Protein C +

Thrombin/Thrombomodulin Complex

Figure 19.4 Activated protein C resistance pathway.

Reference ranges vary from lab to lab but in general the normal ratio is 2 or greater. A range of <2 is diagnostic.

aPTT is decreased when is APC is added to the normal plasma. Plasma from patients with APCR has a lower ratio than the reference ranges established for normal patients. A DNA test is available to confirm the specific point mutation in patients with factor V Leiden.

Prothrombin Mutations

Prothrombin mutation (G20210A) is the second most prevalent cause of an inherited form of hypercoagula-bility. It is caused by a single point mutation. It is an autosomal dominant disorder that causes an increase in concentration of plasma prothrombin. The risk of venous thromboembolism increases as the plasma pro-thrombin level increases to a level greater than 115 IU/dL.1 As with factor V Leiden, prothrombin mutation tends to follow a geographic and ethnic distribution with the highest prevalence in whites from southern Europe. About half of the cases are reported in northern Europe.1

Similar to factor V Leiden, the thrombotic episodes develop early before the age of 40.1

Other Inherited Thrombotic Disorders

Elevated activity levels of factor VIII are associated with VTE. It has been reported that if factor VIII activity is greater than 150%, the risk for VTE increases to 3-fold, and if the activity is greater than 200%, the thrombotic risk increases to 11-fold.1 Factor XII deficiency is also associated with thrombosis.

Factor XII is a contact factor that initiates the intrinsic pathway activation. Patients with factor XII deficiency will have a prolonged aPTT but no bleeding problem. Factor XII plays a major role in the fibrinolytic system and in activation of plasminogen to plasmin. Therefore, patients with factor XII deficiency would have an impaired fibrinolysis and are prone to thrombosis.3

Dysfibrinogenemia is an inherited abnormality of the fibrinogen molecule with variable clinical presentation. Twenty percent of cases may present arterial or venous thrombosis. Bleeding has been reported in 20% of cases, and 60% of patients may be asymptomatic.3

Tissue factor pathway inhibitor (TFPI) deficiency is another marker for thrombosis. TFPI plays an important role in prevention of clot formation. It inhibits factor Xa and factor VIIa-TF complex.3 The deficiency of this inhibitor is associated with thromboembolic disorder.

Hyperhomocysteinemia can be inherited or acquired. Homocysteine is an amino acid formed during the conversion of methionine to cysteine. Hyperhomocysteinemia results from either deficiencies of the enzymes necessary for production of homocysteine (inherited form) or deficiencies of vitamin cofactors (B6, B12, and folate) in an acquired form. Increased levels of homocysteine in the blood are reported to be a risk factor for stroke, MI, and thrombotic disorder.1,3

Disorders of the fibrinolytic system such as plasminogen deficiency, tPA deficiency, and increased plasminogen activator inhibitor are associated with thrombotic disease.1

Acquired Thrombotic Disorders

There are many situations that may lead to acquired thrombotic disorders. They may be associated with underlying diseases such as cancer, surgery, liver disease, nephrotic syndrome, DIC, pregnancy, and vitamin K deficiency. Drugs such as oral contraceptives or hormone replacement therapy may predispose to thrombosis.

Lupus Anticoagulant/Antiphospholipid Syndrome

The antiphospholipid (aPL) syndrome is an acquired disorder in which patients produce antibodies to phospholipids binding protein known as beta-2-glycoprotein I (P2GPI) or apolipoprotein (aPL).5 Clinical manifestations of aPL antibodies are associated with thrombosis and fetal losses. The IgG2 subtype of aPL is usually associated with thrombosis. Thrombotic episodes include venous and arterial thrombosis and thromboembolism. The usual age at the time of thrombosis is generally about 35 to 45. Men and women are equally affected.5 Thrombosis may occur spontaneously or may be associated with other predisposing factors such as hormone replacement therapy, oral contraceptives, surgery, or trauma. A small number of patients with aPL antibodies may manifest bleeding if there is a concurrent thrombocytopenia or coagulopathy such as hypoprothrombinemia.5

The most common form of aPL antibodies are lupus anticoagulant (LA) and anticardiolipin (ACA). The thrombotic manifestations may be primary (independent autoimmune disorder) or secondary (associated with other autoimmune disorders such as systemic lupus erythematosus [SLE]). In vitro, LA acts against phospholipid-dependent coagulation assays such as aPTT, which was not corrected with 1:1 mix with normal plasma.4,5 This will be explained in the next section. Patients with aPL antibodies may present with thrombosis and fetal loss. Bleeding is uncommon, unless the patient has thrombocytopenia or decreased prothrombin as well.

Laboratory Assays for Antiphospholipid Antibodies

Common tests used to detect lupus anticoagulants are aPTT, Kaolin clotting time (KCCT), dilute Russell viper venom test (DRVVT), and dilute PT. For both a prolonged aPTT and DRVVT, a mixing study should be performed. In a mixing study, the patient plasma is mixed with normal plasma and the test is repeated. In the presence of lupus anticoagulant the mixing study does not correct to normal. Lupus anticoagulant is confirmed by the addition of excess platelets (platelet neutralization test or hexagonal phase phospholipids [DVV Confirm]).4,6. The International Society of Hemo-stasis and Thrombosis has recommended four criteria for the diagnosis of lupus anticoagulants: (1) prolongation of a phospholipid-dependent test, (2) evidence for the presence of an inhibitor (mixing study), (3) evidence that the inhibitor is directed against phos-pholipids (confirmatory test), and (4) lack of any other specific inhibitor (Table 19.3). Other factors that are helpful in the diagnosis of lupus anticoagulants are the clinical presentation since these patients lack bleeding. Lupus anticoagulant may coexist with anticardi-olipin antibodies in patients presenting with an acquired thrombosis and fetal loss. Therefore, the test for ACLA is recommended as well. ACLAs are detected by the ELISA method.6 Other detectable antibodies are anti-^2CPI.6

Heparin-Induced Thrombocytopenia

HIT is an immune-mediated complication associated with heparin therapy. HIT may develop in 3% to 5% of patients receiving unfractionated heparin.1 HIT usually develops between 5 and 14 days after heparin ther-

Table 19.3

Criteria for the Diagnosis of Lupus Anticoagulant

Prolongation of at least one phospholipid-dependent tests

Lack of correction of mixing studies

Correction of the abnormal result with the addition of excess phospholipids

Lack of any other specific inhibitor

Figure 19.5 Pathophysiology of HIT.

apy. About 36% to 50% of patients with HIT develop life-threatening thrombosis. The thrombotic tendency can last for at least 30 days.1 Venous thrombosis (extremity venous thrombosis) is more common than arterial thrombosis. Other complications of HIT include thrombocytopenia, heparin-induced skin lesions (10% to 20% of patients), and heparin resistance.1 The pathogenesis of HIT is that antibodies are produced against heparin-platelet factor 4 complex. This immune complex binds to platelet FC receptors, causing platelet activation, formation of platelet microparticles, thrombocytopenia, and hypercoagula-ble state (Fig. 19.5).

HIT is independent of dosage or route of administration of heparin. This condition should be suspected in any patient whose platelet count falls below 50% of the baseline value after 5 days of heparin treatment1 and in patients who develop thrombosis with or without thrombocytopenia during heparin therapy.1

Laboratory Diagnosis of HIT

Laboratory diagnosis of HIT includes functional assays or immunoassays. Functional assays measure platelet activation or aggregation in the presence of HIT serum and heparin. Functional assays include heparin-induced platelet aggregation, heparin-induced platelet adenosine triphosphate (ATP) release by lumiaggre-gometry, 14C-serotonin release assay (14C-SRA) release by ELISA, and platelet microparticle formation by flow cytometry. Heparin-platelet factor 4 antibodies are detected by ELISA. When HIT is suspected, heparin should be stopped immediately and be replaced by alternative anticoagulant drugs (danaparoid, arga-troban). Warfarin should be avoided in the acute phase of thrombosis because it may cause venous limb gangrene.1 Patients receiving heparin should have a base line platelet count and platelet monitoring every third day between 5 and 14 days.1

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