Arterial Thrombosis

Arterial thrombosis initially occurs under conditions of rapid blood flow and often is the result of a process that damages the vessel wall. The thrombus is composed of tightly coherent platelets that contain small amounts of fibrin and few erythrocytes and leukocytes (white thrombus). The most serious consequence of arterial thrombosis is vascular occlusion. Arterial thrombotic events occur in a number of congenital and acquired diseases (Table 11-29).

Cardiac Catheterization

The most common cause of an arterial thrombotic event in children is the use of cardiac vascular catheters. Without prophylactic anticoagulation, the incidence of an

Table 11-28. Treatment of Venous Thrombotic Events and Thromboembolism

Treatment

Indications

Anticoagulant therapy Thrombolytic therapy

Intracaval filter

Majority of patients with a venous thrombotic event (see anticoagulant therapy) Massive pulmonary embolism with hemodynamic compromise; patients with extensive iliofemoral thrombosis (see thrombolytic therapy) Pulmonary embolism despite adequate anticoagulant therapy

Pulmonary embolectomy Massive pulmonary embolism despite thrombolytic therapy

Table 11-29. Predisposing Causes of Arterial Thrombosis

Acquired

Catheterization Cardiac

Umbilical artery

Renal artery—kidney transplantation Hepatic artery—liver transplantation Vascular Injury Infections Periarteritis nodosa Systemic lupus erythematosus (SLE) Kawasaki disease

Hemolytic uremic syndrome (HUS) Thrombotic thrombocytopenic purpura (TTP) Cardiac Blalock-Taussig shunts Fontan operation Endovascular stents Cyanotic congenital heart disease Primary endocardial fibroelastosis Enlarged left atrium with arterial fibrillation Hypertension Myocarditis Hematologic/Hemostatic Elevated levels of LP(a) Elevated PAI-1 Reduced t-PA

Elevated level of fibrinogen

Antiphospholipid syndrome (APLS)

Chronic disseminated intravascular coagulation (DIC)

Elevated levels of fibrin degradation products (D-dimers)

Hyperhomocysteinemia

Hypereosinophilic syndrome

Myeloproliferative disorders (MDS)

Polycythemia vera (PV)

Chronic myelogenous leukemia (CML)

Essential thrombocythemia (ET)

Paroxysomal nocturnal hemoglobinuria (PNH)

Hyperleukocytosis (acute leukemia)

Sickle cell disease

Hemoglobin SC disease

Thrombotic thrombocytopenic purpura (TTP) Activated protein C concentrate administration Other Shock

Nephrotic syndrome Diabetes mellitus Hyperlipidemia Hypercholesterolemia Cigarette smoking Elevated CRP Malignancy Obesity

Physical inactivity

Table 11-29. (Continued)

Congenital/inherited

R506Q mutation in the factor V gene [(factor V Leiden)—activated protein C resistance] G20210A mutation in the prothrombin (factor II) gene

Homozygous C677T mutation in the methylenetetrahydrofolate reductase gene (C677T

MTHFR) Antithrombin (AT) deficiency Protein C deficiency Protein S deficiency Marfan syndrome Familial hypercholesterolemia Mitral valve prolapse

Abbreviations: Lp(a), lipoprotein a; PAI-1, plasminogen activator inhibitor-1; t-PA, tissue thromboplasminogen activator; CRP, C-reactive protein arterial thrombotic event from femoral artery catheterization is about 40%. Anticoagulation with heparin (100-150 U/kg) reduces the incidence of arterial thrombotic events to 8%.

Cardiac Procedures

Blalock-Taussig Shunts

The short length and very high flow in these shunts may result in arterial thrombosis. The incidence varies from 1 to 17%. For anticoagulant management, see page 361.

Fontan Operation

In this procedure the incidence of an arterial thrombotic event ranges from 3 to 19%. Arterial thrombotic events may occur anytime following the surgery and it is the major cause of early and late morbidity and mortality. For anticoagulant management, see pages 360-361.

Endovascular Stents

These stents are used increasingly to manage some patients with congenital heart disease (e.g., pulmonary artery stenosis, pulmonary vein stenosis, coarctation of aorta). Therapeutic doses of heparin are given at the time of stent insertion, followed by aspirin therapy (5 mg/kg/day).

Umbilical Artery Catheterization

Incidence of an arterial thrombotic event from an umbilical arterial catheter is markedly reduced by a low dose continuous heparin infusion (3 to 5 unit/h).

Renal Artery Thrombosis

Renal arterial thrombosis is commonly associated with kidney transplant. The incidence is about 0.2-3.5% in children. Prophylactic administration of low-molecular-weight heparin (LMWH) 0.4 mg/kg twice daily for 21 days is effective anticoagulant therapy.

Hepatic Artery Thrombosis

Hepatic artery thrombosis is a very serious complication of liver transplantation. It usually occurs within 2 weeks. The reported incidence in children can be as high as

42%. The detection of a hepatic artery thrombosis includes Doppler, angiography, and CT of the liver. The prophylactic use of LMWH and aspirin is controversial. The mortality from hepatic artery thrombosis may be as high as 70% in children. Anticoagulant therapy alone is not effective in hepatic artery thrombosis. Surgical intervention and retransplantation usually are necessary. Thrombolytic therapy has been successful in about 20% of children.

Kawasaki Disease

The acute phase of Kawasaki disease may be associated with arteritis, arterial aneurysms, valvulitis, and myocarditis. The incidence of coronary artery aneurysm, stenosis, or thrombosis is about 25% without initial treatment. There is strong evidence that early use of IV gammaglobulin and aspirin can reduce the coronary artery involvement of Kawasaki disease.

Antiphospholipid Antibody Syndrome

Antiphospholipid antibody syndrome (APLS) may result in an arterial thrombotic event including stroke in children. The lupus anticoagulants and APLS are discussed on pages 338-343.

Specific Risk Factors

Homocysteine

Homocysteine is a sulfur-containing amino acid formed during the metabolism of methionine, an amino acid derived from dietary protein. When excess methionine is present, homocysteine is linked with serine to form cystathionine in a reaction catalyzed by cystathionine p-synthetase, a vitamin B6-dependent enzyme. Otherwise homocysteine acquires a methyl group from N5-methylhydrofolate in a reaction catalyzed by the vitamin B12-dependent enzyme methionine synthetase.

Hyperhomocysteinemia, a risk factor for venous thrombosis, can be caused by genetic disorders affecting the trans-sulfuration or remethylation pathways of homo-cysteine metabolism, or by folic acid deficiency, vitamin B12 deficiency, vitamin B6 deficiency, renal failure, hypothyroidism, increasing age, and smoking. A rare example of excessive hyperhomocysteinemia is homozygous homocystinuria due to cystathionine P-synthetase deficiency; 50% of affected patients present with venous or arterial thrombosis by the age of 29 years. Homozygosity for the C677T mutation in the meth-ylenetetrahydrofolate reductase gene is a cause of mild hyperhomocysteinemia. It has been shown that excess homocysteine has the following effects:

• Toxic on the endothelium.

• Promotes thrombosis by platelet activation.

• Causes oxidation of LDL cholesterol.

• Increases levels of von Willebrand factor and thrombomodulin.

• Increases smooth muscle proliferation.

The mean total homocysteine levels in the newborn in various studies are 5.84, 7.4, and 7.8 |imol/L. Daily folic acid (2.5 mg), vitamin B6 (50 mg), and vitamin B12 (1 mg) lower plasma homocysteine levels.

Lipoprotein (a)

Lipoprotein (a), [Lp(a)], is a distinct serum lipoprotein composed of a low-density lipid particle with disulfide links along a polypeptide chain (apolipoprotein a). Lp(a) regulates fibrinolysis by competing with plasminogen. Elevated levels of Lp(a) are associated with coronary artery disease and represents an independent risk factor for spontaneous stroke and venous thrombosis in childhood.

Fibrinogen

High levels of fibrinogen are associated with cardiovascular events in both men and women. Individuals with high fibrinogen concentrations have a risk of cardiovascular disease about 2.3 times higher than individuals with lower levels. Cigarette smoking substantially increases fibrinogen levels, a relationship that is both dose-dependent and reversible.

Fibrin Degradation Products (D-Dimers)

The breakdown of cross-linked fibrin yields a number of degradation products, most notably D-dimers. Elevated levels of D-dimers are associated with thrombosis. Low levels of D-dimers are useful for excluding a diagnosis of acute thrombosis. D-dimers are a sensitive marker for fibrin turnover that allow recognition of covert coagulation. Alternately, it may indicate preclinical atherosclerosis, because levels are elevated for years before arterial thrombosis occurs.

Tissue Plasminogen Activator

This fibrinolytic protein is synthesized and secreted in the vascular endothelium and has a very short half-life. Individuals with reduced levels of t-PA are associated with higher risk for coronary artery disease. Low-dose aspirin therapy may reduce coronary artery disease in these individuals.

Plasminogen Activator Inhibitor 1

PAI-1 is an antifibrinolytic protein and is synthesized and secreted in the vascular endothelium. Individuals with elevated levels of PAI-1 antigen are prone to recurrent episodes of spontaneous thrombosis and coronary artery disease. Aspirin therapy may have a beneficial effect in individuals with elevated PAI-1 antigen.

C-Reactive Protein

C-reactive protein (CRP) is a typical acute-phase reactant. In response to acute injury, infection, or other stimuli, serum levels of CRP increase several-fold. It is produced in the liver, regulated primarily via interleukin-6 production by activated leukocytes and fibroblast and endothelial cells. Inflammation plays an essential role in plaque rupture and atherosclerosis. CRP may act as an indirect marker for preclinical atherosclerosis.

General Risk Factors

Cigarette Smoking

Smokers have a twofold increase of developing coronary artery disease and a 50% increased risk of dying from it. Smoking interacts in synergistic fashion with hyper-cholesterolemia, hypertension, and oral contraceptives.

Cholesterol

The precise mechanism by which LDL cholesterol increases the risk of coronary artery disease and stroke is not known. Lipid parameters other than total cholesterol and LDL cholesterol may be useful predictors of coronary artery disease or may aid in tailoring lipid-lowering therapy. Studies show that for every 1 mg/dL decrease in HDL cholesterol, there is a corresponding 3-4% increase in coronary artery disease.

Hypertension

Studies showed that a 7-mmHg increase from the baseline in diastolic blood pressure is associated with a 27% increase in risk of coronary artery disease and a 42% increase in stroke.

Pregnancy

Venous thrombosis occurs in 60% of women with antithrombin deficiency and in 20% with a deficiency of either protein C or S.

Diabetes

Among people with diabetes, atherosclerotic complications are a major cause of morbidity and mortality. Coronary artery disease is the cause of death in 69% of individuals with diabetes.

Obesity

Obesity early in life is a strong predictor of later cardiovascular disease. Observational studies have demonstrated increased risk of coronary artery disease mortality and morbidity among obese individuals.

Physical Inactivity

Physical inactivity is second only to hypercholesterolemia as a contributing cause of coronary artery disease.

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