Pathophysiology of Thrombosis

VTE forms as a result of excessive fibrin production from the action of thrombin on fibrinogen. Factors that enhance fibrinogen synthesis and promote its catalysis to fibrin include systemic inflammation, traumatic or immune-related vascular trauma, inherited thrombophilias and hemoglobinopathies, cancer, pregnancy, and sluggish blood flow. Venous injury, slow blood flow, and hypercoagulability are the cardinal inciting mechanisms for VTE, and most clinical decision rules for VTE incorporate these factors. In addition, each year of life independently increases the likelihood of imbalanced clot formation.²

Anatomy

The venous anatomy of the lower extremity is divided into the deep and superficial systems. The superficial venous system consists primarily of the greater and short saphenous veins and the perforating veins. The deep venous system includes the anterior tibial, posterior tibial, and peroneal veins, collectively called the calf veins. The calf veins join together at the knee to form the popliteal vein, which extends proximally and becomes the femoral vein at the adductor canal. The femoral vein sometimes is called the superficial femoral vein, and this nomenclature contributes to confusion in interpreting radiology reports. A clot in the superficial femoral vein is indeed a DVT and should be treated as such. The femoral vein joins with the deep femoral vein to form the common femoral vein, which subsequently becomes the external iliac vein at the inguinal ligament. Proximal DVT refers to a clot in the popliteal vein or higher, whereas distal clot refers to an isolated calf vein thrombosis.

Clinical Presentation

The initial symptoms of DVT can be as subtle and nonspecific as a mild cramping sensation or sense of fullness in the calf, without objective swelling, and may be difficult to differentiate clinically from myriad other, unrelated disorders (Box 88-1). Many patients use the term charley horse to describe the sensation of an early DVT. It is precisely at this early stage, however, that DVT can be treated most effectively to minimize the potential morbidity and mortality associated with VTE. Because the left iliac vein is vulnerable to compression by the left iliac artery, leg DVT occurs with a slightly higher frequency in the left leg compared with the right; bilateral leg DVT is found in fewer than 10% of ED patients diagnosed with DVT. Likewise, the clinical signs of DVT vary and may include unilateral swelling, edema, erythema, and warmth of the affected extremity; tenderness to palpation along the distribution of the deep venous system; dilation of superficial collateral veins; and a palpable venous “cord.” The classic Homan’s sign (pain felt in the calf or posterior aspect of the knee on passive dorsiflexion of the foot while the knee is extended) is insensitive and nonspecific for DVT and has no role in clinical assessment of the patient. Upper extremity DVT refers to a thrombosis in the axillary vein and causes arm swelling on the same side as an indwelling catheter or recent intravenous infusion site. In the absence of a catheter, the most frequent location of arm DVT is on the dominant hand side. Patients frequently note that their rings become tight as an early sign of DVT.

Diagnosis

Diagnosis of DVT and PE starts with an estimation of the pretest probability (PTP). This estimation may be accomplished either by the clinical gestalt of an experienced practitioner or in conjunction with a clinical decision tool, such as that derived and validated by Wells and colleagues (Table 88-1). Patients with a low PTP can have DVT excluded with a normal quantitative D-dimer.

Treatment

When the diagnosis of DVT has been established, anticoagulation should be initiated, unless contraindicated, with a low-molecular-weight heparin (e.g., enoxaparin 1 mg/kg subcutaneously [SQ] every 12 hours), fondaparinux (5-10 mg SQ once daily, depending on patient weight), or unfractionated heparin (70-80 units/kg intravenous bolus followed by 17-18 units/kg/hr infusion), assuming normal renal function. The treatments work equally well and are safe in the absence of contraindications to anticoagulation. Treatment requires transition to oral anticoagulation with warfarin for at least 3 months. Hospital admission is obviated by initiation of outpatient low-molecular-weight heparin or fondaparinux therapy in the ED or ED observation unit, followed by self-administration at home (with appropriate patient teaching) or home administration by a visiting nurse. If admission is contemplated, after heparin has been given, the first dose of warfarin can be given in the ED to help reduce overall length of stay in the inpatient unit. Patients should be encouraged to ambulate after anticoagulation for DVT. Bed rest promotes DVT extension, increases the risk of embolization, and ultimately predisposes the patient to the postphlebitic syndrome. Patients who cannot be given anticoagulants or who have a recurrence of VTE despite anticoagulation therapy should be considered for vena caval intervention.

Complications

Although the most feared complication of DVT is fatal PE, DVT damages venous valves, causing venous insufficiency. Venous insufficiency, in turn, manifests as a spectrum ranging from painless varicosities to severe postphlebitic syndrome, which can cause unremitting pain and swelling, varicose veins, skin changes, and nonhealing ulcers. Figure 88-1 shows the leg of a construction worker with a femoral DVT that produces swelling on the job, impairing his ability to work.

Pathophysiology of Pulmonary Vascular Occlusion

The pulmonary vascular tree normally has a low resistance to fluid flow, and young persons without cardiopulmonary disease (e.g., congestive heart failure, chronic obstructive lung disease, advanced sarcoidosis, pulmonary fibrosis, scleroderma, and primary pulmonary hypertension) can tolerate at least 30% obstruction, often with minimal symptoms or signs. Pulmonary infarction is a more dramatic exception. Although a segmental pulmonary artery constitutes only about one sixteenth of the entire pulmonary vascular circuit, a clot lodged deeply in a segmental artery can obstruct blood flow to a sufficient degree to cause tissue necrosis. The patient can feel focal, sharp, pleuritic pain and exhibit a splinting response to breathing. Over several days the infarcted segment becomes consolidated on chest radiography and exudes a pleural effusion, manifesting an intense underlying inflammatory process. Chest pain from noninfarcting PE can be highly variable and vague. About 30% of patients with definite PE have no perception of chest pain.

In contrast, if asked in a detailed and structured way, about 90% of patients with noninfarcting emboli admit to the sensation of dyspnea. The dyspnea may be constant and oppressive or may be intermittent and perceived only with exertion, possibly because of an exercise-induced increase in pulmonary vascular resistance. Rest dyspnea seems to be the clinical manifestation of distorted and irregular blood flow within the lung, referred to as ventilation-perfusion inequality. With each breath a patient with PE wastes ventilation because of increased alveolar dead space (alveoli that are ventilated but not perfused). A lodged clot can redistribute blood flow to areas of the lung with already high perfusion relative to ventilation and therefore cause more blue blood to pass through the lung without being fully oxygenated. This venous admixture is probably the primary cause of hypoxemia with PE and the increased alveolar-arterial oxygen difference (the A-a gradient). About 15% of patients with PE have a normal A-a gradient of oxygen (with normal defined as age in years/4 + 4), however, and the A-a gradient is abnormally high in most patients who are evaluated for PE but ultimately found to not have PE. In a multicenter registry of 348 patients with PE, 37 (10.6%) had a pulse oximetry reading of 100% at the time of arrival to the ED, while breathing room air. Despite its shortcomings as a single diagnostic step, the presence of hypoxemia (pulse oximetry <95%, breathing room air) that cannot be explained by a known disease process increases the probability of PE. Conversely, a normal oxygen saturation can be used only when considered together with multiple other clinical features and should not alone or independently be used to forego testing for PE (Box 88-2).^18,19 In addition, when PE is diagnosed, the severity of hypoxemia represents a powerful independent predictor of patient outcome.

PE also causes highly variable effects on vital signs. In the ED, about half of all patients with PE have a heart rate greater than 100 beats/min.¹¹ Tachycardia from PE probably results from impaired left ventricular filling, leading to a pathophysiologic process that parallels that of hemorrhagic shock. In one study, the probability of PE was not reduced in patients who normalized any vital sign while in the ED.¹² When PE obstructs more than 50% of the vasculature, it usually causes an acute increase in right ventricular pressure. In contrast to the left ventricle, the right ventricle does not show an elastic response to acutely increased afterload; it quickly dilates, showing echocardiographic hypokinesis early in the course. In about 40% of cases, the right ventricular damage persists for at least 6 months and probably longer. Arterial hypotension represents an ominous hemodynamic consequence of PE; it occurs in only about 10% of patients but signifies a fourfold increase in risk of death compared with normotensive patients.²⁰ In its most extreme form, PE can obstruct the right ventricular outflow entirely, either by casting the entire pulmonary vascular tree (Fig. 88-2) or by acutely occluding the main pulmonary artery. Pulseless electrical activity (PEA) is the most common electrocardiogram (ECG) result from obstructive PE. The survival rate for cardiac arrest from PE is abysmally low, even if the arrest is witnessed and heroic treatment is initiated.

Clinical Presentation

Table 88-2 presents a listing of factors that significantly increase the probability of PE in the ED population.¹¹ As is the case for cardiac risk factors in the evaluation of acute chest pain, variables that increase the probability of PE in epidemiologic studies are not useful for individual ED patients with signs and symptoms suggesting PE. From an epidemiologic standpoint, people who smoke are at a significantly higher risk for venous clots than are people who do not smoke. However, in the ED, smoking by a given patient does not seem to increase that person’s risk for PE over that of a nonsmoker with an otherwise identical clinical presentation. It is possible that smokers are simply more likely to have other lung problems that manifest a clinical presentation similar to PE. As many as 50% of patients diagnosed with PE have no apparent clinical risk factors for VTE, but testing for genetic thrombophilia has no value in the ED setting.¹³