Warfarin use and the risk of valvular calcification.

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.

Guidelines and the use of inferior vena cava filters: a review of an institutional experience.

BACKGROUND AND OBJECTIVES: Based on the American College of Chest Physicians 2004 antithrombotic therapy for venous thromboembolism (VTE) and the Eastern Association for the Surgery of Trauma 2002 guidelines, placement of an inferior vena cava (IVC) filter is indicated in patients who either have, or are at high risk for, VTE, but have a contraindication or failure of anticoagulation. Our aim is to compare clinical characteristics and outcomes of patients receiving IVC filters within-guidelines (WG) and outside-of-guidelines (OOG). METHODS: The 558 patients who received an IVC filter were divided into two groups called WG or OOG. The WG group met the criteria described above and the OOG group did not have a contraindication to or a failure of anticoagulation. RESULTS: The WG group had 362 patients and the OOG group had 196 patients. The OOG group had one (0.5%) patient with post-filter pulmonary embolism (PE), two (1%) with IVC thrombosis, and seven (3.6%) with deep vein thrombosis (DVT). The WG group had five (1.4%) patients with post-filter PE, 13 (3.6%) with IVC thrombosis, and 34 (9.4%) with DVT. All patients who developed post-filter PE had a DVT before filter placement, and patients who did not have a prior VTE event were at a significantly lower risk of developing post-filter IVC thrombosis and PE. CONCLUSION: Our data do not support the use of an IVC filter outside of guidelines in patients without prior VTE who can tolerate anticoagulation because of the low risk of developing PE.

Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is an immune-mediated syndrome caused by heparin. Complications range from thrombocytopenia to thrombocytopenia with thrombosis. We report a prospective, historical- controlled study evaluating the efficacy and safety of argatroban, a direct thrombin inhibitor, as anticoagulant therapy in patients with HIT or HIT with thrombosis syndrome (HITTS). METHODS AND RESULTS: Patients with HIT (isolated thrombocytopenia, n=160) or HITTS (n=144) received 2 microgram. kg(-1). min(-1) IV argatroban, adjusted to maintain the activated partial thromboplastin time 1.5 to 3.0 times baseline value. Treatment was maintained for 6 days, on average. Clinical outcomes over 37 days were compared with those of 193 historical control subjects with HIT (n=147) or HITTS (n=46). The incidence of the primary efficacy end point, a composite of all-cause death, all-cause amputation, or new thrombosis, was reduced significantly in argatroban-treated patients versus control subjects with HIT (25.6% versus 38.8%, P=0.014). In HITTS, the composite incidence in argatroban-treated patients was 43.8% versus 56.5% in control subjects (P=0.13). Significant between-group differences by time-to-event analysis of the composite end point favored argatroban treatment in HIT (P=0.010) and HITTS (P=0.014). Argatroban therapy, relative to control subjects, also significantly reduced new thrombosis and death caused by thrombosis (P<0.05). Argatroban-treated patients achieved therapeutic activated partial thromboplastin times generally within 4 to 5 hours of starting therapy and, compared with control subjects, had a significantly more rapid rise in platelet counts (P=0.0001). Bleeding events were similar between groups. CONCLUSIONS: Argatroban anticoagulation, compared with historical control subjects, improves clinical outcomes in patients who have heparin-induced thrombocytopenia, without increasing bleeding risk.

Evaluation of solvent/detergent-treated plasma in patients with a prolonged prothrombin time.

OBJECTIVES: To compare the laboratory and clinical outcome of patients who received solvent/detergent-treated plasma (SDP) and fresh-frozen plasma (FFP). METHODS: A randomized, double-blinded study to assess the ability of SDP and FFP to reduce a prolonged prothrombin time (PT) to

Clopidogrel: a new antiplatelet drug.

Clopidogrel is a new drug in the recently developed class of thienopyridine derivatives that inhibits platelet function by an inhibitory action exerted through the membrane adenosine diphosphate receptor. Clopidogrel is a prodrug that must be metabolized to an active metabolite in the liver. The basic chemistry, pharmacodynamics and pharmacokinetics of the drug are reviewed. Clinical trials with clopidogrel, including its use in patients with stents postangioplasty, adverse reactions, and potential advantages over other agents are summarized.

Treatment of proximal vein thrombosis with subcutaneous low-molecular-weight heparin vs intravenous heparin. An economic perspective.

BACKGROUND: Subcutaneous low-molecular-weight heparin is at least as effective and safe as classic intravenous heparin therapy for the treatment of proximal vein thrombosis. Anticoagulant monitoring is not required with low-molecular-weight heparin. OBJECTIVE: To perform an economic evaluation of these therapeutic approaches by comparing cost and effectiveness. PATIENTS AND METHODS: A randomized trial in 432 patients with proximal vein thrombosis that compared intravenous heparin and low-molecular-weight heparin with objective documentation of clinical outcomes provided the opportunity to perform an analysis of cost-effectiveness to rank these alternative therapies in terms of both their cost and effectiveness. The economic viewpoint of this analysis was that of a third-party payer (ie, a ministry of health in Canada or an insurance company in the United States). RESULTS: In the intravenous heparin-treated group, the cost incurred for 100 patients was $414,655 (Canadian dollars) or $375,836 (US dollars), with a frequency of objectively documented venous thromboembolism of 6.9%. In the low-molecular-weight heparin-treated group, the cost incurred for 100 patients was $399,403 (Canadian dollars) or $335,687 (US dollars), with a frequency of objectively documented venous thromboembolism of 2.8%, thus providing a cost saving of $15,252 (Canadian dollars) or $40,149 (US dollars). Multiple sensitivity analyses were performed, and these procedures did not alter the findings of the study. CONCLUSIONS: The findings indicate that low-molecular-weight heparin therapy is at least as effective and safe but less costly than intravenous heparin treatment. The potential for outpatient therapy in up to 37% of patients who are receiving low-molecular-weight heparin would substantially augment the cost saving.

Subcutaneous low-molecular-weight heparin compared with continuous intravenous heparin in the treatment of proximal-vein thrombosis.

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 heparin (0.5 percent) and in 11 patients receiving intravenous heparin (5.0 percent), a reduction in risk of 91 percent (P = 0.006). This apparent protection against major bleeding was lost during long-term therapy. Minor hemorrhagic complications were infrequent. Ten patients receiving low-molecular-weight heparin (4.7 percent) died, as compared with 21 patients receiving intravenous heparin (9.6 percent), a risk reduction of 51 percent (P = 0.049). CONCLUSIONS: Low-molecular-weight heparin is at least as effective and as safe as classic intravenous heparin therapy under the conditions of this study and more convenient to administer. The simplified therapy provided by low-molecular-weight heparin may allow patients with uncomplicated proximal deep-vein thrombosis to be cared for in an outpatient setting.

Clinical use of the total dose intravenous infusion of iron dextran.

Eighty-seven patients with anemia and absent bone marrow hemosiderin were given treatment with total dose intravenous infusions of iron dextran. The effect of rate of infusion and premedication with diphenhydramine, aspirin, and methylprednisolone on acute and delayed reactions was assessed. All patients were monitored for 72 hours after infusion. Two patients reacted to the test dose. One responded with generalized body pain that lasted approximately 5 minutes. In one an anaphylactoid reaction developed, which was promptly terminated by intravenous methylprednisolone, subcutaneous epinephrine, and intravenous diphenhydramine. Transient delayed adverse reactions easily controlled by nonsteroidal anti-inflammatory drugs occurred in 37 patients. The most common delayed reaction was a syndrome characterized by arthralgia, myalgia, and fever. Seven subjects had a chronic disease in addition to anemia with absent bone marrow iron. In all seven normal hemoglobin and hematocrit values were attained after treatment. The results of our experience with total dose intravenous iron dextran therapy suggest that it be the preferred method of replenishment in clinical situations where parenteral administration of iron is indicated. An unexpected benefit was the efficaciousness of this method of administration in patients with iron deficiency and coexisting chronic disease. A protocol for its administration is proposed.

Endothelial loss due to leukocytes in canine experimental vein-to-artery grafts.

Vein-to-artery grafts develop areas of endothelial loss with fibrin and leukocytes which lead to early thrombosis and may lead to subsequent atherosclerosis of the graft. En face monolayers were prepared which removed greater than 90% of vascular intima. Unevenly distributed leukocytes and endothelial cells were counted using a standardized sampling of calibrated oil immersion fields of 0.01 mm2. Nongrafted veins had 14 +/- 1 evenly arranged endothelial cells per field without gaps or leukocytes, while 10-min grafts had 13 +/- 2 with rare leukocytes. Four-hour grafts from normal dogs had 9 +/- 2 endothelial cells with gaps and 97 +/- 37 neutrophils and 44 +/- 25 monocytes. Leukopenic dogs (vinblastine-treated) had normal numbers of endothelial cells (14 +/- 1) with scanty leukocytes. We conclude that leukocytes cause endothelial loss in vein-to-artery grafts that can be prevented by intense leukopenia. This may lead to practical approaches to protecting such grafts in humans.

Changes in fibrinolytic activity during the course of a single hemodialysis session.

Cardiopulmonary bypass, a form of extracorporeal circulation, markedly increases blood fibrinolytic activity. Accordingly, we measured the effect of hemodialysis, another form of extracorporeal circulation, on fibrinolytic activity in 13 patients with end stage renal disease during and after a single hemodialysis session. Total fibrinolytic activity on fibrin plates, which reflects plasminogen activator levels, was below normal prior to dialysis, rose well above normal at one hour, and then dropped gradually so that just prior to the end of a dialysis session it was still significantly elevated. Within 30 minutes of the end of dialysis, fibrinolytic activity fell rapidly, approaching predialysis levels. In contrast, 5 patients studied before and 3 hours into a peritoneal dialysis session showed no change in their subnormal levels of plasminogen activator. Plasminogen and alpha-2 antiplasmin levels did not change significantly during the course of hemodialysis. Thus, hemodialysis, but not peritoneal dialysis, transiently increases fibrinolytic activity without consuming plasminogen, a pattern consistent with the release of tissue type plasminogen activator.

Disseminated intravascular coagulation. Complication of LeVeen peritoneovenous shunts.

Disseminated intravascular coagulation (DIC) occurred in three of five patients after insertion of a LeVeen shunt for intractable ascites. Four episodes of DIC in these patients ranged in severity from progressive and life-threatening to transient and asymptomatic. Interruption of the shunt in two patients stopped the DIC. Careful monitoring for DIC following shunt insertion allows rational decisions to protect the patient against life-threatening hemorrhage or thrombosis. Disseminated intravascular coagulation occurred in two patients during a trial intravenous infusion of ascites and occurred in one patient even when the surgical procedure was modified to minimize the volume and rate of the infused ascites.

Detection of factor XIIIa (active fibrin-stabilizing factor) in normal plasma.

Factor XIIIa (active fibrin-stabilizing factor) generated in heat-defibrinated plasma by the addition of thrombin can be measured by 14C-putrescine incorporation into casein. Modification of this assay be substituting 3H-putrescine of high specific activity as the donor amine permits measurement of amine incorporation by plasma even in the absence of added thrombin. Incorporation is calcium dependent, inhibited by iodoacetamide, and absent from congenital factor XIII-deficient plasma and from normal platelets. The transamidating activity detected by radioenzymatic assay catalyzed the formation of gamma-gamma dimers and alpha polymers of fibrin and was thus biologically functional. This fibrin cross-linking activity was absent from factor XIII-deficient plasma. These experiments show (1) some factor XIII is present in plasma as factor XIIIa; (2) this factor XIIIa can cross-link fibrin and thus has biologic activity as well; and (3) this activity is not present in factor XIII-deficient plasma. Factor XIIIa in normal plasma is possibly activated in vivo, perhaps by circulating thrombin, factor Xa, or other proteolytic enzymes.

Heparin-induced thrombocytopenia.

Two patients with underlying thromboembolic disorders developed severe thrombocytopenia while receiving heparin sodium; one of these patients developed recurrence of the thrombocytopenia and possible heparin-induced pulmonary emboli when heparin was restarted. In a prospective study of patients receiving heparin in a coronary care unit (CCU), nine of 37 patients developed transient mild thrombocytopenia (platelet counts ranging from 88,000 to 150,000/cu mm). Heparin added to citrated platelet-rich plasma caused platelet aggregation in the two original patients. In three of six CCU patients tested, and in 17 of 87 other subjects, with maximum aggregation at concentrations of heparin likely to be present in vivo during therapy. We herein discuss evidence that suggests that heparin may cause or aggravate thrombosis by causing platelet aggregation. The occurrence of severe heparin-induced thrombocytopenia is well documented, and mild transient thrombocytopenia may be more common than has been recognized. Studies of heparin efficacy should take these responses into account.

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.