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Eastern J Med: 14 (2)
Volume: 14  Issue: 2 - 2009
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DERLEME
1.Pathogenesis & Laboratory approach to Thrombophilia
Renu Saxena, Monica Sharma
Pages 29 - 35
Thrombophilia is a term used for any hypercoagulable state, either inherited or acquired. The former is considered after excluding acquired predisposing causes like trauma, immobility, Dirseminated inta vascular cuagulation, pregnancy and anitphospholipid syndrome etc. It frequently results from interplay of genetic and acquired factors. An individual’s risk for DVT would be determined by the combination of his or her baseline propensity for thrombosis and the magnitude of the acute insult. Inherited hypercoagulable states may be secondary to deficiency of natural clotting inhibitors or elevated procoagulants or increased fibrinolytic factors . Amongst these, activated protein C resistance, is the commonest underlying cause .Testing for thrombophilia is best performed in stages. Highest-yield assays (screening tests) should be performed first and, if positive, should be followed by appropriate confirmatory tests. Cornerstone of initial treatment is heparin, either unfractionated or low molecular weight, followed by oral anticoagulation.

2.Thrombosis in neonates and children
Tulika Sethi
Pages 36 - 45
The incidence of thrombosis is lower in children than in adults, however thrombosis related pediatric morbidity and mortality are significant. The incidence of thrombosis is maximum in neonates and during adolescence. The hemostatic system in the newborn differs from children and adults. Children till 6 months of age have lower levels of the vitamin-K–dependent coagulation factors II, IX, and X, compared to adults. Levels of thrombin inhibitors, such as antithrombin and heparin cofactor II, are similarly low at birth. Levels of protein C and S are low at birth. Protein S levels approach adult values by the age of 3-6 months, but protein C levels remain low even into childhood. Furthermore, plasminogen levels are low in newborns and infants. Thrombin generation is decreased (probably because of low prothrombin levels) and delayed in newborns compared with adults. There is a second peak of thrombosis during adolescence with more adult like risk factors In this article we will review the literature for pertinent clinical and management issues of experts in the field of neonatal and pediatric thrombosis. The material is presented in a manner that is to relevant to clinical practice.

3.Role of endothelial nitric oxide synthase gene in vascular diseases
M.S. Akhter, Arijit Biswas, Renu Saxena
Pages 46 - 50
The endothelial nitric oxide synthase (eNOS or NOS 3) is expressed in the endothelium where it produces Nitric Oxide (NO) from L-arginine. NO a powerful short lived vascular substance, plays a key role to maintain vascular homeostasis. Association of endothelial nitric oxide synthase gene variants and nitric oxide has been found in many vascular diseases chiefly stroke, coronary artery disease and hypertension. The variants have been associated with low plasma nitric oxide concentrations and reduced vascular reactivity, however difficulties in measuring those phenotypes implicates that their functions remain unclear. While a large no of studies report the association of NOS3 gene with vascular diseases, a few are contradictory to such reports. So a need for large scale genetic association studies using tagging polymorphisms to confirm or refute the role of NOS3 gene in vascular diseases is strongly warranted.

4.Antiphospholipid syndrome
Mohan B. Agarwal
Pages 51 - 56
Antiphospholipid syndrome is characterized by arterial or venous thrombosis and/or recurrent miscarriages together with presence of anticardiolipin antibodies and/or lupus anticoagulant and/or anti-ß2-glycoprotein 1 positivity. The exact pathogenic role of antibodies in the development of thrombosis still remains to be fully elucidated. Novel mechanisms involving both the complement pathway and micro-particles have been described. This knowledge might identify novel therapeutic targets and improve the management.

5.Acute pulmonary embolism
Ritesh Agarwal, Subhash Varma
Pages 57 - 68
Pulmonary embolism is a common illness with a potential for considerable morbidity and mortality. It is often misdiagnosed because patients present with a wide array of symptoms and signs. The clinical setting can raise suspicion, and certain inherited and acquired risk factors predispose susceptible individuals. A quantitative D-dimer level in the blood is the best screening test where pretest clinical probability is low. Computed tomographic angiography has become the most commonly used modality for diagnosis in all other settings. Treatment requires rapid and accurate risk stratification before development of right ventricular dysfunction and cardiogenic shock. Anticoagulation is the cornerstone of treatment. Thrombolysis is mainly indicated in patients with hemodynamic compromise and hypotension. Right ventricular dysfunction on echocardiography identifies another high-risk group who might require thrombolysis even if normotensive on presentation. This article reviews the current concepts in the diagnosis and management of pulmonary embolism.

6.Medical management of deep vein thrombosis
Manoranjan Mahapatra, Pravas Mishra, Tulika Seth, Renu Saxena
Pages 69 - 72
Making a diagnosis of deep vein thrombosis requires both clinical assessment and objective testing. Once a patient is diagnosed with an acute deep vein thrombosis, low-molecular- weight heparin is the agent of choice for initial therapy and oral anticoagulant therapy is the standard for long-term secondary prophylaxis. Therapy should continue for at least 3 months; the decision to continue treatment beyond 3 months is made by weighing the risks of recurrent thrombosis and anticoagulant related bleeding, and is influenced by patient preference.

7.Thromboprophylaxis in the general medical patients: making sense of the current guidelines and controversial issues
Pravas Mishra
Pages 73 - 77
There is sufficient data for thromboprophylaxis in surgical patients. If we follow these guidelines for medically ill patients it would result in giving anticoagulants to a large number of patients. The guidelines are based upon prevention of asymptomatic DVT as an endpoint. The number of such patients who develop symptomatic DVT is very small. It would be worthwhile studying the risk factors for DVT in those with symptomatic DVT. We could then target thromboprophylaxis at a selected group of acutely ill medical patients who would benefit most by this intervention.

8.Diagnostic strategy in heparin induced thrombocytopenia
Meganathan Kannan, Sarfraz Ahmad, Jawed Fareed
Pages 78 - 83
Heparin-induced thrombocytopenia occurs due to the formation of antibodies against the complex formed between heparin and platelet factor 4 (H-PF4) leading to platelet/endothelial cell activation followed by thrombocytopenia. Diagnosis of H-PF4 antibodies are mainly based on two different assays; functional and immunologic assays. While the functional assays are based on the platelet activation, the immunogical assays are based on the binding of IgG antibodies to H-PF4 complexes. Even though 14C-Serotonin Release Assay is high in sensitivity, the most commonly used functional assays are Platelet aggregation test and Heparin-ınduced platelet aggregation The immunologic assays include solid-phase detection, fluid-phase detection, enzyme-linked lmmunosorbent assay, particle gel immunoassay; the commonly used is enzyme-linked ımmunosorbent assay occurrence of HIT may vary not only based on the patients’ group but also based on the type of diagnostic technique used. The methodological variations observed in our experience are discussed in this review. In the current review we discuss the diagnostic approach, importance in the diagnosis of Fc?RIIa receptor polymorphism, controversies in diagnosis of HIT and preventive measures.

9.An update on new anticoagulant drugs
Jawed Fareed, Rakesh Wahi, Debra A. Hoppensteadt
Pages 84 - 93
The conventional management of thrombotic and cardiovascular disorders is based on the use of heparin, oral anticoagulants and aspirin. Despite remarkable progress in life sciences, these drugs still remain a challenge and mystery to us, and their use is far from optimized. The development of low molecular weight heparins and the synthesis of heparinomimetics, such as the chemically synthesized pentasaccharide, represent a refined use of heparin. Additional drugs from this knowledge will continue to develop; however, none of these drugs will match the polypharmacology of heparin. Aspirin still remains the leading drug in the management of thrombotic and cardiovascular disorders. The newer antiplatelet drugs such as ADP receptor inhibitors, GPIIb/IIIa inhibitors and other specific inhibitors have limited effects and have been tested in patients who have already been treated with aspirin. Warfarin provides a convenient and affordable approach in the long-term outpatient management of thrombotic disorders. The optimized use of these drugs still remains to be the approach of choice to manage thrombotic disorders. The new anticoagulant targets, including specific sites in the hemostatic network such as tissue factor, individual clotting factors (IIa, VIIa, IXa, Xa, XIIa and XIIIa), recombinant forms of serpins (antithrombin, heparin co-factor II and tissue factor pathway inhibitors), recombinant activated protein C, thrombomodulin and site specific serine proteases inhibitors complexes have also been developed. There is a major thrust on the development of orally bioavailable anticoagulant drugs (anti-Xa and IIa agents), which are slated to replace oral anticoagulants. Both the anti-factor Xa ( Rivaroxaban and Apixaban) antithrombin (Dabigatran) agents have been developed for oral use and have provided impressive clinical outcomes in sponsor trials for the post surgical prophylaxis of venous thrombosis; however, safety concerns related to liver enzyme elevations and thrombosis rebound have been reported with their use. For these reasons the US FDA did not approve the orally active antithrombin agent Ximelagatran for several indications. More recently the Columbian health authorities reject dabigatran for similar reasons. The synthetic pentasaccharide (Fondaparinux) has undergone an aggressive clinical development. Unexpectedly, Fondaparinux also produced major bleeding problems at minimal dosages. Fondaparinux represents only one of the multiple pharmacologic effects of heparins. Thus, its therapeutic index will be proportionately narrower. The methylated pentasaccharide, namely Idraparinux, is effective for long term prophylaxis, but its use is associated with bleeding. Other forms of pentasaccharide such as the biotinylated form which can be reversed with fucoidin are also developed. The newer antiplatelet drugs have added a new dimension in the management of thrombotic disorders. The favorable clinical outcomes with aspirin and Clopidogrel have validated COX-1 and P2Y12 receptors as targets for new drug development. Prasugrel, a novel thienopyridine, Cangrelor and AZD 6140 represent newer P2Y12 antagonists. Cangrelor and AZD 6140 are direct inhibitors, whereas Prasugrel requires metabolic activation. While clinically effective, recent results have prompted a closure of a large clinical trial with Prasugrel due to bleeding. The newer anticoagulant and antiplatelet drugs are attractive for several reasons; however, none of these are expected to replace the conventional drugs in poly-therapeutic approaches. Heparins, warfarin and aspirin will continue to play a major role in the management of thrombotic and cardiovascular disorders beyond 2010.

10.Venacaval filter in venous thromboembolic disease
Priya Jagia, Sharma Sanjiv
Pages 94 - 97
Venous thromboembolic disease includes lower limb deep vein thrombosis and pulmonary embolism which are dreaded sequelae of certain medical and surgical conditions. This article reviews the use of Inferior venacava filter to prevent pulmonary thromboembolism in patients with deep venous thrombosis.



 
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