Blood Hypercoagulability Research Articles

Kidney disease associated with primary antiphospholipid syndrome: clinical signs and histopathological features in an experience of five cases

The primary antiphospholipid syndrome (PAPS) is characterized by the presence of circulating antiphospholipid antibodies, clinically associated with blood hypercoagulability. Renal involvement in course of PAPS is very frequent, although the true prevalence of PAPS-correlated kidney disease is difficult to estimate. We reviewed 270 consecutive renal biopsies examined in our Nephrology Division of Bari University Hospital between 1998 and 2004 to identify those performed in patients with PAPS. We identified five biopsies performed in patients with PAPS. In three patients the diagnosis of PAPS was made at onset of the kidney disorder, while in the other two cases the initial diagnosis was primary focal segmental glomerulosclerosis (FSGS). In these cases the subsequent finding of positive antiphospholipid antibodies reoriented the diagnosis toward PAPS-correlated nephropathy. The clinical onset of kidney disease consisted of acute renal failure in three patients and urinary abnormalities in the other two. Histological examination of renal biopsies showed vascular lesions (intimal fibrous hyperplasia, arteriolar hyalinosis, double outline of the capillary walls) in four patients. Focal segmental glomerulosclerosis was present in four patients, two of whom showed double outline of the capillary walls. All patients had tubulo-interstitial lesions, while immunofluorescence was positive in only two patients. All patients preserved stable renal function throughout follow-up (mean value: 10.6 years, range 4 months-24 years). The prevalence of PAPS-correlated nephropathy in our population was 1.85% Our data confirm that PAPS-associated nephropathy has slow progression and rarely leads to end-stage renal failure. The prevalence of PAPS-correlated nephropathy is likely underestimated because some patients with a diagnosis of primary focal sclerosis may actually be affected by PAPS.

The MET oncogene drives a genetic programme linking cancer to haemostasis

The close relationship between activation of blood coagulation and cancer is an old enigma. In 1865, migrans trombophlebitis ('a condition of the blood that predisposes it to spontaneous coagulation') was described as a forewarning of occult malignancy (Trousseau's sign). This pioneering observation emphasized the existence of haemostasis disorders associated with cancer onset; this phenomenon has since been extensively reported in clinical and epidemiological studies, but has so far resisted a mechanistic explanation. Here we report a mouse model of sporadic tumorigenesis based on genetic manipulation of somatic cells. Targeting the activated, human MET oncogene to adult liver caused slowly progressing hepatocarcinogenesis. This was preceded and accompanied by a syndrome manifesting first with blood hypercoagulation (venous thromboses), and then evolving towards fatal internal haemorrhages. The pathogenesis of this syndrome is driven by the transcriptional response to the oncogene, including prominent upregulation of plasminogen activator inhibitor type 1 (PAI-1) and cyclooxygenase-2 (COX-2) genes. In vivo analysis showed that both proteins support the thrombohaemorrhagic phenotype, thus providing direct genetic evidence for the long-sought-after link between oncogene activation and haemostasis.

Ätiologie und Management von Thrombosen der Vena jugularis interna

Thromboses of the upper limp and neck are rare in comparison with those of the lower extremities. Internal jugular vein thrombosis (IJVT) is a serious event with a potentially fatal outcome. Complications include pulmonary embolism, sepsis with septic emboli to different organs and tissues as well as intracranial propagation of the thrombus with cerebral edema. As any thrombosis, IJVT is precipitated by Virchow's triad: endothelial damage, alteration of blood flow and hypercoagulability. The history and examination in patients with an IJVT may be vague and misleading. Patients may present with a painful swelling of the neck but they may also be absolutely asymptomatic. Imaging procedures frequently used to diagnose an IJVT include sonography with color-coded duplex sonography, computed tomography, magnetic resonance imaging as well as magnetic resonance venography. Up to date, there is no standardized treatment regimen for patients with an IJVT. This retrospective study includes all ten patients with an IJVT who were seen at our department between January 2000 and January 2004. There were six female and four male patients. The average age was 49.7 years, ranging from 28 to 79 years. In five cases, the thrombosis was associated with a malignant tumor. In four patients, it was caused by a deep neck space infection and in one case the IJVT was due to cervical, intravenous drug abuse. Two patients were found to be pregnant (one tumor patient and one patient with a deep neck space infection). In all cases, a ten day treatment regimen with intravenous antibiotics and anticoagulant therapy was initiated. Oral or subcutaneous anticoagulation was continued for six weeks to six months. No complications were seen in any patient. In three patients a revascularization of the affected vessel could be demonstrated with color-coded duplex sonography six months after the initial presentation. Thrombosis of the IJV is probably underdiagnosed. Since the clinical presentation may be vague or misleading, a high degree of suspicion is required to make the diagnosis. The potential complications such as pulmonary embolism or intracranial propagation of the thrombus may be fatal. Whenever the thrombosis is not caused by an inflammatory process, a malignant tumor should be excluded. We recommend a therapy with intravenous antibiotics as well as a systemic anticoagulation. Ligation or resection of the internal jugular vein is reserved for patients who develop complications despite adequate medical therapy.

Femoral head blood flow reduction and hypercoagulability under 24 h megadose steroid treatment in pigs

Femoral head blood flow reduction and hypercoagulability under 24 h megadose steroid treatment in pigs

Correction of hypercoagulability and amelioration of pulmonary arterial hypertension by chronic blood transfusion in an asplenic hemoglobin E/β-thalassemia patient

AbstractChronic transfusion of packed red blood cells, in addition to other ongoing treatment with warfarin, acetyl salicylic acid, desferrioxamine, and other supportive measures, was given to a splenectomized hemoglobin E/β-thalassemia woman with pulmonary arterial hypertension (PHT). Serial measurements of plasma thrombin-antithrombin III complex (TAT) levels and right-sided cardiac catheterization were used to monitor changes after treatment. Reduction of plasma TAT levels from 7.5 to 3.8 μg/L (normal, 3 ± 2.4 μg/L), pulmonary vascular resistance (PVR) from 553.8 to 238.6 dyne.sec.cm-5(normal, 67 ± 30 dyne.sec.cm-5), and mean pulmonary arterial pressure from 51 to 32 mm Hg (normal, 9 to 19 mm Hg) occurred in tandem. Normalization of blood hypercoagulability as reflected in plasma TAT level by chronic blood transfusion was the likely basis for improvement of increased PVR, being secondary to thrombotic pulmonary arteriopathy and subsequently PHT. (Blood. 2004;103: 2844-2846)

Strategies Against High Blood Pressure in the Early Morning

Acute myocardial infarction and cerebrovascular disease reportedly show peak onset in the early morning, when blood pressure increases. The increase of blood pressure, or morning surge, may result from increased sympathetic activity reactive to arousal. The circadian pattern of vascular events is considered to be related to the morning surge in blood pressure, sympathetic activity, and hypercoagulability. Although there is no direct evidence indicating a causal relationship between the morning surge in blood pressure and vascular complications, it may be postulated that morning blood pressure surge is a factor which affects hypertensive complications. There may be two possible approaches to morning blood pressure surge; the pharmacodynamic and pharmacokinetic approach. On the basis of pharmacodynamics, drugs with adrenergic α–blocking actions are usually selected. From a pharmacokinetic view, it is essential to maintain blood concentration of a drug at the critical early morning period. On this point, use of long acting agents, changes in drug regimen and the development of a chronobiological system has been studied, with many studies reporting successful results in lowering morning blood pressure. Further study whether such kinds of treatments improve long term outcomes in hypertensive patients are desired.

Femoral head blood flow reduction and hypercoagulability under 24 h megadose steroid treatment in pigs

The pathogenesis of corticosteroid-induced femoral head necrosis is assumed to be ischemia. The purpose of this study was to investigate the perfusion pattern of the femoral head and plasma coagulability during 24 h corticosteroid megadose treatment, as recommended by the National Acute Spinal Cord Injury Studies (NASCIS), in the awake big animal model. Blindedly, 9 animals underwent megadose methylprednisolone infusion (30 mg/kg intravenously as an initial bolus, followed by 5.4 mg/kg/h for further 23 h) while 9 animals served as placebo treated controls. Regional blood flow of the systematically subdivided femoral head, proximal femur, acetabulum, and soft tissue hip regions was investigated by the microsphere technique at steady state (phase 1), after the initial bolus infusion (phase 2), and after the completed treatment (phase 3). Plasma coagulability was examined in phases 1 and 3. Blood flow of the femoral head epiphysis and metaphyseal cancellous bone was unchanged after one hour of steroid infusion, but decreased after the completed treatment at 24 h in the experimental group. Femoral head blood flow reduction was global without a tendency to more pronounced blood flow decrease in any subregion. Plasma fibrinogen was significantly higher after 24 h of steroid infusion than in the placebo control group. 24 h high dose methylprednisolone treatment causes femoral head blood flow reduction and hypercoagulability of plasma in the normal awake immature pig. These findings may be pathogenetic factors in the early stage of steroid-induced osteonecrosis.

Paradoxical Emboli from Calf and Pelvic Veins in Cryptogenic Stroke

The increased prevalence of patent foramen ovale in patients with cryptogenic strokes suggests the occurrence of paradoxical embolism. The identification of deep venous thromboses (DVTs) in this population would strengthen this hypothesis. The purpose of this study was to image the subdiaphragmatic venous system in a cohort of patients with cryptogenic strokes. In 37 patients with cryptogenic brain ischemia and interatrial communication, duplex studies of calf, popliteal, and femoral veins, and magnetic resonance imaging venograms of the pelvis veins were performed. In 10 patients, DVTs were diagnosed that were considered to be the cause of cryptogenic brain ischemia on probable (n = 6) or possible (n = 4) bases. In these patients, the median time from stroke to DVT was 3.25 days. In 5 of these 10 patients, DVTs did not involve popliteal and femoral veins, areas thought most important to pulmonary embolism, but instead were isolated to calf or pelvic veins. Although none of these 10 patients had abnormal blood hypercoagulation tests, 8 of the 10 did have clinical conditions suggesting predisposition to developing DVTs, such as concomitant neoplasms or pulmonary embolism. Increased evidence for paradoxical embolism may emerge when diagnostic strategies use multiple imaging methods and evaluate a broad extent of the subdiaphragmatic veins.

Desmopressin (DDAVP) and factor VIII: the tale as viewed from Milan (and Malmö)

Desmopressin (DDAVP) and factor VIII: the tale as viewed from Milan (and Malmö)

Antithrombotic drugs in vascular medicine: a historical perspective.

Many new antithrombotic and antiplatelet drugs have been developed that have markedly improved prophylaxis and treatment of thrombotic diseases. Clopidogrel, a potent new antiplatelet compound, is the first clinical alternative to aspirin for long-term oral treatment and prevention of arterial thrombosis. Another new, exciting category of antiplatelet compounds is the GPIIb/IIIa-antagonists, the first antiintegrins in clinical use and the most potent inhibitors of platelet aggregation. Low molecular weight heparins (LMWHs) are the quantitatively dominating group of new antithrombotics, which has replaced unfractionated heparin for the prophylaxis and treatment of venous thromboembolism. Current clinical evidence suggests that LMWHs might replace unfractionated heparin for the treatment and prophylaxis of atherothrombotic complications in acute coronary syndromes in the near future. Fondaparinux is the first synthetic pentasaccharide and a selective inhibitor of factor Xa with exciting clinical data; it could become an alternative LMWH for prophylaxis of arterial and venous thromboembolism in high-risk patients. The field of oral thrombin inhibitors is still dominated by the coumarins. However, much effort is being undertaken to develop new orally active drugs from which ximelagatran is currently the leading compound with a predicted better safety and efficacy profile. Alternatively, inhibitors of factor VIIa might be of interest as well. Open questions include, in particular, the possible individualization of drug therapy in dependence on the kind of disturbed platelet function or blood hypercoagulability, respectively.

Tissue factor expression in atrial endothelia associated with nonvalvular atrial fibrillation: possible involvement in intracardiac thrombogenesis

Introduction: Tissue factor plays a key role in the extrinsic coagulation pathway and is induced by inflammatory cytokines. Atrial myocarditis has been detected recently in some patients with lone atrial fibrillation. Virchow's triad of low blood flow, hypercoagulability, and endothelial dysfunction, enhances thrombus formation. The present study was designed to elucidate the role of endothelial dysfunction in thrombogenesis associated with nonvalvular atrial fibrillation. Material and methods: We investigated tissue factor expression in the endothelia of left atrial appendages obtained from seven patients with nonvalvular atrial fibrillation and cardiogenic thromboembolism. Tissues were divided into 7–13 sections and compared with control specimens from four patients who died of noncardiac events. Expression of tissue factor, von Willebrand factor and tissue factor pathway inhibitor was evaluated by immunohistochemistry. Results: Histopathologically, inflammatory cells infiltrated the endocardium and all seven patients showed features of persistent myocarditis. Activated T cells [15.3±9.4 cells/high power field (HPF, mean±S.D.) vs. control 2.2±4.4/HPF ( P=0.0294)] and a few macrophages [5.1±8.4 cells/HPF vs. control 2.4±3.5 cells/HPF ( P=NS)] infiltrated the endocardium. Tissue factor was overexpressed in the endothelia particularly in tissues containing inflammatory cells and denuded matrix of the endocardium, compared with the control group. Von Willebrand factor, but not tissue factor pathway inhibitor, was also overexpressed in these tissues. Conclusion: Tissue factor expression induced by local inflammation is involved in the pathogenesis of thrombosis in patients with nonvalvular atrial fibrillation.

DVT prophylaxis in the perioperative setting.

In last month's BJPB, Agnes Arnold discussed the pathophysiology of deep vein thrombosis and suggested ways that the risk could be reduced, particularly with respect to DVTs resulting from endothelial damage in surgery. In this, the second of a two-part series, Agnes continues by looking at hypercoagulability of blood and venous stasis and the impact of these conditions on the risk of DVT.

Thrombin activity and platelet microparticle formation are increased in type 2 diabetic platelets: a potential correlation with caspase activation

Diabetics suffer from many complications including a prothrombotic condition. Activated platelet membrane provides an anchor, phosphatidylserine, for the attachment of the prothrombinase complex, which allows increased thrombin formation. This study aimed to further elucidate the interrelationship between coagulation proteins and activated platelets in type 2 diabetic blood. We found that there was a significant increase (30×) in thrombin activity in the type 2 diabetic (ZDF) blood as compared to age-matched (ZL) controls ( p<0.001). There was also a significant increase in the number of platelet microparticles in the type 2 diabetic rat compared to the lean control ( p<0.001). Further, there were significant increases in caspase-3, -6, and -8 activities in the type 2 diabetic rats as compared to the lean controls ( p<0.05). The combination of increased thrombin activity, increased PMP formation and increased caspase activity may contribute to the hypercoagulability of the diabetic blood. These results give more insight into the mechanisms underlying the interrelationship between diabetic platelets and coagulation proteins causing a prothrombotic condition in this patient population at increased risk from thromboembolic events.

Pathogenesis of venous thromboembolism.

Three factors are related with the pathogenesis of venous thrombosis: (1) blood stasis, (2) hypercoagulability, and (3) vessel damage. Local and systemic factors are implicated in blood stasis. Remarkable advances have been recently achieved regarding the understanding of the concept of hypercoagulability, with special emphasis to thrombophilic molecular abnormalities. Increased thromboembolic risk has been described in patients with antithrombin III, protein C, or protein S deficiencies as well as factor V Leiden, prothrombin mutation G20210A, or hyperhomocystinemia. Vessel wall has a remarkable role in protecting against and in promoting thrombosis. The role of inflammation on venous thrombosis is under investigation.

Cerebral resuscitation potentials for cardiac arrest.

Permanent brain damage after cardiac arrest and resuscitation is determined by many factors, predominantly arrest (no-flow) time, cardiopulmonary resuscitation (low-flow) time, and temperature. Research since around 1970 into cardiopulmonary-cerebral resuscitation has attempted to mitigate the postischemic-anoxic encephalopathy. These efforts' results have recently shown outcome benefits as documented in clinically relevant outcome models in dogs and in clinical trials. Pharmacologic strategies have so far yielded relatively disappointing results. In a recent exploration of 14 drugs in dogs, only the antioxidant tempol administered at the start of prolonged cardiac arrest improved functional outcome in dogs. Cerebral blood flow promotion by hypertensive reperfusion and hemodilution has resulted in improved outcome in dogs, and brief hypertension after restoration of spontaneous circulation is associated with improved outcome in patients. Postarrest hypercoagulability of blood seems to yield to therapeutic thrombolysis, which is associated with improved cerebral outcome in animals and patients. In a clinically relevant dog outcome model, mild postarrest cerebral hypothermia (34 degrees C), initiated with reperfusion and continued for 12 hrs, combined with cerebral blood-flow promotion increased from 5 to >10 mins the previously longest normothermic no-flow time that could be reversed to complete cerebral recovery. Mild hypothermia by surface cooling after prolonged cardiac arrest in patients has been found effective in recent clinical studies in Australia and Europe. Preliminary data on the recent randomized study in Europe have been reported. For presently unresuscitable cardiac arrests, research since the 1980s in dog outcome models of prolonged exsanguination cardiac arrest has culminated in brain and organism preservation during cardiac arrest (no-flow) durations of up to 90 mins, perhaps 120 mins, at a tympanic temperature of 10 degrees C and complete recovery of function and normal histology. This "suspended animation for delayed resuscitation" strategy includes use of an aortic flush of cold saline (or preservation solution) within the first 5 mins of no flow. This strategy should also be explored for the larger number of patients with unresuscitable out-of-hospital cardiac arrests. Suspended animation for prolonged preservation of viability could buy time for transport and repair during hypothermic no flow followed by resuscitation, or it could serve as a bridge to prolonged cardiopulmonary bypass.

Experimental study on effect of bushen huoxue xiezhuo decoction in treating minute lesion nephropathy

To explore the therapeutic effect and mechanism of Bushen Huoxue Xiezhuo Decoction (BHXD) in treating minimal change nephropathy (MCN) in rats. The MCN model rats established by a single intravenous injection of Adriamycin were divided into the model, BHXD group, and a normal group was set up for control. The effect of treatment on renal function, hemorrheologic parameters, renal tissue TGF-beta 1 expression and polyanion sites on glomerular basement membrane were observed dynamically. After treatment, all the parameters between the BHXD group and the model group were significantly different respectively, morphological observation also showed the pathological changes in the BHXD group were milder than those in the model group. BHXD treatment could markedly improve the renal function, alleviate blood hypercoagulability and hyperviscosity, protect the anion barrier and delay the progression of glomerular fibrosis and sclerosis.

Hypercoagulability in patients with obstructive sleep apnea

Background: Obstructive sleep apnea (OSA) has been linked to cardiovascular complications such as stroke and myocardial infarction. Previous studies demonstrate that OSA patients show elevated fibrinogen levels and increased platelet aggregation that are reversed with 1 night of nasal continuous positive airway pressure treatment (NCPAP). Questioning overall coagulability in OSA, we examined whole blood coagulability in 11 chronically NCPAP treated OSA subjects, 22 previously untreated OSA subjects, and in 16 of these after 1 night of NCPAP treatment. Patients and methods: During full polysomnography, subjects from each group had blood drawn prior to bedtime (21:00 h) and upon waking in the morning (07:00 h). Results: Untreated OSA patients had faster P.M. clotting times than chronically treated OSA patients (3.33±0.31 versus 6.12± 0.66 min, P<0.05 by ANOVA). A.M. values showed similar results (4.31± 0.34 min versus 7.08±0.52 min, P<0.05 by ANOVA) for the respective groups. One overnight treatment with nasal CPAP did not produce a significant change in A.M. whole blood coagulability (4.35 ±0.43 to 5.31±0.53 min; n=16; P=0.1) in 16 treated subjects. Conclusions: These data indicate a relationship between obstructive sleep apnea and blood hypercoagulability status that appears to be reversed by chronic NCPAP treatment. These data suggest that NCPAP might protect against the development of cardiovascular complications in OSA patients.

Correlation between Grade III Placenta and Plasma Antithrombin III Activity in Full Term Pregnancy

We evaluated whether the presence of a grade III placenta correlates with blood hypercoagulability in pregnancy between 37 and 39 weeks of gestation. The placenta was graded by ultrasound in 155 healthy full-term women and the plasma levels of antithrombin III (AT III) activity, thrombin-antithrombin complex (TAT) and D-dimer were correlated with each placental grade. AT III activity levels tended to decrease with advancing placental grade from I to III (p < 0.05). D-dimer showed the same tendency while TAT did not. The incidence of reduced AT III activity levels (<70%) in women with a grade III placenta was about twice those in women with a grade II or I placenta, and that of AT III <80% was 3-fold greater. We concluded that the presence of a grade III placenta in full-term pregnancies correlates with blood hypercoagulability.

Inferior vena cava malformation as a risk factor for deep venous thrombosis in the young.

Conditions which result in hypercoagulable blood or venous stasis may predispose to the development of deep vein thrombosis (DVT). Most of the recently described risk factors for DVT induce a hypercoagulable state. Over a 3-year period we have observed anomaly of the inferior vena cava (IVC) in four young patients presenting with spontaneous unprovoked DVT. This is a greater than expected rate (5% observed versus 0.5% expected). Further, bilateral DVT, which constitutes less than 10% of cases in most series, was present in three of the four cases. Anomaly of the IVC is a rare example of a prevalent congenital condition that predisposes to DVT, presumably by favouring venous stasis. This diagnosis should be considered in young patients with spontaneous and bilateral DVT.

Hypercoagulability in Obstructive Sleep Apnea

In patients with obstructive sleep apnea, blood hypercoagulability may contribute to an increased risk of cardiovascular events. The main causes of hypercoagulability related to obstructive sleep apnea are hyperfibrinogenemia, decreased fibrinolytic activity, platelet function abnormalities, erythrocytosis, and vascular endothelial dysfunction. This hypercoagulable state may be related to recurrent episodic hypoxia during sleep apnea.