVC, MAC or AVC. Logistic regression analyses were also conducted to investigate whether the relationship stands after adjustment for confounding risk factors such as age, sex, race, ejection fraction, smoking, hypertension, diabetes, dyslipidemia, coronary artery disease (CAD), glomerular filtration rate, calcium, phosphorus, calcium‐phosphorus product, alkaline phosphatase, use of aspirin, beta blockers, angiotensin‐converting enzyme inhibitors or angiotensin receptor blockers, and statins. Results: There was a significant association between the use of warfarin and the risk of calcification [unadjusted odds ratio = 1.71, 95% CI = (1.34–2.18)]. The association still stands after adjustment for confounding risk factors. MVC, MAC or AVC was present in 473 of 725 patients (65%) on warfarin vs. 225 of 430 patients (52%) not on warfarin (P < 0.0001). Whether this is a causal relationship remains unknown. Conclusions: Use of warfarin in patients with AF is associated with an increased prevalence of MVC, MAC or AVC.

Endotoxin induced disseminated intravascular clotting: evidence that it is mediated by neutrophil production of tissue factor.

Abstract Cycloheximide is a potent inhibitor of protein synthesis. Its effects on endotoxin induced human neutrophil tissue factor production in vitro and endotoxin induced disseminated intravascular clotting (DIC) in rabbits were examined. Endotoxin added to citrated whole human blood led to the production of tissue factor except when neutrophils were absent from the blood. The production of this tissue factor was inhibited by cycloheximide. Cycloheximide added after the tissue factor was formed had no effect. We concluded that neutrophil production of tissue factor depends on protein synthesis. Eight steroid prepared rabbits were given intravenous cycloheximide prior to and after endotoxin injection. None of the rabbits developed DIC as measured by change in fibrinogen level or development of glomerular capillary thrombi. Six rabbits given endotoxin alone showed a 37% mean drop in fibrinogen level and four showed glomerular capillary thrombi. Rabbits treated with cycloheximide alone did not show any glomerular fibrin or change in fibrinogen level. They were capable of developing DIC since infusion of endotoxin and rabbit brain tissue factor caused a fall in fibrinogen level and development of glomerular fibrin. This adds further evidence that neutrophil production of tissue factor is necessary for endotoxin induced DIC.

Variability of response to clopidogrel: possible mechanisms and clinical implications.

Clopidogrel has been shown to inhibit adenosine diphosphate-induced platelet aggregation and has been demonstrated to be effective in reducing the risk of arterial thrombotic events in several large clinical studies. However, the clinical benefit could be attenuated by the variability of response to the antiplatelet effects of clopidogrel in as many as 30% of patients. Multiple mechanisms likely contribute to clopidogrel variability of response, including inappropriate dosing or underdosing of clopidogrel, drug–drug interactions, and genetic polymorphisms. The best laboratory procedure to screen for possible clopidogrel variability of response remains to be determined.

Aspirin resistance: mechanisms and clinical implications.

Acetylsalicylic acid (aspirin) has been shown to irreversibly interfere with platelet function, an effect that is associated with a reduction in morbid and mortal arterial thrombotic events in multiple clinical studies. This clinical benefit appears to be attenuated by resistance to the antiplatelet effects of aspirin in up to 35% of patients. The mechanisms for aspirin resistance are multifactorial and include noncompliance with aspirin therapy, diabetes mellitus, cell–cell and drug–drug interactions, genetic polymorphisms, and coronary artery disease. It has not been determined what the best laboratory procedure is to screen for aspirin resistance. Those individuals at high risk for aspirin resistance might best be treated with an additional oral antiplatelet drug (eg, clopidogrel) to achieve maximal protection against arterial thrombotic events.

Production of thromboplastin (tissue factor) and thrombi by polymor phonuclear neutrophilic leukocytes adhering to vein walls

Abstract Separation of dog femoral and jugular veins from surrounding structures and transient stasis of blood flow for 30 seconds resulted in a lesion characterized by adhesion of neutrophils to the venous endothelium. Neutrophils harvested from this lesion 5 hours later had developed thromboplastic (tissue factor) activity. In immediately removed veins and veins from neutropenic dogs, this lesion did not occur and scrapings of the vein wall did not have thromboplastic activity. In some veins, gross or microscopic thrombosis was seen. It has been reported that neutrophil adhesion to veins also occurs during human surgery. We suggest, therefore, that neutrophils adhering to veins and producing thromboplastin may be a pathogenetic mechanism of deep vein thrombosis in man.

The defibrination syndrome.

Defibrination is a fairly common clinical entity seen in a wide variety of clinical disorders. With an awareness of the likely clinical settings, a high degree of suspicion, and widely available sensitive laboratory tests, the diagnosis is ordinarily easily made. The best therapy is usually that which is directed at the underlying disease rather than at the defibrination syndrome itself. In certain symptomatic cases, heparin and/or replacement therapy is indicated, especially if the underlying disorder cannot be immediately successfully treated. On occasion, antifibrinolytic therapy will be useful, always with due regard to the danger of renal cortical necrosis. Depending on the clinical setting, it may be advisable to give heparin with the antifibrinolytic therapy to minimize that danger.

Plasma factor Xa-inhibitory activity in alcoholic liver disease and the effect of heparin

Abstract Factor Xa-inhibitor (Xa-I) activity was measured in twenty patients with alcoholic liver disease and found to be more than 3 standard deviations below normal in fourteen patients. When trace amounts of heparin were added to these plasmas, the Xa-I activity was potentiated to the same level as normal plasma with heparin added. This suggests that Xa-I is actually present in alcoholic liver disease, but has less than normal activity. Possible explanations such as the lack of endogenous heparin or the presence of an inhibitor are discussed.

Neutropenia in Congenital and Adult Babesiosis

OBJECTIVES Anemia and thrombocytopenia are expected hematologic abnormalities in patients with acute babesiosis, whereas neutropenia (defined as an absolute neutrophil count of ≤1,800 neutrophils/μL for adults and <1,200 neutrophils/μL for infants) is not usually considered a feature of this infection. We studied the frequency with which neutropenia occurs in congenital and adult cases of babesiosis. METHODS The frequency of neutropenia in cases of congenital babesiosis was determined based on a literature review and on the findings in an unreported case. The frequency of neutropenia in adult patients was assessed based on a review of the medical records of 51 patients who were diagnosed with babesiosis between 2010 and 2013 at two medical centers in the Northeastern United States. RESULTS Four (80%; 95% confidence interval [CI], 36%-98%) of five infants with congenital babesiosis whose neutrophil count was reported were neutropenic. Among 51 adult cases with babesiosis, 11 (22%; 95% CI, 12%-35%) were neutropenic on clinical presentation, and seven others developed neutropenia over the next 1 to 21 days. Thus, a total of 18 (35%; 95% CI, 24%-49%) of the adult patients with babesiosis had neutropenia. CONCLUSIONS Neutropenia appears to be a common finding in infants with congenital babesiosis and is also observed not infrequently in adults with this infection.