Hypercoagulable states include activated protein C resistance (factor V Leiden), protein C deficiency, protein S deficiency, antithrombin III deficiency, and hyperprothrombinemia (prothrombin gene mutation). Except for hyperprothrombinemia, each of these results in clot formation because of a lack of adequate anticoagulation rather than an overproduction of procoagulant activity; hyperprothrombinemia is caused by excess thrombin generation.

The most common site of the problem in the coagulation cascade is at factor Va, which is required for the formation of the prothrombinase complex with factor Xa, which leads to the thrombin burst and fibrin generation during hemostasis. Protein C is the major inhibitor of factor Va. It acts by cleaving factor V into an inactive form, thereby slowing the activation of factor X. The negative effect of protein C is enhanced by protein S. A quantitative or qualitative reduction in either of these two proteins thus results in the unregulated procoagulant action of factor Xa.

Activated protein C resistance is the most common inherited hypercoagulable state. It results from a mutation in the factor V gene. This mutation alters the three-dimensional conformation of the cleavage site within factor Va, where protein C usually binds. Protein C is then unable to bind to factor Va and is, therefore, unable to inactivate it. Coagulation is not inhibited.

Antithrombin inhibits the coagulation cascade at an alternative site. It inhibits the serine proteases: factors II, IX, X, XI, and XII. Antithrombin deficiency results in an inability to inactivate these factors, allowing the coagulation cascade to proceed unrestrained at multiple coagulation steps.

Hyperprothrombinemia is the second most common hereditary hypercoagulable state and the only one so far recognized as being due to the overproduction of procoagulant factors. It is caused by a mutation of the prothrombin gene that leads to elevated prothrombin levels. The increased risk of thrombosis is thought to be due to excess thrombin generation when the Xa–Va–Ca2+–PL complex is activated.


How might this woman be evaluated for the presence of an inherited hypercoagulable state?

C. This patient may be evaluated by various laboratory tests for the presence of an inherited hypercoagulable state. A quantitative evaluation of the relative amounts of protein C, protein S, and antithrombin can be performed. Qualitative tests that assess the ability of these proteins to inhibit the coagulation cascade can be measured via clotting assays. The presence of the specific mutation in factor V Leiden can be assessed via polymerase chain reaction testing.

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A number of genetic risk factors for VTE has been identified, which include Factor V Leiden, protein C deficiency, protein S deficiency, and anti-thrombin deficiency.

Similarly, there are a number of acquired risk factors (aging, cancer, obesity, congestive heart failure, stroke, and anti-phospholipid antibodies) and transiently acquired risk factors (immobility, trauma, hospitalization, pregnancy, central venous catheters, oral contraceptives, and hormonal therapy).

Certain hospitalized patient populations are recognized to have higher risks of developing VTE, and this list of patients include hip or knee surgery patients, spinal cord injury patients, major trauma patients, cancer patients, neurosurgery patients, and patients undergoing major general surgery or gynecological surgery procedures. Patient populations with relatively lower VTE risks have also been identified (medical patients, gynecological, and general surgical patients undergoing minor surgery).

Risk stratification of VTE risk is important during any patient encounter, because without proper VTE risk-stratification and prophylaxis, the DVT incidences in some high-risk patients are reported to be as high as 80%.


Diagnosis Risk Factors Characteristic Findings Diagnostic Testing
Pulmonary embolism Immobilization, recent surgery, stroke, paralysis, prior venous thromboembolism, malignancy, recent central venous instrumentation Dyspnea, pleuritic pain, calf or leg pain or swelling, jugular venous distention Computed tomography, ventilation-perfusion scan, pulmonary angiography
Special considerations: Thrombolytic therapy for submassive pulmonary embolism (PE) is a controversial treatment modality. It has been advocated for patients with evidence of right ventricular dilation or hypokinesis on echocardiography, but this indication for use is generally not widely accepted. Thrombolysis for cardiac arrest from PE has been successful in case reports, but does not seem to be helpful in cases of pulseless electrical activity.§ Thrombolytic regimens for PE range from 2 to 24 h infusions. For imminent or actual cardiac arrest, a bolus therapy is indicated. One such regimen is tPA, 0.6 mg/kg over 2 min.





Pulmonary embolus refers to obstruction of the pulmonary artery or one of its branches by material (eg, thrombus, tumor, air, or fat) that originated elsewhere in the body.1


PE can be classified by the following:

The temporal pattern of presentation (acute, chronic) – Patients with PE can present acutely, subacutely, or chronically:

•Acute – Patients with acute PE typically develop symptoms and signs immediately after obstruction of pulmonary vessels.

•Chronic – Patients with chronic PE slowly develop symptoms of pulmonary hypertension over many years (ie, chronic thromboembolic pulmonary hypertension; CTEPH).


Hemodynamically stable and unstable PE are defined as the following:

•Hemodynamically unstable PE is that which results in hypotension. Hypotension is defined as a systolic blood pressure <90 mmHg or a drop in systolic blood pressure of ≥40 mmHg from baseline for a period >15 minutes or hypotension that requires vasopressors or inotropic support and is not explained by other causes such as sepsis, arrhythmia, left ventricular dysfunction from acute myocardial ischemia or infarction, or hypovolemia. Although hemodynamically unstable PE is often caused by large (ie, massive) PE, it can sometimes be due to small PE in patients with underlying cardiopulmonary disease. Thus, the term "massive" PE does not necessarily describe the size of the PE as much as its hemodynamic effect. (See 'Pathophysiologic response to PE' below.)

•Hemodynamically stable PE is defined as PE that does not meet the definition of hemodynamically unstable PE. There is a spectrum of severity within this population ranging from patients who present with small, mildly symptomatic or asymptomatic PE (also known as "low-risk PE") to those who present with mild or borderline hypotension that stabilizes in response to fluid therapy, or those who present with right ventricle dysfunction (also known as "submassive" or "intermediate-risk" PE). (See "Thrombolytic (fibrinolytic) therapy in acute pulmonary embolism and lower extremity deep vein thrombosis", section on 'Hemodynamically stable patients'.)

The distinction between hemodynamically stable and unstable PE is important because patients with hemodynamically unstable PE are more likely to die from obstructive shock (ie, severe right ventricular failure). Importantly, death from hemodynamically unstable PE often occurs within the first two hours, and the risk remains elevated for up to 72 hours after presentation [1,2]. (See "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism", section on 'Hemodynamically unstable patients' and "Thrombolytic (fibrinolytic) therapy in acute pulmonary embolism and lower extremity deep vein thrombosis", section on 'Hemodynamically unstable patients' and "Treatment, prognosis, and follow-up of acute pulmonary embolism in adults", section on 'Prognosis'.)

The anatomic location (saddle, lobar, segmental, subsegmental) – Saddle PE lodges at the bifurcation of the main pulmonary artery, often extending into the right and left main pulmonary arteries. Approximately 3 to 6 percent of patients with PE present with a saddle embolus [3,4]. Traditionally, saddle PE was thought to be associated with hemodynamic instability and death. However, retrospective studies suggest that among those diagnosed with a saddle embolus, only 22 percent are hemodynamically unstable, with an associated mortality of 5 percent [3,4]. Clot that is "in transit" through the heart is often classified as a form of PE, even though the thrombus has not yet lodged in a pulmonary artery. Clot-in-transit is associated with high mortality (up to 40 percent).

Most PE move beyond the bifurcation of the main pulmonary artery to lodge distally in the main lobar, segmental, or subsegmental branches of a pulmonary artery. PE can be bilateral or unilateral, depending on whether they obstruct arteries in the right, left, or both lungs. Smaller thrombi that are located in the peripheral segmental or subsegmental branches are more likely to cause pulmonary infarction and pleuritis (image 1). (See 'Pathophysiologic response to PE' below.)

The presence or absence of symptoms (symptomatic or asymptomatic) – Symptomatic PE refers to the presence of symptoms that usually leads to the radiologic confirmation of PE, whereas asymptomatic PE refers to the incidental finding of PE on imaging (eg, contrast-enhanced computed tomography performed for another reason) in a patient without symptoms. (See "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism", section on 'Diagnosis'.)


Massive acute pulmonary embolism may cause syncope due to obstruction of the pulmonary vascular bed and reduction in cardiac output.12


What constitutes the Virchow triad of predisposing factors for venous thrombosis?

A. The Virchow triad consists of three possible contributors to the formation of a clot: (1) decreased blood flow; (2) blood vessel injury or inflammation; and (3) changes in the intrinsic properties of the blood.


This patient has no history of immobility or other cause of decreased blood flow. She does, however, have a history of blood vessel injury (ie, deep vein thrombosis). Despite the absence of symptoms of a lower extremity thrombus, this is still the most likely site of origin of the pulmonary embolus. Finally, the recurrence now of thrombus formation along with the family history of clots is suggestive of a change in the intrinsic properties of the blood, as seen in the inherited hypercoagulable states.



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VTE is a major cause of morbidity and mortality in hospitalized patients and the leading cause of preventable hospital deaths. Approximately two-thirds of the patients with VTE present with DVT, with the remaining one-third of patients present with PE alone.

The 30-day mortality of patients suffering a thrombotic event is 25%, and of those patients who survive their initial event, 30% will develop recurrent VTE within 10 years.


1. Nasal oxygen. Monitor SpO2. Intubation may be needed.

2. Anticoagulate with Low Molecular Weight Heparin

Rationale: body weight–adjusted subcutaneous LMWH is the preferred initial therapy for acute nonmassive PE (Chest2004;126:401s–428s).

Generic Name Brand Name
1. dalteparin Fragmin
2. enoxaparin Lovenox
3. tinzaparin Innohep

Prevents clot propagation, decrease inflammation, and allow intrinsic fibrinolysis to lyse the clot

  • a.  If unfractionated heparin is chosen (eg, patient with severe renal failure), administer bolus with 80 units/kg IV and start an infusion at 18 units/kg/h. Titrate the infusion to maintain the PTT at 2–2.5 × control value. Check the PTT 6 h after rate adjustments.

    b. Monitor the platelet count for heparin-induced thrombocytopenia.

    c. Start oral warfarin (Coumadin) by day 3 of heparin therapy to achieve and maintain an INR of 2–3

3. In massive PE, administer thrombolytic therapy (TPA) if not contraindicated.

4. Consider pulmonary embolectomy for hemodynamically unstable patients with massive PE if medical therapy is not successful.

5. If anticoagulation is contraindicated (eg, recent surgery, stroke, GI bleeding) or if PE recur despite anticoagulation, consider placement of a vena caval filter placement.

6. Work Up for hypercoagulable state.

Indications: Patients with recurrent thrombosis, a family history of thrombosis, spontaneous abortions, and systemic lupus erythematosus


  • Increased risk of thrombosis and recurrent spontaneous abortions with lupus anticoagulants.
  • May present with DVT, including pain, swelling, and redness of the limb with normal pulses and extremity perfusion.
  • May present with pulmonary emboli with or without obvious DVT, including an acute onset of shortness of breath, hypoxemia, tachycardia, and chest pain.
  • Hypercoagulable states may present with thrombosis at unusual sites (eg, the central nervous system sagittal sinus, the abdominal mesenteric veins).





Physical Exam


Laboratory Tests



Essentail Criteria to Establish Diagnosis




Prophylaxis consists of mechanical and/or pharmacologic measures. Hospitalized surgical patients are at significantly increased risk of VTE development secondary to stasis, hypercoagulability, and venous endothelial injury that are produced by local and systemic effects of trauma, operations, aging, and pre-existing conditions.

The incidence of DVT in general surgical patients without appropriate prophylaxis is roughly 20% to 30%, with most of the patients being relatively asymptomatic. Patients with major traumatic injuries, spinal cord injuries, as well as orthopedic surgery patients undergoing joint replacements are among the highest risk populations for VTE.

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A 57-year-old man undergoes total knee replacement for severe degenerative joint disease. Four days after surgery, he develops acute onset of shortness of breath and right-sided pleuritic chest pain. His father died after a pulmonary embolism (PE). The patient is now in moderate respiratory distress with a respiratory rate of 28 breaths/min, heart rate of 120 beats/min, and blood pressure of 110/70 mm Hg. Oxygen saturation is 90% on room air. Lung examination is normal. Cardiac examination reveals tachycardia but is otherwise unremarkable. The right lower extremity is postsurgical, healing well, with 2+ pitting edema, calf tenderness, erythema, and warmth; the left leg is normal.

What is the most likely diagnosis?




A 58-year-old woman complains of the sudden onset of right chest pain and shortness of breath 4 days following an uncomplicated laparoscopic left hemicolectomy for adenocarcinoma of the descending colon. Prior to this time, the patient has had an uncomplicated course, and was in the process of receiving her instructions for discharge from the hospital. During your assessment, she appears anxious and complains that she is unable to “catch her breath.” Her temperature is 37.9°C (100.3°F), pulse rate is 105 bpm, blood pressure is 138/80 mm Hg, and respiratory rate is 32 breaths/minute. She is receiving O2 by nasal cannula with an O2 saturation of 96% by pulse oximetry. Despite her O2 saturation, the patient is complaining that she is having difficulties with her breathing. There is no jugular venous distension. Her lungs are clear with slightly diminished breath sounds at both bases. Her legs are mildly edematous bilaterally and her left calf is mildly tender to palpation. Laboratory studies reveal a white blood cell (WBC) count of 10,000/mm3 with normal differential, normal hemoglobin, hematocrit, and platelet count. The serum electrolytes are normal. An arterial blood gas reveals pH 7.45, PO2 73 mm Hg, PCO2 34 mm Hg, and HCO3 24 mEq/L. A 12-lead electrocardiogram (ECG) reveals sinus tachycardia. Serum creatinine kinase and troponin levels are within normal limits. A portable chest radiograph (CXR) demonstrates no infiltrates, no effusion, and minimal atelectasis in both lower lung fields.


What is the most likely diagnosis?


What should be your next steps?

Answers to Case 51: Venous Thromboembolism (VTE)

Summary: A 58-year-old woman develops sudden onset of chest pain and shortness of breath 4 days following laparoscopic colectomy for adenocarcinoma of the colon. Her physical examination does not identify any significant abnormalities other than calf tenderness. Her laboratory studies are non-contributory. Arterial blood gas reveals hypoxemia and respiratory alkalosis. The CXR and ECG do not demonstrate obvious pathology.

  • Most likely diagnosis: Pulmonary embolism (PE) is likely given the sudden onset of chest pain and shortness of breath in a patient without prior history of pulmonary pathology, who has just undergone laparoscopic colectomy for adenocarcinoma of the colon.

  • Next steps: Initiate systemic anticoagulation therapy for presumptive diagnosis of PE, transfer the patient to the intensive care unit, and obtain confirmatory imaging studies.



  1. Learn to risk-stratify patients and determine pretest probability for VTE.

  2. Learn the applications of prophylaxis for VTE for surgical patients.

  3. Learn the diagnostic and therapeutic approaches for patients with VTE.


The differential diagnosis for a 58-year-old woman who develops the sudden onset of chest pain and shortness of breath during the postoperative period, which includes acute coronary syndrome, acute lung injury, respiratory infection, pneumothorax, and PE. Since all of these possible diagnoses are potentially lethal if not identified and treated in a timely fashion, the clinician must be prepared to investigate and address the patient’s symptoms immediately. Her physical examination is essentially normal with the exception of calf tenderness and nonspecific diminished breath sounds at both lung bases. The laboratory data such as CBC, cardiac enzymes, and ABG are useful during the initial evaluation to point us toward or away from certain diagnoses. The ECG and CXR are equally important to help establish or rule out certain cardiac and pulmonary processes. We know that at this time, the patient has a history of colon cancer and a postoperative course that had been unremarkable up until this time. Her physical examination does not reveal pulmonary edema or pneumonia. The fact that she has had an unremarkable recovery from her colectomy reduces our suspicion for acute lung injury; this complication is commonly caused by an intra-abdominal infectious process in patients following intestinal surgery. The cause of her calf tenderness is currently unknown but may represent deep venous thrombosis (DVT) in that location. Her ABG results suggest respiratory alkalosis and hypoxemia. For all the reasons mentioned above, this patient has a high pretest probability for VTE, and based on our initial assessment, it is acceptable to initiate systemic anticoagulation therapy for the presumptive diagnosis of PE. Once this is initiated with appropriate supportive care, we can obtain the necessary confirmatory studies.

A 52-year-old woman developed acute shortness of breath 3 weeks after a hysterectomy. She denied leg pain or swelling. She has no chronic medical problems and takes no medications. Her pulse is 105 beats/min, respiratory rate is 20 breaths/min, and the rest of her examination is unremarkable.

She had an elevated hemidiaphragm on chest X-ray (CXR). These findings placed her at moderate risk for pulmonary embolism (PE) based on the Geneva score.

Chest X Ray demonstrated a moderate-sized PE shown below. She was treated with anticoagulation without complications.

CXR showing a wedge-shaped pulmonary infarction with the base on the pleural surface and the apex at the tip of a pulmonary artery catheter; the catheter caused the occlusion of a peripheral artery. (From Miller WT Jr. Diagnostic Thoracic Imaging. New York: McGraw-Hill; 2006:272, Figure 5-61. Copyright 2006.)



A 26-year-old white man with no significant past medical history presents to the emergency department because of sudden onset of shortness of breath and chest pain. An arterial blood gas reveals that he is hypoxic. A ventilation-perfusion scan of the chest is consistent with a pulmonary thromboembolus. He has no identifiable risk factors for deep venous thrombi. This patient is most likely to have

The correct answer is B.

Any of the above conditions are possible causes of a hypercoagulable state. The most common inherited hypercoagulable condition is factor V Leiden, which is an inherited mutation in factor V that removes the cleavage site for protein C; thus, protein C cannot inactivate activated factor V.


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A 57-year-old man with a history of hypertension is admitted to the hospital with pulmonary embolism after having sudden onset of chest discomfort. His blood pressure is 132/62 mmHg, heart rate is 85 bpm, and oxygen saturation is 95% on room air. Echocardiography reveals normal right heart size and function, and cardiac troponin I is undetectable. Lower extremity Doppler ultrasound reveals an extensive deep vein thrombus from the right femoral popliteal vein. The patient is started on low-molecular-weight heparin and concomitant warfarin. On rounds the following day, he asks if insertion of an inferior vena cava (IVC) filter would be appropriate. What is the most appropriate answer?




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