THROMBOPHILIA

lectue 15 by dr Alaa F. Alwan

THROMBOPHILIA (HYPERCOAGULABILITY)
Patients with a tendency to thrombosis are defined as having thrombophilia. The term inherited thrombophilia should be used for individuals with predisposing genetic defects. Hypercoagulability and thrombophilia are synonymous. Thrombophilia is usually suspected in patients with one or more of the following clinical features: idiopathic thrombosis, thrombosis at a young age, recurrent thrombosis, and thrombosis at an unusual site.

Inherited hypercoagulable states

Activated protein C resistance due to factor V Leiden mutation
Prothrombin gene mutation
Antithrombin deficiency
Protein C deficiency
Protein S deficiency
Elevated factor VIII level
Dysfibrinogenemia (rare)
Hyperhomocysteinemia

Acquired hypercoagulable states

Antiphospholipid syndrome (Lupus anticoagulant)
Malignancy
Nephrotic syndrome
Paroxysmal nocturnal hemoglobinuria
Postoperative state
Immobilization
Old age
Pregnancy
Oral contraceptives or other estrogen use


PROPHYLAXIS
Stasis should be eliminated whenever possible. This includes the wearing of elastic stockings or a supportive hose and also intermittent pneumatic compression. Early ambulation is encouraged after surgery or illness. Prophylactic heparin therapy must be considered in high-risk groups and is mandatory for surgical patients during the peri- and postoperative period. Heparin and its derivative, low-molecular-weight heparin (LMWH), are the anticoagulants of choice for prophylaxis and treatment of DVT
TREATMENT
The continous intravenous infusion of heparin has been, until recently, the preferred mode of therapy in the treatment of DVT or PE. In adult patients with an average weight of 70 kg, doses of 30,00040,000 U over 24 h (12002000 U/ h with a loading dose of 5000 U) are usually required. Subcutaneous heparin (e.g., 15,000 U every 12 h) can be used as an alternative to the intravenous route. The therapy must be monitored by maintaining the aPTT between 1.8 and 2.5 times the normal time. Warfarin therapy can be started on day 2 after the initiation of heparin therapy. Thus on days 57, one can expect that warfarin is in the therapeutic range (international normalized ratio [INR] > 2) (see p. 341) and heparin can be discontinued. Oral anticoagulant therapy should be continued for at least 3 mo and longer than 3 mo when the thrombophilic state persists. Inferior vena caval filter placement is recommended when there is a contraindication or complication of anticoagulant therapy in a patient with or at high risk for proximal vein thrombosis or PE. It is also recommended for recurrent embolisms that occur despite adequate anticoagulation and for chronic recurrent embolism with pulmonary hypertension. scussed shortly.
ANTIPLATELET DRUGS
1. Aspirin. The antithrombotic effects of aspirin are attributed to its ability to irreversibly inhibit platelet cyclooxygenase, thus reducing the synthesis of TxA2, a potent inducer of platelet aggregation and vasoconstriction. The inhibitory effects of aspirin persist for the life span of platelets, because the drug irreversibly acetylates cyclooxygenase. The recommended oral dose is between 100 and 300 mg daily.
2. Ticlopidine and Clopidogrel. Ticlopidine and clopidrogrel inhibit platelet aggregation induced by ADP and a variety of other agonists. Unlike aspirin, the inhibitory effects on platelet function are delayed for 2448 h after administration, limiting the potential value when rapid antithrombotic action is required. The recommended dose of ticlopidine is 200 mg as tablets twice daily. The most serious side effect is neutropenia occurring in 12%, less serious side effects are diarrhea and skin rashes. For this reason, clopidogrel has been introduced, which has the same antithrombotic properties as ticlopidine without the side effects. The recommended dose is a 75-mg tablet, once daily.
3. GP IIb/IIIa-Receptor Antagonists. GP IIb/IIIa antagonists inhibit platelet aggregation in response to all agonists, including collagen and thrombin, because they block fibrinogen bridging between platelets, the final common pathways of platelet aggregation.
ANTITHROMBOTIC THERAPY
1. Unfractionated Heparin
Unfractionated heparin (UFH) is a mucopolysaccharide from either porcine or bovine sources with an average molecular weight (MW) of 15,000 Daltons. The anticoagulant effect is produced by its interaction with AT. Binding of a pentasaccharide sequence to AT causes a conformational change that accelerates its interaction with thrombin and the other serine proteinases (i.e., factors Xa, IXa, XIa, and XIIa). UFH can be administered by intravenous or subcutaneous route. The biological half-life is 11.5 h. The bioavailability is only 30% after subcutaneous administration. This is due to binding to a number of plasma proteins, endothelial cells, von Willebrand factor, and neutralization by platelet factor (PF) 4. For this reason the LMWH were introduced (discussed later). The main indications for heparin are the treatment of DVT, PE, acute myocardial infarction, and unstable angina pectoris. It is also used in cardiopulmonary bypass surgery and for anticoagulation during pregnancy as it does not cross the placenta. For treatment of acute thromboembolic events, continuous intravenous infusion with a perfusion pump has been the standard treatment for decades until the LMWHs were introduced.
2. Low-Molecular-Weight Heparins
LMWH is manufactured from UFH, usually of porcine origin, by controlled depolymerization using either chemical or enzymatic techniques. LMWH-fractions have an MW of about one-third of UFH (MW 5000). The smaller size with its reduced negative charge causes less binding to plasma proteins and endothelial cells, resulting in a much better bioavailability and more predictable anticoagulant response than UFH. The longer half-life allows a single daily subcutaneous dosage as thrombosis prophylaxis. The various LMWHs differ in mean molecular weight, aminoglycan content, and anticoagulant activity, which is usually expressed as anti-Xa activity. In contrast to UFH, LMWH have only minor anti-IIa activity. Thus, even when used in higher therapeutic doses, the aPTT will not be prolonged and cannot be used for monitoring. Because evidence is accumulating that LMWHs have fewer serious complications than UFH, such as bleeding, heparin-induced immune thrombocytopenia (HIT), and osteoporosis, UFH has been replaced by LMWH in thrombosis prophylaxis in many institutions. Recent randomized trials have shown that LMWHs are also safe and effective in the treatment of uncomplicated DVT and even PE at home as compared to intravenous UFH in the hospital. The rates of recurrent thromboembolism and major bleeding did not differ in the two treatment approaches. The dose is weight-adjusted and laboratory monitoring is not required. The positive results of a number of studies and one or two daily doses of LMWH required will likely lead to the use of LMWHs in outpatient treatment of uncomplicated VTE in the majority of patients.
Complications of Heparin Therapy
The main adverse effects of UFH include bleeding, thrombocytopenia, and osteoporosis after prolonged therapy. the effects of heparin can be reversed quickly by intravenous infusion of protamine sulfate.. The drug can be also used to reverse some of the action of LMWH. Heparin-induced immune thrombocytopenia (HIT) is a quite frequently recognized complication of heparin therapy that usually occurs within 510 d after initiation of heparin treatment. When HIT is diagnosed, heparin in all forms must be discontinued immediately. For patients requiring ongoing anticoagulation, two alternatives are possible:
1. Danaparoid
2. Hirudin or argatroban, both are direct thrombin inhibitors

3. Oral Anticoagulants(warfarin)

Oral anticoagulants produce an anticoagulant effect by inhibiting the vitamin K-dependent factors II, VII, IX, and X. Once absorbed from the intestinal tract, they are bound to plasma proteins (9799%), primarily to albumin. Therefore, interactions with other drugs capable of displacing these agents from binding sites must be taken into consideration.
Complications and Interactions
Bleeding. Patients with life-threatening hemorrhage or overdosage (error, suicidal) require immediate correction of the PT. The administration of prothrombin complex preparations simultaneously with vitamin K is necessary.
Teratogenic effects have been described with coumarin derivatives. Fetal exposure during the first trimester may result in embryopathies (nasal hypoplasia, epiphyseal abnormalities). Oral anticoagulants are therefore contraindicated in the first trimester of pregnancy. LMWH is recommended throughout the pregnancy, if anticoagulation is mandatory.
Contraindications to Fibrinolytic Therapy
Absolute contraindications
Established hemorrhage
Cerebrovascular accident, head injury in the past 2 mo
Neurosurgery during past 2 mo
Intracranial aneurysm or neoplasm
Aortic dissection
Proliferative diabetic retinopathy
Relative contraindications
Surgery during past 10 d
Arterial puncture previous 7 d
Prior organ biopsy
Recent obstetric delivery
Past history of gastrointestinal bleeding
Severe hypertension (systolic > 200 mmHg, diastolic > 110 mmHg)