Chapter 234: Clotting Disorders

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

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.

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

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.

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).

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.

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.

PROTHROMBIN GENE MUTATION

The most common mutation of the prothrombin gene (20210A) leads to increased prothrombin biosynthesis with about a 30% increase in circulating prothrombin levels, creating a hypercoagulable state. Prothrombin mutations are inherited in an autosomal dominant manner with mutations in the prothrombin gene present in about 2% of Caucasians.² Heterozygotes account for up to 10% of patients with initial episodes of deep venous thrombosis.⁷ Patients with prothrombin gene mutation present with increased risk of venous thromboembolism and pregnancy complications, similar to activated protein C resistance from factor V Leiden.

ANTITHROMBIN DEFICIENCY

Several mutations to the antithrombin gene exist, many leading to antithrombin deficiency. Two percent of patients with a history of thrombosis have an antithrombin deficiency,⁸ and it is more prevalent in Asian populations. Antithrombin deficiency is classified into two main groups. In type 1, the measured level of antithrombin is diminished, whereas patients with type 2 have a normal amount of antithrombin, but the function is greatly diminished due to conformational changes in the protein. Antithrombin deficiency is inherited in an autosomal dominant fashion. Heterozygous patients have a fivefold increased risk of thrombotic events, typically pregnancy complications and venous thromboembolism. Homozygous antithrombin deficiency is incompatible with life.

PROTEIN C AND S DEFICIENCIES

Protein C and protein S deficiencies, like antithrombin deficiency, are transmitted in an autosomal dominant fashion, but with more varied clinical presentations. Prevalence can only be estimated, because not all patients with heterozygous defects develop inappropriate thrombosis. Heterozygous protein C deficiency is thought to be present in 1:250 to 1:500 people, and heterozygous protein S deficiency is estimated to occur in about 1:500 individuals.⁹ Homozygous protein C or S deficiency is rare and presents as neonatal purpura fulminans. Patients with heterozygous protein C or S deficiency are at higher risk for venous thromboembolism, and like antithrombin deficiency, these disorders can be associated with either decreased total amount of protein C or S or decreased functional activity. In general, lower protein function is associated with higher risk and frequency of thrombotic events. Protein C and S deficiency, like antithrombin deficiency, is more prevalent in the Japanese and Chinese populations with up to 65% percent of adults with venous thromboembolism having a deficiency of protein C, protein S, or antithrombin.⁹

Patients with heterozygous protein C or S deficiency are at higher risk for warfarin-induced skin necrosis because warfarin inhibits protein C and S synthesis. Warfarin-induced skin necrosis is rare and is prevented by both avoiding loading doses of warfarin and continuing heparin products until the INR is therapeutic. Therefore, any patient who develops warfarin-induced skin necrosis should be evaluated for protein C or S deficiency.

HYPERHOMOCYSTEINEMIA

Three enzymes are involved in the metabolism of homocysteine: methylenetetrahydrofolate reductase, cystathionine β-synthase, and methionine synthase. Inherited functional deficiency in the first two enzymes is associated with an increased risk of both arterial and venous thrombosis, as well as atherosclerosis.² The presence of elevated homocysteine in the blood is a marker of the functional enzyme deficiency. Heterozygotes for a variant mutation in either methylenetetrahydrofolate reductase or cystathionine β-synthase are found in approximately 15% of individuals with European, Middle Eastern, and Asian ancestry, compared with approximately 1% to 2% of African Americans.

Patients with profound hyperhomocysteinemia, generally because of homozygous inheritance of a dysfunctional enzyme, have the condition termed congenital homocystinuria, and have significant skeletal and ocular problems as well as mental retardation, developmental delay, and thrombotic events. Heterozygotes for a dysfunctional enzyme do not have the skeletal, ocular, or mental complications, but have a two- to fourfold increased risk for venous thrombosis. As with other hypercoagulable disorders, the presence of hyperhomocysteinemia can combine with other thrombotic conditions to greatly increase the risk of venous thrombosis; factor V Leiden mutation combined with hyperhomocysteinemia produces about a 20-fold increase in the risk for venous thrombosis.^2,10

ACQUIRED CLOTTING DISORDERS

PREGNANCY AND ESTROGEN USE

The coagulation changes in pregnancy (Table 234-5) represent an adaptive measure to prevent excessive hemorrhage with delivery.¹¹ Many of these changes are anatomic in nature, whereas some are related to the relatively high estrogen state. These changes promoting thrombosis are similar but less profound in women taking oral contraceptive and hormone replacement therapy.

The exact mechanism of how exogenous estrogen therapy leads to a hypercoagulable state is complex and not completely understood, but higher doses of estrogen clearly confer a higher risk for clotting. The current low doses for estrogens in oral contraceptives are associated with a smaller but still clinically significantly increased risk of thrombosis. Estrogen use has been associated with modest increases in several procoagulant proteins (factors VII, VIII, X, prothrombin, and fibrinogen) as well as decreases in anticoagulant proteins (antithrombin, protein S, protein C). Use of oral contraceptives or hormone replacement therapy in a patient with known heterozygosity for factor V Leiden puts the patient at an even higher risk for thrombosis, approximately a 15-fold increase.

MALIGNANCY

Malignancy is associated with increased risk for thrombus formation, but the exact mechanisms are not completely understood.^12,13 For patients with the new diagnosis of cancer, the risk of venous thromboembolism is highest in the first 3 months after diagnosis, with an odds ratio of about 50. Some types of cancers are more likely to promote thrombosis than others, with pancreatic, brain, acute myelogenous leukemia, gastric, esophageal, gynecologic, kidney, and lung cancers having the highest association with thrombosis. Cancer also increases the incidence of arterial thrombotic events, such as myocardial infarction and ischemic stroke.¹² Other manifestations of hypercoagulability in cancer patients include chronic disseminated intravascular coagulation, nonbacterial thrombotic endocarditis, migratory superficial thrombophlebitis, and thrombotic microangiopathy. Chemotherapy itself can also affect coagulation in many ways, such as downregulation of proteins C and S, induction of tissue factor production by endothelial cells, and direct cell damage.

Use low-molecular-weight heparin for the initial treatment of venous thromboembolism in patients with active cancer.¹³ Long-term anticoagulation following the diagnosis of venous thromboembolism in these patients should be with a low-molecular-weight heparin for 6 months as opposed to warfarin.¹³ Prophylactic anticoagulation for primary prevention of venous thromboembolism in ambulatory medical oncology patients is not recommended.¹³

HEPARIN-INDUCED THROMBOCYTOPENIA

Heparin-induced thrombocytopenia is a consumptive coagulopathy in which components of the clotting cascade are inappropriately activated, forming arterial and venous thrombus.¹⁴ Platelet factor 4 is a cell-signaling molecule that plays a central role in this syndrome. Platelet factor 4 neutralizes heparin and heparin-like endogenous compounds, and the heparin–platelet factor 4 combination inhibits local antithrombin activity, thereby promoting coagulation. Heparin-induced thrombocytopenia develops when patients develop antibodies against the heparin–platelet factor 4 complex. A complex of heparin, platelet factor 4, and the antibody binds to platelets, activating them. The platelets then form small microparticles that initiate clot formation. The measured platelet count falls because platelets are bound in both small and large clots. Also, the heparin–platelet factor 4 antibody complex can stimulate endothelial cells and monocytes to release tissue factor, which further triggers the coagulation cascade.

The typical presentation of heparin-induced thrombocytopenia has the platelet count falling to 50,000 to 60,000/mm³ (50 to 60 × 10⁹/L) within 5 to 15 days after starting heparin treatment. Despite the low platelet counts, the patient is hypercoagulable for days to weeks, even after heparin is stopped. Rarely, patients can develop a rapid-onset presentation within hours of initiation of heparin.

With more outpatients being treated with heparin products for venous thromboembolism or other thrombophilias, patients with heparin-induced thrombocytopenia may present to the ED with this syndrome.¹⁴ The diagnosis of heparin-induced thrombocytopenia hinges on laboratory findings and cannot be definitely diagnosed on clinical grounds alone.¹⁵ Thrombocytopenia is almost universally present (with the exception being patients with preexisting thrombocytosis). Suspect the syndrome when platelets have dropped approximately 50% from a recent value in a patient currently or recently taking a heparin product. All heparin products, both unfractionated and low-molecular-weight, must be stopped. These patients need anticoagulation because the risk for thrombosis is highest in the first week after diagnosis.¹⁴ Vitamin K antagonists, such as warfarin, should be avoided in acute heparin-induced thrombocytopenia because these can increase the risk of microvascular thrombosis acutely due to transient relative protein C deficiency. Hematology consultation should be sought.

WARFARIN-INDUCED SKIN NECROSIS

Warfarin inhibits the production of vitamin K–dependent coagulation factors, with the serum levels of the individual factors decreasing according to their half-life. Upon initiation of warfarin, protein C is decreased before most of the procoagulant proteins. This decrease in protein C leads to a transient relative protein C deficiency, which can lead to clinically significant hypercoagulability.

Warfarin-induced skin necrosis presents with painful, red lesions usually located over the extremities, breasts, trunk, or penis.¹⁶ Lesions typically start with an initial central erythematous macule, extending over hours to a localized edema, developing central purpuric zones and then necrosis. Prevention of this complication is one of the reasons loading doses of warfarin are avoided. Thrombin inhibitors, such as low-molecular-weight heparin, should be administered and continued until therapeutic anticoagulation is achieved with warfarin.¹⁶ Rarely, warfarin-induced skin necrosis occurs despite appropriate initiation of heparin treatment. When it does, approximately one-third of patients will prove to have an inherited protein C deficiency.

ANTIPHOSPHOLIPID SYNDROME

Antiphospholipid syndrome (APS) is an autoimmune disorder that is a cause of acquired thrombophilia.¹⁷ Many of the specific antibodies discovered have targets that are not phospholipids, but rather proteins that interact with phospholipids, such as prothrombin, protein C, and protein S. The most common specific antibodies associated with APS are β₂-glycoprotein I and lupus anticoagulant. Lupus anticoagulant was initially discovered in patients with systemic lupus erythematosus and prolongation of the activated thromboplastin time; hence, the name lupus anticoagulant. However, in vivo, the lupus anticoagulant acts as a procoagulant and is associated with thrombosis.¹⁷

Prevalence of APS is about 40 to 50 cases per 100,000 persons. Up to 5% of normal, healthy young people have antiphospholipid antibodies; this number increases with age and comorbid conditions, but only a minority of these patients develops APS. Antiphospholipid antibodies are positive in approximately 13% of patients with stroke, 11% with myocardial infarction, and 9.5% with deep venous thrombosis.¹⁸ As with most autoimmune disorders, APS is more common in women and is diagnosed from a combination of laboratory findings and clinical findings (Table 234-6).

Most patients with APS have no other predisposing conditions (primary APS). However, many patients with APS also have other conditions thought to be associated with their APS (secondary APS). Typical conditions include other rheumatologic or autoimmune disorders such as systemic lupus, infections, and drug exposures (e.g., phenytoin, hydralazine, cocaine).

Although most patients with APS present with isolated, recurrent thrombotic events, about 1% have a rapidly progressive form known as catastrophic antiphospholipid syndrome, representing acceleration in the pathophysiologic processes of APS with widespread small-vessel occlusions in multiple organs.¹⁹ It is unknown why some APS patients develop such a severe course. Common triggers include infection, trauma, anticoagulation problems, and cancer. However, 40% of the time, no obvious trigger can be found. Mortality of catastrophic APS is approximately 50% despite treatment.

Obviously, APS patients with recurrent thrombotic events need lifelong anticoagulation. Pregnant women with APS need anticoagulation with subcutaneous unfractionated or low-molecular-weight heparin or low-dose aspirin therapy. Because many normal healthy patients have antiphospholipid antibodies, prophylaxis without a personal history of thrombosis is not recommended. In the rare event of catastrophic APS, a multipronged approach involving anticoagulation, steroids, plasmapheresis, and/or IV γ-globulin is typically used.

HYPERCOAGULABILITY ASSOCIATED WITH OTHER DISORDERS

Many other conditions are associated with increased risk of clotting. Patients with nephrotic syndrome have an increased risk of hypercoagulability for complex reasons. In several cases, this is simply a matter of increased urinary excretion of anticoagulant proteins. The nephrotic syndrome can also lead to increased endothelial injury and platelet aggregation. Patients with several different forms of vasculitis, such as Behçet's syndrome, antineutrophil cytoplasmic antibody–associated vasculitis, and granulomatosis with polyangiitis have a slightly increased risk of thrombosis. Hyperviscosity syndromes, such as essential thrombocythemia, polycythemia vera, Waldenström's macroglobulinemia, multiple myeloma, and sickle cell disease, also place patients at increased risk for thrombosis. Most risk factors for cardiovascular disease, such as smoking and diabetes, are also risk factors for venous thromboembolism to varying degrees.²⁰ Diabetes alone slightly increases the risk for thrombosis in younger patients without other obvious risks for thrombosis.²¹ Patients with human immunodeficiency virus have a 2- to 10-fold increased risk for venous thromboembolism compared to the general population.²²