Clotting Disorders

INTRODUCTION

Most patients who develop an arterial or venous thrombosis do so because of local factors (e.g., a focal atherosclerotic lesion producing a thrombus in an coronary artery) or major systemic events (e.g., trauma, surgery, or prolonged immobilization). However, several inherited genetic mutations predispose patients to venous thromboembolism with some studies finding up to 50% of patients with venous thromboembolism having a thrombophilia (Table 234-1).¹ Importantly, risk for clotting from genetic, acquired, and environmental factors is additive or even multiplicative; a patient with mild deficiency may develop a deep venous thrombosis when started on estrogen.²

TABLE 234-1 Hypercoagulable States

Inherited	Acquired
Activated protein C resistance due to factor V Leiden mutation	Pregnancy Oral contraceptives/hormone replacement therapy
Prothrombin gene mutation 20210A	Malignancy
Protein C deficiency	Heparin-induced thrombocytopenia
Protein S deficiency	Antiphospholipid syndrome
Antithrombin deficiency	Warfarin-induced skin necrosis
Hyperhomocysteinemia, severe	Hyperviscosity syndromes
	Human immunodeficiency virus (HIV)

PATHOPHYSIOLOGY

Several physiologic systems ensure that blood clots do not extend beyond the necessary area. The two most clinically important pathways involve antithrombin and protein C (see Figures 232-1 and 232-2 and Table 234-2). Antithrombin is a plasma-based protein that inhibits several activated coagulation factors, primarily thrombin, factor Xa, and factor IXa. Both unfractionated heparin and low-molecular-weight heparin possess anticoagulant activity by increasing the rate by which antithrombin inhibits these factors: approximately 2000- to 4000-fold for thrombin, about 500- to 1000-fold for factor Xa, and about a million-fold for factor IXa. Protein C is a vitamin K–dependent plasma protein that binds to the endothelial cell surface and is activated by thrombin. Activated protein C cleaves both factor Va and factor VIIIa, inhibiting both the common pathway and the intrinsic pathway. Protein S, another vitamin K–dependent plasma protein, is a cofactor that increases the inhibitory action of activated protein C by about 20-fold.

TABLE 234-2 Functions of Coagulation Proteins in Protein C and Antithrombin Systems

Factor	Function	Pertinent Disorders
Prothrombin (factor II)	Precursor to thrombin, which converts fibrinogen to fibrin.	Prothrombin mutations, 20210A and others
Factor V, activated	Complexes with Factor Xa, calcium, and phospholipid to convert prothrombin to thrombin.	Activated protein C resistance due to factor V Leiden mutation
Protein C, activated	Cleaves activated factors Va and VIIIa.	Congenital protein C deficiency Activated protein C resistance due to factor V Leiden mutation Neonatal purpura fulminans Warfarin-induced skin necrosis
Protein S	Cofactor for activated protein C. Cofactor for tissue factor pathway inhibitor (which inhibits extrinsic pathway of coagulation). Counteracts factor Xa’s protection of factor Va from degradation.	Congenital protein S deficiency Neonatal purpura fulminans Warfarin-induced skin necrosis
Antithrombin	Inhibits thrombin, factor Xa, and factor IXa. Binds heparins, leading to increased antithrombin activity.	Antithrombin deficiency
Phospholipids	Present on cell membranes of endothelial cells that line blood vessels. The activity of several proteins in the coagulation cascade is enhanced when bound to phospholipids.	Antiphospholipid syndrome

CLINICAL FEATURES

Thrombophilic disorders are rarely diagnosed in the ED. Instead, the emergency physician’s primary responsibilities are to (1) recognize higher risk of thrombosis in patients with a known thrombophilia, and (2) obtain pertinent information to suspect an undiagnosed hypercoagulable state (Table 234-3).³

TABLE 234-3 Features Suggestive of Thrombophilia

Early thrombosis (age 45 y and younger)

Recurrent thrombotic events or fetal loss

Family history of thrombosis or recurrent fetal loss

Thrombosis in unusual location (mesenteric, cerebral, axillary, or portal veins)

DIAGNOSIS

Laboratory testing specific for hypercoagulable conditions is not helpful in an ED setting.^4,5 Some factor levels cannot be reliably measured in the setting of acute thrombosis or while the patient is taking a vitamin K antagonist such as warfarin. The focus is to suspect the thrombophilia, refer for evaluation, and appropriately manage acute thrombosis. The ED diagnostic approach to individual episodes of suspected thrombosis in a thrombophilic patient is site specific (e.g., cerebral circulation, coronary circulation, or peripheral venous system). Using a normal serum d-dimer level to exclude venous thromboembolism in patients with known hypercoagulable disorders has not been validated.

TREATMENT AND DISPOSITION

Initial management and disposition of individual episodes of confirmed thrombosis in a patient with thrombophilia is similar to that of a patient without known thrombophilia. Duration of treatment does differ (Table 234-4).

TABLE 234-4 Management of Inherited and Acquired Thrombophilias

Situation	Management
First episode of thrombosis	Unfractionated heparin or low-molecular-weight heparin for 5 d and/or until therapeutic anticoagulation achieved with an oral anticoagulant. Continue anticoagulation for 6 mo to 2 y; some advocate lifelong treatment.
Second episode of thrombosis	Lifelong anticoagulation.
Pregnancy	Begin unfractionated heparin or low-molecular-weight heparin at diagnosis of pregnancy. May use warfarin in postpartum period.
Active malignancy	Use low-molecular weight heparin for treatment of venous thromboembolic events
Oral contraception	Avoid.
Hormone replacement therapy	Avoid.

Patients not currently on anticoagulation should consider prophylactic anticoagulants for high-risk situations such as surgery, pregnancy and the postpartum period, and prolonged travel. Estrogen-based oral contraceptive pills and hormone replacement therapy should be avoided in patients with known thrombophilia because of the thrombotic risk.

SPECIFIC CONDITIONS ASSOCIATED WITH THROMBOPHILIA

INHERITED CLOTTING DISORDERS

ACTIVATED PROTEIN C RESISTANCE (FACTOR V LEIDEN)

Activated protein C resistance caused by the factor V Leiden mutation is the most prevalent inherited hypercoagulable disorder; approximately 5% of the U.S. population of European descent is heterozygous for this mutation.⁶ In this disorder, the gene for factor V has a single point mutation that makes factor Va resistant to inhibition by activated protein C (factor V Leiden). This leads to overabundant conversion of prothrombin to thrombin. Factor V Leiden is inherited in an autosomal dominant pattern, with most patients being heterozygous for the mutation. Heterozygotes for factor V Leiden have a sevenfold increased risk of deep venous thrombosis compared with noncarriers, with homozygotes having a 20-fold increase in risk. Factor V Leiden is more highly associated with deep vein thrombosis than pulmonary embolism⁶ and has been observed in up to 21% of patients with first-time deep venous thrombosis.⁷ Activated protein C resistance also produces pregnancy complications such as severe pre-eclampsia, placental abruption, fetal growth restriction, and stillbirth.