Case 1: Unstable ICU patient
A 56-year-old man is evaluated in the ICU for hypotension. He was admitted 3 hours ago for acute onset dyspnea. A CT angiogram performed upon admission showed a large, central pulmonary embolism. Treatment was started with subcutaneous low-molecular-weight heparin, and he was transferred to the ICU for monitoring. An hour later he became hypotensive.
On physical examination, blood pressure is 78/54 mm Hg, pulse rate is 120/min, and respiration rate is 28/min. Oxygen saturation is 93% on 4 L/min of oxygen through nasal cannula. Lungs are clear on auscultation. Cardiac examination reveals a grade 2/6 systolic murmur above the left lower sternal border. The second heart sound is persistently split.
Which of the following is the most appropriate treatment?
A. Add recombinant tissue plasminogen activator (rtPA)
B. Change to apixaban
C. Change to intravenous unfractionated heparin infusion
D. Continue low-molecular-weight heparin
Case 2: Testing in the ED
A 25-year-old woman is evaluated in the emergency department for mild shortness of breath and right lateral chest pain of 2 days' duration. She reports no orthopnea or lower extremity edema. Medical history is unremarkable other than anxiety related to meeting the demands of her new job as an engineer. She takes no medications.
On physical examination, she is in no apparent distress. Vital signs are normal. Oxygen saturation is 99% breathing ambient air. The lungs are clear to auscultation. No peripheral edema is noted.
Her Wells Criteria for Pulmonary Embolism score is 0.
A complete blood count, electrocardiogram, and chest radiograph are normal.
Which of the following tests should be performed next to rule out pulmonary embolism?
A. CT angiography of the chest
D. No further testing
Case 3: Postoperative patient
A 74-year-old woman is evaluated in the hospital for loss of consciousness 1 day after total hip replacement. She suddenly became unresponsive and hypotensive while sitting in bed. Before this event she was doing well and discharge planning was under way. She has a remote history of penicillin allergy manifesting as hives. She received one dose of prophylactic cefazolin at the time of surgery. Her only medications are oxycodone and low-molecular-weight heparin.
On physical examination, blood pressure is 76/48 mm Hg, pulse rate is 116/min, and respiration rate is 26/min. Oxygen saturation is 80% on a 100% oxygen nonrebreather mask. The skin is cool and mottled but without rash. Cardiac sounds are soft, without murmur, but with persistent splitting of the second heart sound. Jugular venous distention is noted. The lungs are clear bilaterally.
Which of the following is the most likely diagnosis?
A. Anaphylactic shock
B. Opiate overdose
C. Pulmonary embolism
D. Tension pneumothorax
Case 4: Rash after treatment
A 32-year-old woman is evaluated for a painful rash occurring bilaterally on her lower extremities, which began 2 days ago. She was admitted to the hospital 5 days ago for diagnosis and treatment of pulmonary embolism with heparin and warfarin. Her father had a pulmonary embolism after a long airplane ride. Her medical history is otherwise unremarkable, and she takes no other medications.
On physical examination, vital signs are normal. She has nonblanchable macules and papules and areas of cutaneous necrosis in an angulated reticular pattern on the lower legs; findings on the feet are shown. The examination is otherwise unremarkable.
Laboratory studies show a normal complete blood count, a normal peripheral blood smear, and an international normalized ratio of 4.
Which of the following is the most likely diagnosis?
A. Factor V Leiden mutation
B. Plasminogen activator inhibitor 1 deficiency
C. Protein C deficiency
D. Prothrombin gene mutation
Case 5: Risk scoring
A 59-year-old woman arrives at the emergency department with left lower leg swelling of 2 weeks' duration and shortness of breath of 1 week's duration that has worsened during the past 6 hours. She reports no chest pain or hemoptysis. She has no history of recent travel, surgery, malignancy, or immobilization. She takes no medications.
On physical examination, temperature is 37.7 °C (99.9 °F), blood pressure is 140/85 mm Hg, pulse rate is 102/min, and respiration rate is 19/min. Oxygen saturation is 95% breathing ambient air. Edema of the left lower extremity is noted.
Laboratory studies show an elevated D-dimer level.
CT angiography shows a right subsegmental pulmonary embolism.
The patient's Pulmonary Embolism Severity Index score is 59.
It is determined the patient can be safely treated as an outpatient.
Which of the following is the most appropriate treatment?
D. Low-molecular-weight heparin
Case 6: Brain mass and PE
A 55-year-old woman is evaluated in the hospital after diagnosis of pulmonary embolism. She was admitted to the hospital 3 days ago for evaluation of a brain mass with imaging features characteristic of glioblastoma. Twenty-four hours after brain biopsy, the patient developed chest pain and dyspnea. Imaging confirmed a filling defect in the right pulmonary artery.
On physical examination, blood pressure is 110/60 mm Hg, pulse rate is 100/min, respiration rate is 18/min, and oxygen saturation is 93% with the patient receiving 2 L/min of nasal oxygen. Cardiopulmonary examination shows mild tachycardia but is otherwise normal. Right upper and lower facial numbness and right arm weakness and numbness are noted. Biceps, triceps, and brachioradialis reflexes are increased on the right, as is right-sided hyperreflexia. An extensor plantar response is present on the right.
Results of laboratory studies show a serum creatinine level of 1.7 mg/dL (150 µmol/L).
Which of the following is the most appropriate treatment?
B. Inferior vena cava filter placement
C. Intravenous alteplase
D. Intravenous heparin
E. Subcutaneous low-molecular-weight heparin
Answers and commentary
Correct answer: A. Add recombinant tissue plasminogen activator (rtPA).
The most appropriate treatment is thrombolytic therapy with rtPA. This patient has a large pulmonary embolism and is most likely becoming hypotensive from acute right ventricular (RV) failure. RV failure is the leading cause of death among patients with acute pulmonary embolism. In patients with hemodynamic collapse, treatment with thrombolytics is associated with decreased mortality and improvement in clinical and echocardiographic parameters. Although this patient has no contraindications to rtPA, thrombolytics carry a significant side effect profile, including an up to 2% risk of intracranial hemorrhage, but this should be considered relative in patients with life-threatening, high-risk pulmonary embolism. In patients with contraindications to thrombolysis, and in those in whom thrombolysis has failed to improve the hemodynamic status, surgical or catheter-based embolectomy should be considered if surgical expertise and resources are available.
According to the Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-line Therapy (AMPLIFY) study, apixaban is an equivalent option to conventional heparin therapy for the initial treatment of pulmonary embolism. In this patient with hemodynamic collapse, it would not be more beneficial than low-molecular-weight heparin (LMWH) and is less beneficial than rtPA therapy.
In patients with acute pulmonary embolism, unfractionated heparin, LMWH, a new oral anticoagulant such as apixiban, or fondaparinux (a factor Xa inhibitor) should be started immediately unless otherwise contraindicated. Because this patient is experiencing hemodynamic collapse despite therapy with LMWH, continuing that treatment alone would not be appropriate.
Treatment of patients with acute pulmonary embolism with unfractionated heparin infusion appears to be associated with increased risk of adverse effect compared to LMWH administration. The 2014 European Society of Cardiology guidelines for diagnosis and management of pulmonary embolism recommend LMWH or fondaparinux rather than unfractionated heparin in hemodynamically stable patients because they are associated with a lower risk of heparin-induced thrombocytopenia and major bleeding events. However, the guidelines caution that LMWH and fondaparinux have not been tested in the setting of hypotension and shock and thus are not preferred modes of initial anticoagulation in that patient population.
- In patients with pulmonary embolism and hemodynamic collapse, treatment with thrombolytics is associated with decreased mortality and improvement in clinical and echocardiographic parameters.
Correct answer: D. No further testing.
The patient requires no further testing for pulmonary embolism. Many patients present to the emergency department with shortness of breath or chest pain. Inappropriate use of D-dimer testing and CT angiography led to the development of new American College of Physicians guidelines regarding the evaluation of patients with possible pulmonary embolism (PE). These guidelines use clinical decision tools (such as the Pulmonary Embolism Rule-Out Criteria [PERC]) to help risk stratify patients who present with shortness of breath or chest pain.
The PERC are defined as
- Age younger than 50 years
- Heart rate less than 100/min
- Oxygen saturation 95% or greater
- No hemoptysis
- No estrogen use
- No previous deep venous thrombosis or PE
- No unilateral leg swelling
- No surgery or trauma requiring hospitalization in the last 4 weeks
To avoid unnecessary testing, patients with a low pretest probability using a validated prediction tool such as the Wells Criteria for Pulmonary Embolism and negative PERC should undergo no further evaluation. In patients with intermediate pretest probability or positive PERC, the D-dimer level should be obtained. Patients with a high pretest probability should proceed directly to imaging, without D-dimer testing.
Because this patient has a low pretest probability and the PERC are negative, neither D-dimer testing nor CT angiography of the chest should be performed. A study of multiorgan ultrasonography was shown to be helpful in the diagnosis of PE in adults with a Wells score of 4 or greater or a positive D-dimer test. A positive test was defined by any one of the following: one or more pulmonary subpleural infarctions on lung ultrasonography; right ventricular dilatation or thrombi on heart ultrasonography; or deep venous thrombosis on lower extremity ultrasonography. Multiorgan ultrasonography was found to be 90% sensitive and 86% specific compared with CT angiography. Multiorgan ultrasonography was significantly more sensitive than individual ultrasonographic examinations of the lungs, heart, or lower extremities.
Echocardiography is unlikely to be helpful in this patient because her pretest probability of pulmonary embolism was very low, and echocardiography alone is an insensitive test.
- Patients identified as low risk and meeting the Pulmonary Embolism Rule-Out Criteria do not require D-dimer testing to eliminate the need for further diagnostic imaging.
Correct answer: C. Pulmonary embolism.
This patient most likely has a pulmonary embolism. This patient has hypoxemic respiratory failure and shock. Severe hypoxemia is generally defined as an arterial PO2 of 60 mm Hg (8.0 kPa) or less or an oxygen saturation of 89% or less while breathing ambient air. The most common causes of hypoxemic respiratory failure are conditions that lead to mismatch between the ventilation of inspired air in the alveoli and perfusion of adjacent alveolar capillaries by blood (called ventilation-perfusion [V/Q] mismatch). Conditions such as pulmonary embolism lead to V/Q mismatch. Hypoxemia due to V/Q mismatch should resolve with oxygen therapy. However, extremes of V/Q mismatch (known as a shunt) do not fully resolve with supplemental oxygen because inspired gas does not interface with the shunted blood in the lungs. In addition, this patient has evidence of cardiogenic shock, including hypotension, elevated jugular venous pressure, fixed splitting of the second heart sound, and cool, mottled skin. Although cardiogenic shock can occur for many reasons, in this patient, it is the result of the pulmonary embolism causing a mechanical blockage in the pulmonary circulation, leading to impaired cardiac output from the right ventricle. Fat emboli following long-bone fractures can mimic pulmonary emboli.
Anaphylactic shock is a type of distributive shock, as might occur if a patient with an allergy to penicillin were given either penicillin or a related agent to which she reacted. Anaphylaxis is an IgE-mediated reaction and manifests within minutes to 1 hour after exposure to the implicated antigen. Anaphylactic shock would result in hypotension and warm extremities, typically with hives or rash. The patient is hypotensive, but does not have a rash. Respiratory failure could be present but would be associated with wheezing or stridor.
Opioid overdose can cause hypercapnic respiratory failure with hypoxemia occurring as the result of hypoventilation. Although the hypoxemia improves with oxygen, it does not improve the hypercapnea. Opioid overdose cannot account for the findings of obstructive shock.
Tension pneumothorax can cause respiratory failure and cardiogenic shock as a result of poor right ventricular filling. It should be suspected in patients with hypotension, diminished breath sounds on the affected side, distended neck veins, and tracheal deviation away from the affected side. Risk factors for tension pneumothorax include trauma, recent pulmonary procedure, mechanical ventilation, and underlying cystic lung disease. The patient has no risk factors for tension pneumothorax, and her lung findings do not support this diagnosis.
- The most common causes of hypoxemic respiratory failure are conditions that lead to ventilation-perfusion mismatch or shunt; hypoxemia due to ventilation-perfusion mismatch with shunting does not improve with supplemental oxygen.
Correct answer: C. Protein C deficiency.
The most likely diagnosis is protein C deficiency. The patient's skin condition is most likely retiform purpura. The term “retiform” describes the angulated or netlike configuration that reflects the vascular structure in the skin. The color is often a dark brick-red or purple. Retiform purpura is caused by local skin ischemia caused by occlusion or breakdown of vascular integrity that may lead to necrosis, which may become life-threatening if not aggressively treated. Various conditions can cause retiform purpura, many of which disrupt arterial blood flow. Thrombotic and embolic causes should be considered first. Thrombotic causes include alterations to the coagulation cascade such as disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, and drug-induced thrombosis (warfarin or heparin).The patient's clinical presentation is consistent with warfarin-induced skin necrosis, which is a rare complication of warfarin therapy. The pathophysiology is thought to be caused by a transient hypercoagulable state resulting from protein C deficiency, which can be inherited or acquired. A family history of pulmonary embolism suggests the possibility of inherited protein C deficiency. Congenital protein C deficiency is an autosomal dominant inherited thrombophilia associated with an increased risk of venous thromboembolism. When protein C is activated, it inactivates the activated coagulation factors V and VIII, which are needed for factor X activation. When warfarin is initiated, an initial reduction in protein C activity of 50% occurs, which leads to a transient hypercoagulable state. If the patient is receiving heparin and warfarin therapy, the lesions may appear when the heparin is discontinued, which likely accounts for the appearance of the rash on day 3 of her hospitalization. Treatment involves the discontinuation of warfarin, continuation of alternate anticoagulation (such as a non–vitamin K antagonist oral anticoagulant), vitamin K for warfarin reversal, and fresh frozen plasma in an attempt to improve decreased protein C levels.
Warfarin-induced skin necrosis is not associated with factor V Leiden mutation, plasminogen activator inhibitor 1 deficiency, or prothrombin gene mutation.
- Protein C or S deficiency is associated with warfarin-associated skin necrosis.
Correct answer: A. Apixaban.
This patient should be treated with apixaban. Patients with pulmonary embolism (PE) were previously hospitalized for anticoagulant therapy. However, admission rates are decreasing because of the recognition that appropriate patients can be safely managed in the outpatient setting. The Outpatient Treatment for Pulmonary Embolism (OTPE) trial was an open-label, randomized, noninferiority trial. A total of 344 patients with acute, symptomatic, objectively confirmed PE were randomly assigned to inpatient or outpatient management. Patients were classified as low risk or high risk of death using the Pulmonary Embolism Severity Index (PESI). Among patients with low-risk PESI scores who were randomly assigned to outpatient or inpatient care, recurrent venous thromboembolism (VTE) occurred within 90 days in 1 of 171 (0.6%) outpatients and zero inpatients, a finding that met the criteria for noninferiority. The PESI stratifies patients into five risk categories for all-cause 30-day mortality based on 11 clinical parameters (see Table).
In the appropriate clinical setting, patients with a PESI score less than 65 are very low risk for 30-day mortality (0%), and those with a score less than 85 are low risk for 30-day mortality (1%); patients in these categories can be considered for outpatient management. This patient's PESI score is 59. Therefore, outpatient management can be considered, but the appropriate agent must be selected. The 2016 American College of Chest Physicians guidelines recommend non–vitamin K antagonist oral anticoagulants as first line for patients without cancer with VTE. Dabigatran and edoxaban require bridging with parenteral anticoagulation, whereas apixaban and rivaroxaban can be used as monotherapy in the treatment of VTE.
Long-term low-molecular-weight heparin has traditionally been considered first-line treatment in patients with malignancy, although recent data suggest that non–vitamin K antagonist oral anticoagulants are equally effective. This patient does not have cancer; therefore, apixaban is a more appropriate choice.
- Patients with a Pulmonary Embolism Severity Index score of less than 65 are at low risk of death and may be managed in the outpatient setting with a non–vitamin K antagonist oral anticoagulant, such as apixaban or rivaroxaban.
Correct answer: D. Intravenous heparin.
This patient should receive intravenous heparin. Venous thromboembolism (VTE) is a common complication in patients with brain tumors, occurring in up to 30% of patients with high-grade glioma. Risk of VTE is correlated with higher-grade malignancies and is associated with release of the potent procoagulant tissue factor. Other factors, including immobilization and recent surgery, increase the risk. The risk of intracranial hemorrhage with the use of anticoagulants complicates the management of VTE in patients with brain tumor, including patients undergoing brain surgery. Although brain tumors have a risk of hemorrhage, therapeutic anticoagulation is generally considered safe. Intravenous heparin is the best choice for this patient because it has a short half-life and is reversible should hemorrhage occur. Although evidence does not support routine use of preanticoagulation neuroimaging to assess for hemorrhage, noncontrast head CT can be considered and is the most cost-effective test in this situation.
Apixaban is not indicated. Although non–vitamin K oral anticoagulants are a recommended therapy for VTE, evidence is insufficient to support their use in the setting of central nervous system tumors.
Inferior vena cava (IVC) filter placement is not indicated. IVC filters incur an increased risk of subsequent deep venous thrombosis and should be reserved for patients with an absolute contraindication to anticoagulation. The presence of a primary brain tumor and recent biopsy do not absolutely preclude anticoagulation.
Alteplase, a tissue plasminogen activator, is contraindicated in most central nervous system tumors. This class of drugs can be considered in low-risk tumors, such as meningioma, but not high-risk tumors, such as glioblastoma multiforme.
Subcutaneous low-molecular-weight heparin (LMWH) is an effective treatment for VTE but should be avoided in this patient because of her kidney dysfunction. LMWH also lacks an effective reversal agent and has a prolonged duration of action, making it a less optimal choice in a patient at increased risk of bleeding.
- In patients with glioblastoma multiforme and pulmonary embolism, anticoagulation with heparin is the most appropriate treatment.