الفهرس 
Chapter I: Pathways of HaemostasisOnly 14 pages are availabe for public view
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Abstract
Haemostasis is the process of blood clot formation at the site of vessel injury. When a blood vessel wall is disrupted, the haemostatic response must be quick, localized, and carefully regulated. Haemostasis is maintained in the body via three mechanisms: Vascular spasm (Damaged blood vessels constrict), Platelet plug formation (Platelets adhere to damaged endothelium to form platelet plug i.e, primary Haemostasis) and then degranulate and Blood coagulation (Clots form upon the conversion of fibrinogen to fibrin, and its addition to the platelet plug i.e, secondary Haemostasis).
Thrombophilia is a term used to describe a group of conditions in which there is an increased tendency, often repeated and often over an extended period of time, for excessive clotting. Venous thromboembolism (VTE) results from the interaction of the Virchow triad (venous stasis, endothelial injury, and hypercoagulability).
These include conditions due to:
1) Family history of clotting or a diagnosis based on a demonstrated genetic mutation such as factor V Leiden, protein C and S deficiencies, antithrombin and prothrombin 20210A mutations.
2) An acquired condition such as lupus inhibitor or antiphospholipid antibody.
The inherited deficiencies of AT, PC, and PS account for only 1% to 5% of all patients with VTE. Laboratory evaluation includes functional and antigenic assays.
The risk of VTE in heterozygous AT deficiency is increased 5 to 50fold compared with the general population. There is a 50% risk of VTE developing during a patient’s lifetime or during pregnancy. Diagnosis of quantitative (type I) or qualitative (type II) deficiency can be made with an algorithmic approach.
PC deficiency accounts for 2.5% to 5% of unselected patients with a first VTE. Heterozygous deficiency increases VTE risk by 7 fold and carries an increased risk for warfarin-induced skin necrosis.
Laboratory investigation of PS deficiency is more complex with 3 distinct assay types: PS activity (clot-based) measures function as a cofactor for APC; free PS is an immunologic measure of the unbound fraction; and total PS antigen quantifies free and bound PS.
Hyperhomocysteinemia is an established risk factor for thrombosis. Acquired causes of hyperhomocysteinemia (eg, vitamin B6, vitamin B12, or folate deficiency; hypothyroidism). Severe hyperhomocysteinemia caused by cystathionine β-synthase deficiency manifests as early arterial and/or venous thrombosis.
Increased FVIII activity is associated with VTE risk .The prevalence of FVIII of more than 150 U/L is 20% to 25% in patients with VTE, Thus, FVIII testing should be delayed for 6 months or longer after a VTE and for at least 6 weeks postpartum. If FVIII activity is high, retesting in 3 to 6 months will confirm persistence.
The FVL point mutation (G1691A) renders the first factor V cleavage site more resistant to the APC/PS complex, FVL heterozygotes have a 3 to 7 fold and homozygotes an 80 fold increased risk of VTE.
Most laboratories use a strategy to first screen for APCR with the second-generation (V-deficient) test. If the APCR result is abnormal, genotyping for FVL is reflexively performed. DNA analysis alone would not identify acquired APCR (such as lupus anticoagulant [LA] or rare factor V mutations that can also cause APCR .There are 3 major types of antiphospholipid antibodies (APAs): LAs, anticardiolipin (aCL), and anti β 2 glycoprotein-1 (anti-β2GP1) antibodies.
LAs prolong clotting times by binding to phospholipids and interfering with their ability to serve as an essential clotting surface. Because of heterogeneous antibody specificity, no single test is 100% sensitive; thus, 2 or more phospholipid-based screening tests must be used to detect LAs, often the combination of a low-concentration phospholipid PTT and dilute Russell viper venom time.
Changes in plasma coagulation during pregnancy favour the procoagulant properties so as to prevent blood loss during delivery. There is an increase in several clotting factors (II, V, VII, VIII, X), an increase in plasminogen-activator inhibitors (PAI-1 and PAI-2) and von Willebrand’s factor, a reduction in protein S, greater resistance to activated protein C, and reduced antithrombin activity . Patients with acquired or hereditary thrombophilic risk factors may have vascular complications during pregnancy, including deep vein thrombosis (DVT) and pulmonary embolism (PE), and also recurrent abortions with antiphospholipid syndrome.
In general, patients with a familial or acquired thrombophilia and acute venous thromboembolism should be management in standard fashion with intravenous unfractionated heparin, low-molecular-weight heparin or fondaparinux. Special attention may be required for patients with deficiencies of antithrombin or protein C. Some patients with antithrombin deficiency may be relatively heparin resistant. Antithrombin concentrate can be used in special circumstances such as recurrent thrombosis despite adequate anticoagulation, unusually severe thrombosis or difficulty achieving adequate anticoagulation, before major surgery or in obstetric situations when the risks of bleeding from anticoagulation are unacceptable. Antithrombin concentrate appears to have a low risk of transmitting bloodborne infections.
Hereditary protein C deficiency can be associated with warfarin-induced skin necrosis. Consequently, warfarin should be started only after therapeutic heparinization, and the initial warfarin dose should be low (e.g., 2 mg) and increased slowly.
Conclusive evidence supporting widespread thrombophilia screening is important and testing of those subgroups at be highest risk may useful.