Clinical and Applied Thrombosis/Hemostasis

Cardiac surgery involving cardiopulmonary bypass (CPB) is often associated with important blood loss, allogeneic blood product usage, morbidity, and mortality. Coagulopathy during CPB is complex, and the current lack of uniformity for triggers and hemostatic agents has led to a wide variability in bleeding treatment. The aim of this review is to provide a simplified picture of the data available on patients’ coagulation status at the end of CPB in order to provide relevant information for the development of tailored transfusion algorithms. A nonsystematic literature review was carried out to identify changes in coagulation parameters during CPB. Both prothrombin time and activated partial thromboplastin time increased during CPB, by a median of 33.3% and 17.9%, respectively. However, there was marked variability across the published studies, indicating these tests may be unreliable for guiding hemostatic therapy. Some thrombin generation (TG) parameters were affected, as indicated by a median increase in TG lag time of 55.0%, a decrease in TG peak of 17.5%, and only a slight decrease in endogenous thrombin potential of 7%. The most affected parameters were fibrinogen levels and platelet count/function. Both plasma fibrinogen concentration and FIBTEM maximum clot firmness decreased during CPB (median change of 36.4% and 33.3%, respectively) as did platelet count (44.5%) and platelet component (34.2%). This review provides initial information regarding changes in coagulation parameters during CPB but highlights the variability in the reported results. Further studies are warranted to guide physicians on the parameters most appropriate to guide hemostatic therapy.

Venous thromboembolism (VTE) in adolescents is a serious condition that requires prompt recognition and optimal management to prevent mortality and long-term morbidity. Adolescents account for a large proportion of cases of VTE in children. As teenagers transition from childhood to adulthood, they are at risk of developing medical conditions and exposure to risky habits that predispose them to VTE. This review focuses on the variety of risk factors and comorbidities seen in adolescent VTE and takes a quick look into risk-based preventive strategies for primary and secondary prevention.

Heparin is a widely used clinical anticoagulant. It is also a linear glycosaminoglycan with an average mass between 10 and 20 kDa and is primarily made up of trisulfated disaccharides comprised of 1,4-linked iduronic acid and glucosamine residues containing some glucuronic acid residues. Heparin is biosynthesized in the Golgi of mast cells commonly found in the liver, intestines, and lungs. Pharmaceutical heparin currently used in the United States is primarily extracted from porcine intestines. Other sources of heparin including bovine intestine and bovine lung are being examined as potential substitutes for porcine intestinal heparin. These additional sources are intended to serve to diversify the heparin supply, making this lifesaving drug more secure. The current study examines bovine heparins prepared from both intestines and lung and compares these to porcine intestinal heparin. The structural properties of these heparins are examined using nuclear magnetic resonance, gel permeation chromatography, and disaccharide analysis of heparinase-catalyzed depolymerized heparin. The in vitro functional activities of these heparins have also been determined. The goal of this study is to establish the structural and functional similarities and potential differences between bovine and porcine heparins. Porcine and bovine heparins have structural and compositional similarities and differences.

The association between hereditary thrombophilia and venous thrombosis is well established but controversial data exist with respect to arterial thrombosis. We performed a pilot study on 31 patients with acute myocardial infarction (AMI), 21 patients with unstable angina (UA), and 20 healthy volunteers to investigate the role of various hemostatic gene polymorphisms in young Egyptian patients, who survived their first ischemic heart disease (IHD). Thrombophilic gene polymorphisms were tested using multiplex polymerase chain reaction and reverse-hybridization technique. We showed an increased risk of AMI with factor V (FV) Leiden and prothrombin G20210A heterozygosity. The increased risks of UA was associated with GA and A allele of fibrinogen β-455G→A polymorphism. Conversely, factor XIII (FXIII) Val34Leu GT and T allele were protective in the UA group. Nevertheless, the prevalence of FV H1299R, plasminogen activator inhibitor 1 4G/5G, glycoprotein IIIa C1565T, 5,10-methylenetetrahydrofolate reductase C677T, and A1298C mutations did not differ between patients with IHD and controls. The data have clinical implications regarding screening and thromboprophylaxis in high-risk individuals younger than 40 years.

We compared thrombophilia in 67 cases (59 men and 8 women) with thrombotic events after starting testosterone therapy (TT) versus 111 patient controls having unprovoked venous thrombotic events without TT. In the 67 patients, thrombosis (47 deep venous thrombosis–pulmonary embolism, 16 osteonecrosis, and 4 ocular thrombosis) occurred 6 months (median) after starting TT. Cases differed from controls for factor V Leiden heterozygosity (16 of the 67 [24%] vs 13 [12%] of the 111, P = .038) and for lupus anticoagulant (9 [14%] of the 64 vs 4 [4%] of the 106, P = .019). After a first thrombotic event and continuing TT, 11 cases had a second thrombotic event, despite adequate anticoagulation, 6 of whom, still anticoagulated, had a third thrombosis. Screening for thrombophilia before starting TT should identify men and women at high risk for thrombotic events with an adverse risk–benefit ratio for TT. When TT is given to patients with familial and acquired thrombophilia, thrombosis may occur and recur in thrombophilic men despite anticoagulation.

The etiology of the prothrombotic state in myeloma has yet to be definitively characterized. Similarly, while recent evidence suggests that patients with monoclonal gammopathy of undetermined significance (MGUS) may also be at increased risk of thrombosis, the magnitude and the etiology of this risk have also yet to be defined. The present study aims to characterize patterns of plasma thrombin generation and sensitivity to the anticoagulant activity of activated protein C (APC) at the time of initial diagnosis of myeloma and in response to therapy in comparison to that observed among patients with MGUS and matched, healthy volunteers. Patients presenting with newly diagnosed/newly relapsed myeloma (n = 8), MGUS (n = 8), and matched healthy volunteers (n = 8) were recruited. Plasma thrombin generation was determined by calibrated automated thrombography. Peak thrombin generation was significantly higher in patients with myeloma (383.4 ± 33.4 nmol/L) and MGUS (353.4 ± 16.5 nmol/L) compared to healthy volunteers (276.7 ± 20.8 nmol/L; P < .05). In the presence of APC, endogenous thrombin potential was significantly lower in control plasma (228.6 ± 44.5 nmol/L × min) than in either myeloma (866.2 ± 241.3 nmol/L × min, P = .01) or MGUS plasma (627 ± 91.5 nmol/L × min, P = .003). Within the myeloma cohort, peak thrombin generation was significantly higher at diagnosis (353.2 ± 15.9 nmol/L) than following completion of the third cycle of therapy (282.1 ± 15.2 nmol/L; P < .005). Moreover, sensitivity to APC increased progressively with each cycle of chemotherapy. Further study of the etiology and evolving patterns of hypercoagulability among patients with these conditions is warranted and may have future implications for thromboprophylaxis strategies.

Total joint arthroplasty (TJA) improves the quality of life for patients with end-stage osteoarthritis but is associated with an increased risk of venous thromboembolism (VTE), thus pharmacologic thromboprophylaxis is recommended for most patients. Patients with congenital bleeding disorders may develop severe arthropathies due to repeated hemarthroses and derive similar benefit from TJA as the general population. No guidelines for pharmacologic thromboprophylaxis in this population exist, however, as the risks and benefits are not well defined. We undertook the current study to assess the safety and efficacy of pharmacologic VTE prophylaxis in patients with congenital bleeding disorders undergoing TJA. We retrospectively reviewed the medical records of patients with bleeding disorders who underwent TJA at our academic institution between 1987 and 2012. We identified 28 patients who underwent 38 TJA procedures. Low-molecular-weight heparin (LMWH) was administered in 29 procedures (76%) and was discontinued early in 3 procedures (2 patients) due to nonjoint bleeding. No symptomatic VTE was identified, and no joint or deep wound infections were seen. Twenty-two patients accounting for 31 procedures were contacted to discuss their experience with TJA. All reported decreased pain, and 97% reported improved function after the surgery. Impressively, 97% stated that they would choose to have the surgery again. These results confirm the benefit of TJA in patients with congenital bleeding disorders and end-stage arthropathies and suggest that LMWH thromboprophylaxis is safe. No patient in our cohort developed symptomatic VTE, whether or not thromboprophylaxis was administered, thus necessity of thromboprophylaxis remains an unanswered question.

Hemoglobin Eβ thalassemia is a major public health problem in India, especially in the state of West Bengal. Various thromboembolic events are common, especially in splenectomized patients. Platelet hyperactivity most likely plays a pathogenetic role. To investigate the role of platelets in hypercoagulability, platelet aggregation tests were undertaken in the present study. Platelet-rich plasma from 30 patients with Eβ thalassemia (15 splenectomized and 15 nonsplenectomized) were studied and compared with 15 healthy participants. The 4 agonists used were adenosine 5-diphosphate, adrenaline (epinephrine), collagen, and ristocetin. The current study shows both splenectomized and nonsplenectomized patients had abnormal aggregation compared to normal healthy controls. Splenectomized patients had higher platelet aggregation than nonsplenectomized patients for all 4 agonists; but statistically significant difference among 2 groups was found only for collagen. The present study confirms a role of splenic absence in platelet hyperaggregation.

Genetic variants of cholesteryl ester transfer protein (CETP) and endothelial nitric oxide synthase (eNOS) influence high-density lipoprotein cholesterol (HDL-C) metabolism and nitric oxide (NO) synthesis, respectively, and might increase the risk of coronary artery disease (CAD). This study is to investigate the relationship between genetic polymorphisms and the risk of CAD and to evaluate their potential interactions. A total of 237 patients with CAD and 101 controls were genotyped. The association of the polymorphism with the risk of CAD varied among the ethnic groups. Moreover, the concomitant presence of both CETP B1 and eNOS 4a alleles significantly increased the risk of CAD in the Malay group (OR = 33.8, P < .001) and the Indian group (OR = 10.9, P = .031) but not in the Chinese group. This study has identified a novel ethnic-specific gene–gene interaction and suggested that the combination of CETP B1 allele and eNOS 4a allele significantly increases the risk of CAD in Malays and Indians.

l-Asparaginase is a potent antileukemia agent and an essential part of treatment protocols for acute lymphoblastic leukemia. However, toxicity limits dose escalation, especially in adults. This includes a significant risk of thrombosis, which remains an important source of avoidable morbidity and mortality. Here, we provide a detailed report of 10 cases of cerebral thrombotic complications that occurred over a 5-year period at 4 large tertiary referral hospitals. To our knowledge, this is the first report of this type in the published literature.

In the present study, in vivo thrombolysis efficiency of Brevithrombolase, a nontoxic fibrinolytic enzyme purified from Brevibacillus brevis strain FF02B, was affirmed by significant inhibition of thrombus formation in the k-carrageenan-induced rat tail, in a dose-dependent manner. Brevithrombolase at a dose of 600 µg/kg showed an efficacy that was comparable to streptokinase and plasmin, in dissolving in vivo thrombus of k-carrageenan-treated rats under identical conditions. The in vivo anticoagulant property of Brevithrombolase was demonstrated by its prolongation of activated partial thromboplastin time, prothrombin time, and thrombin time in Wistar rats. However, the Brevithrombolase-treated rats demonstrated an insignificant decrease in fibrinogen (Fg) level of plasma compared with Fg level of control group of rats corroborating in vivo as well as in vitro anticoagulant activity of Brevithrombolase is due to its hydrolytic action on thrombin. These findings unequivocally suggest that Brevithrombolase may serve a promising alternative to the commercial thrombolytic drugs.