Pulmonary Embolism

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Chapter 57 Pulmonary Embolism

Michael P. Gruber, Todd M. Bull

The philosophies of one age have become the absurdities of the next, and the foolishness of yesterday has become the wisdom of tomorrow.

William Osler

Pulmonary embolism (PE) and deep vein thrombosis (DVT) are different manifestations of the same pathologic process best grouped under the designation venous thromboembolism (VTE). As a disease entity, VTE is responsible for significant morbidity and mortality while imparting great socioeconomic impact. Appropriately, much attention has been devoted to its diagnosis and treatment. Although the medical literature has at times presented conflicting opinions, increased numbers of better-designed trials are helping to build consensus toward the optimal approach for the management of PE. This is not to say that significant controversies do not still exist. As in all areas of medicine, as one question is answered, others arise. This chapter presents an overview of the most important literature regarding the clinical approach to PE.

Epidemiology, Risk Factors, and Pathogenesis

Epidemiology

PE is a common clinical problem. In the United States, hospital-based studies estimate the incidence of PE at 1 case per 1000 persons per year, equating to 200,000 to 300,000 hospital admissions per year. Estimates suggest that as many as 30,000 to 50,000 people die from PE annually in the United States, with an estimated 3-month disease-specific mortality rate of 10%. In nearly 20% of cases, the presenting clinical manifestation is sudden death. Data reported from Europe and other parts of the world are broadly similar.

Significant differences in mortality associated with PE for age, gender, and race have been observed. Age-adjusted PE mortality rates are as much as 50% higher among African Americans than whites. Within and between racial strata, PE mortality rates are 20% to 30% higher in men than in women. African American men have the highest reported mortality from PE, at 6.0 deaths per 100,000 persons, followed by African American women at 4.8 deaths per 100,000 persons. The mortality for PE in white males is 2.4 deaths per 100,000 persons and is the lowest in white females at 2.3 deaths per 100,000 persons. The incidence of PE also is age-dependent, with increasing incidence of death with advancing age. From 1979 to 1998, accounting for both gender and race, age-specific mortality rates doubled for each 10-year age group after 15 to 24 years.

In recent decades, the overall mortality rate from PE has decreased dramatically. From 1998 to 2009, the annual in-hospital mortality decreased by approximately 30%. The decline has been observed across gender and ethnic groups and has been attributed to improved risk factor modification, including improved prophylaxis of DVT, better detection and treatment of DVT, and/or enhanced PE diagnostic techniques, which has led to a decrease in disease misclassification.

Risk Factors

The etiopathogenesis of VTE, which includes PE and DVT, is a dynamic process resulting from synergistic interaction between acquired and genetic risk factors. Historically, Rudolph Virchow is credited with describing the classic triad of vascular endothelial injury, hypercoagulability, and venous stasis as the combination of host factors that predispose to VTE. VTE risk factors traditionally are categorized as either genetic (inherited thrombophilia) or acquired.

Inherited Thrombophilia

Inherited thrombophilias may result from qualitative or quantitative defects in coagulation factor inhibitors (antithrombin, protein C, protein S), increased levels or function of coagulation factors (activated protein C resistance, factor V Leiden mutation, prothrombin gene mutation, elevated factor VIII levels), hyperhomocysteinemia, defects in fibrolysis, or altered platelet function. Epidemiologic features of the common inherited thrombophilias are shown in Table 57-1.

Table 57-1 Inherited Thrombophilias

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Antithrombin Deficiency

Formerly termed antithrombin III, antithrombin (AT) is a single-chain vitamin K–independent glycoprotein belonging to the serine protease inhibitor superfamily. AT functions as a natural anticoagulant by binding and inactivating thrombin and the activated coagulation factors IXa, Xa, XIa, and XIIa. The AT molecule also has an active heparin-binding site, which, when heparin-bound, has marked affinity and function for binding and inactivating coagulation factors such as thrombin. The augmentation of the inhibitory activity of AT by heparin is the basis for the clinical use of heparin therapy. Mutations in AT lead to decreased ability of the molecule to inhibit the coagulation cascade, thereby leading to increased risk for thrombosis. AT deficiency is inherited as an autosomal dominant trait affecting males and females equally. Most affected persons are heterozygotic for AT deficiency, because homozygotic inheritance typically is fetal-lethal. Heterozygote AT-deficient people have AT levels that are 40% to 70% of normal. Two different types of AT deficiency caused by more than 250 mutations have been described: Type I AT deficiency is characterized by a quantitative reduction in normally functioning AT. Type II AT deficiency is characterized by both quantitative and qualitative defects, with three different subtypes classified on the basis of the type of receptor defect: (1) abnormality of active thrombin binding site, (2) abnormality of heparin-binding site, and (3) abnormalities of both thrombin- and heparin-binding sites. These classification categories are clinically relevant in that defects in the active thrombin-binding site confer a higher risk for VTE than defects that involve only the heparin-binding site or that are strictly quantitative.

Despite a low prevalence, AT deficiency is considered the most severe inherited thrombophilia, with increased risk of thrombosis as much as 20-fold over that in the absence of such deficiency. In patients with AT deficiency, VTE typically develops during the latter part of the second or third decade of life. The most common sites of thrombosis include the lower extremity and iliofemoral veins. However, other sites including the upper extremities, mesenteric veins, vena cava, renal veins, and retinal veins have been reported. Thrombotic events in AT-deficient persons often are precipitated by acquired thrombophilic risk factors such as surgery, trauma, pregnancy, drugs, or infection. Approximately 60% of affected persons experience recurrent thrombotic events, and clinical signs of PE are evident in up to 40% of these patients.

The diagnosis of AT deficiency should be determined by a functional assay of heparin cofactor activity, which is able to detect all cases of AT deficiency of clinical relevance. AT levels usually are not influenced by warfarin therapy but can be decreased during the acute phase of a thrombotic event, in disseminated intravascular coagulation, or with the concomitant use of heparin. Heparin therapy can lower AT levels by as much as 30%. Screening for AT deficiency is recommended within at least 2 weeks of an acute thrombotic event or at least 5 days after discontinuation of heparin therapy.

Protein C Deficiency

Protein C is a vitamin K–dependent glycoprotein synthesized in the liver. Protein C is activated by the thrombin-thrombomodulin complex. Protein C circulates as an inactive precursor and exerts its anticoagulant function after activation to the serine protease, activated protein C. Once activated, protein C proteolytically degrades activated coagulation factors Va and VIIIa. More than 160 qualitative or quantitative mutations in protein C have been described. Protein C is inherited as an autosomal dominant trait affecting both males and females equally. Homozygous persons typically have more severe and earlier-onset thrombophilia.

Two different subtypes of inherited protein C deficiency have been identified. Type I deficiency is a quantitative disorder characterized by parallel reductions in functional and antigenic levels of protein C to 50% of normal levels. Type II deficiency is a qualitative defect with reductions in functional levels of protein C but preserved antigenic function.

The prevalence of protein C deficiency is estimated at 0.2% to 0.4% in the general population and 3% to 5% in people with VTE. Three clinical syndromes are associated with protein C deficiency: (1) VTE in teenagers and adults, (2) neonatal purpura fulminans in homozygous or doubly heterozygous newborns, or (3) warfarin-induced skin necrosis. Acquired protein C deficiency occurs in a variety of clinical settings, including liver disease, infection, septic shock, disseminated intravascular coagulation, acute respiratory distress syndrome, and postoperative states, and in association with chemotherapeutic drugs.

The diagnosis of protein C deficiency should be made by means of functional testing based on activation with thrombin-thrombomodulin or snake venom. Pregnancy and oral contraceptive use can increase plasma protein C levels. Protein C levels are decreased in acute thrombotic events and during therapy with warfarin. In the absence of warfarin therapy and known medical conditions that result in acquired protein C deficiency, patients with a protein C level less than 55% of normal are very likely to have a genetic abnormality, whereas levels from 55% to 65% normal are consistent with either a deficient state or low normal values. Thus, repeat testing and/or genetic testing is recommended in most populations.

Protein S Deficiency

Protein S is a vitamin K–dependent glycoprotein synthesized by hepatocytes, megakaryocytes, and endothelial cells. Protein S functions as a cofactor of activated protein C for the degradation of activated factors Va and VIIIa. Protein S circulates in plasma in equilibrium as a free functionally active form and an inactive form bound to a carrier protein (C4BP). The bioavailability of protein S is closely linked to the concentration of C4BP. C4BP functions as an important regulator in the protein C–protein S inhibitor pathway.

Three subtypes of protein S deficiency have been defined on the basis of total protein S concentrations, free protein S concentrations, and activated protein C cofactor activity. Type I protein S deficiency is associated with approximately 50% of normal protein S levels, more marked decrease in free protein S concentrations, and decreased functional activity. Type II deficiency is characterized by normal total and free protein S levels but decreased functional activity. Type III deficiency, also known as type IIa, is characterized by normal total protein levels but decreased free protein concentrations and decreased functional activity. Conditions that result in reductions in protein C levels, as mentioned in the preceding section, can similarly influence protein S levels. The prevalence of protein S deficiency is estimated to be 0.03% to 0.1% in the general population and 1% to 5% in patients with VTE. The clinical presentation of VTE in patients with protein S deficiency is similar to that in those with protein C deficiency. Warfarin-induced skin necrosis has been reported with protein S deficiency.

Measurement of the free protein S concentration is the preferred screening test for protein S deficiency. As with protein C, acute thrombosis, pregnancy, oral contraceptive use, comorbid disease, or use of warfarin can alter assay results. Heparin does not alter plasma protein S or protein C concentrations and thus is an acceptable antithrombotic agent for use during diagnostic workup. In patients on warfarin therapy, recommendations support waiting at least 2 weeks after discontinuation to investigate for suspected protein S deficiency.

Factor V Leiden and Activated Protein C Resistance

Factor V Leiden is the most common recognized cause of inherited thrombophilia, accounting for 20% to 50% of new VTE cases. Factor V circulates in the plasma as an inactive cofactor. After activation by thrombin, factor Va serves as a cofactor in the conversion of prothrombin to thrombin. In 1993, investigators in Leiden, The Netherlands, identified a single point mutation in the factor V gene in a cohort of patients with unexplained VTE. The molecular defect is a single amino acid change (arginine506 to glutamine) at one of the activated protein C (APC) cleavage sites, making the factor V molecule resistant to activated protein C at this site. The result of this genetic defect, termed factor V Leiden, is the most common cause of inherited APC resistance, although other mutations have been identified. Factor V Leiden is a common mutation. The prevalence of factor V Leiden in the general population is estimated at 5%. People who are heterozygous for the factor C Leiden mutation have approximately a five-fold increase in VTE risk over that in the general population. People who are homozygous for the mutation are estimated to have an 80-fold increase in VTE risk over that in the general population.

The major clinical manifestation of thrombosis in people with factor V Leiden is venous. Thrombosis in the deep veins of the lower extremities is common, whereas involvement of superficial, portal, and cerebral veins is less common. As might be expected with the high frequency of this mutation in the general population, a synergistic effect with other inherited or acquired VTE risk factors has been observed. In addition to inherited APC resistance, acquired APC resistance has been reported. Users of third-generation oral contraceptives, patients with malignancy, and persons with connective tissue disease—in particular, systemic lupus erythematosus and the antiphospholipid antibody syndrome—have APC resistance.

Activated partial thromboplastin time (aPTT)–based assays serve as the screening test for APC resistance. The aPTT is performed in the presence and then absence of a standardized amount of APC, and the two clotting times are expressed as an APC ratio (aPTT in the presence to aPTT in the absence of APC). APC resistance is associated with a reduced APC ratio. Results of the standard aPTT screening test may be influenced by a variety of factors, including inflammatory states, pregnancy, oral contraceptives, antiphospholipid antibodies, and anticoagulation. Genetic testing for the factor V Leiden mutation also is available.

Prothrombin Gene Mutation

Prothrombin (factor II), the precursor of thrombin, is a vitamin K–dependent protein synthesized in the liver. In 1996, researchers identified a single nucleotide change (guanine to adenine) at nucleotide position 20210 in the prothrombin gene as a risk factor for thrombosis. The prevalence of this mutation is 6% to 18% in people with VTE and 2% to 5% in the general population. Heterozygote carriers of this mutation have 30% higher plasma prothrombin levels than normal, which corresponds to a three-fold higher risk of thrombosis over that in the general population. In view of the relatively low thrombotic risk, controversy remains as to whether this mutation confers an increased risk for recurrent VTE. Studies have shown that the estimated risk of thrombosis associated with the prothrombin G20210A mutation is significantly increased only in those persons with additional thrombotic risk factors. Moreover, studies have demonstrated that the prothrombin G20210A mutation often is co-inherited with factor V Leiden mutation. Approximately 1% to 10% of symptomatic factor V Leiden carriers also have the prothrombin G20210A gene mutation. Diagnostic evaluation for the prothrombin G20210A gene mutation is best completed by direct genomic DNA analysis.

Elevated Factor VIII Levels

High levels of factor VIII are a strong independent risk factor for VTE. The prevalence of increased factor VIII levels in the general population is approximately 11%. In up to 25% of people presenting with VTE, factor VIII levels are higher than normal. Research has demonstrated that for each 10% increase in factor VIII levels, the risk of single-episode and recurrent VTE increases by 10% and 24%, respectively. Elevation in factor VIII level has been shown to remain an independent risk factor for VTE with institution of appropriate controls for inflammation, blood group antigens, and von Willebrand factor levels.

Hyperhomocysteinemia

Homocysteine is an intermediary amino acid formed by the conversion of methionine to cysteine. Hyperhomocysteinemia may result from either acquired or heritable factors. Homocysteine is metabolized by means of two pathways. The first involves the cystathionine B-synthase (CBS) enzyme and requires vitamin B6 as a cofactor. The second involves the enzyme methionine synthase and requires both vitamin B12 and methyltetrahydrofolate reductase (MTHFR). Acquired forms of hyperhomocysteinemia may result from dietary deficiencies in vitamin B12 or B6 or folate. Inherited forms may result from genetic defects in the CBS or MTHFR enzymes.

Evidence suggests that hyperhomocysteinemia is a risk factor for VTE. In people with homocysteine levels higher than two standard deviations above normal, the odds ratio for VTE is two to three times greater than in the control groups. Elevated homocysteine levels also have been associated with premature coronary artery disease and cerebrovascular disease, although debate regarding the strength of these associations continues.

Screening for hyperhomocysteinemia is suggested in patients with unexplained VTE. Sensitive laboratory assays are available for the quantification of total plasma homocysteine concentrations. If elevated plasma homocysteine levels are identified, additional laboratory evaluation may be warranted. Treatment varies with the underlying cause but typically involves supplementation with folate and vitamins B12 and B6.

Hypercoagulability Testing

Ongoing research continues to identify new and increasingly prevalent inherited thrombophilic defects in patients with VTE. Thus, which patients to screen, which tests to perform, and when to initiate hypercoagulability testing constitute important questions. Despite the high prevalence of inherited defects, only limited evidence or expert opinion indicates that the identification of an inherited thrombophilia influences either the duration of therapy or risk of recurrence. Arguments for screening acknowledge the increasing prevalence of identified inherited thrombophilias and, with the increase in the discovery of new mutations, the identification of persons with multiple prothrombotic defects. Multiple defects are now found in 1% to 2% of patients with initial-episode idiopathic VTE. Thus, the identification of patients with multiple defects may affect the risk of VTE recurrence, duration of anticoagulation therapy, and/or alteration of management when additional risk factors for the acquired form of VTE are present, such as surgery, pregnancy, or hormonal therapy. Arguments against screening cite the lack of available evidence supporting alteration in anticoagulation management in the presence of hereditary thrombophilia. The 2008 American College of Chest Physicians (ACCP) Antithrombotic and Thrombolytic Therapy Evidence-Based Clinical Practice Guidelines state that “the presence of hereditary thrombophilia has not been used as a major factor to guide duration of anticoagulation in VTE in these guidelines because evidence from prospective studies suggests that these factors are not major determinates of risk of recurrence.” A 2009 Cochrane database study failed to identify a single randomized controlled trial evaluating the benefit of testing for inherited thrombophilia after VTE in relation to risk of recurrent VTE.

Given the lack of available evidence that testing and identifying inherited thrombophilia influences the duration of therapy, VTE outcomes from screening of asymptomatic relatives, or risk of recurrent VTE, current recommendations for screening are based primarily on clinical judgment and expert opinion. Key points to recognize regarding first-episode VTE are that (1) the strongest risk factor for recurrent VTE is a history of VTE—of particular importance if the first VTE event was idiopathic—and (2) all patients with VTE are at increased risk for recurrence for several years after the initial event. In view of current limitations in medical evidence regarding the impact of inherited thrombophilia with respect to duration of therapy and risk of recurrence, consultation with a hematologic expert is recommended regarding individual patient management decisions.

Screening for Inherited Thrombophilia

In general, the following patient groups may be considered for screening: (1) those with a first VTE before the age of 50 years without an identifiable risk factor such as recent surgery, (2) those with a history of recurrent VTE, and (3) those with a first-degree relative with recurrent VTE. All such patients should be considered “strongly thrombophilic” on the basis of thrombotic history and are appropriate candidates for hereditary thrombophilia testing. The standard testing approach to screening for inherited thrombophilias includes appropriate studies to detect activated protein C resistance/factor V Leiden mutation, prothrombin gene mutation, antiphospholipid antibodies, antithrombin deficiency, protein C deficiency, and protein S deficiency.

Several factors must be considered in decisions regarding screening for inherited thrombophilia in patients presenting with VTE. First, acute VTE can transiently reduce plasma levels of antithrombin, protein C, and protein S, resulting in erroneously low levels. Second, treatment with heparin can result in up to a 30% decrease in antithrombin levels over the first several days of therapy. Third, warfarin reduces the functional activity of protein C and protein S and can rarely elevate levels of antithrombin, potentially resulting in falsely normal levels of antithrombin in deficient patients. To sidestep the effects of therapy on measured levels, it is recommended to test for these defects at least 2 weeks after cessation of anticoagulation therapy. If levels are obtained at time of presentation and are within normal limits, then a deficiency generally is excluded. If levels are low at time of presentation, then repeat testing is recommended on cessation of initial therapy. Screening tests for factor V Leiden mutation, prothrombin gene mutation, anticardiolipin antibodies, or antiphospholipid antibodies are not affected by concurrent use of heparin or warfarin therapy. If an inherited thrombophilia is identified, it is recommended to screen all first-degree relatives of the patient.

Management of Inherited Thrombophilia

The initial management of VTE in patients with inherited thrombophilia does not differ from that in other patients. The long-term management of patients with VTE and inherited thrombophilia remains an area of question. Because no randomized controlled trials have evaluated the optimal duration of anticoagulation therapy in inherited thrombophilia, therapy must be tailored to the individual patient. General guidelines suggest indefinite anticoagulation in patients with a history of (1) a single episode of idiopathic VTE in the presence of more than one allelic abnormality (e.g., homozygosity for factor V Leiden, heterozygosity for factor V Leiden and prothrombin mutation), (2) one spontaneous life-threatening thrombosis such as near-fatal PE or cerebral, mesenteric, or portal vein thrombosis associated with a heritable risk factor, or (3) one episode of spontaneous thrombosis in association with antiphospholipid antibody syndrome or antithrombin deficiency. In patients with heterozygosity for inherited thrombophilia and a single episode of idiopathic VTE, the recommended duration of anticoagulation therapy remains in question. Expert consultation is advised to determine the optimum duration of anticoagulation.

Acquired Risk Factors

Acquired risk factors for VTE are far more prevalent than inherited thrombophilias. Box 57-1 lists common risk factors for acquired VTE.

Box 57-1

Acquired Risk Factors for Venous Thromboembolism

Age >40 years

Smoking

Obesity (body weight >120 kg)

Malignancy

Chemotherapy

Oral contraceptive use or hormone replacement therapy

Prolonged immobilization

Hospitalization
Prolonged air travel

Surgery/trauma

Acute inflammatory states

Acute infection
Inflammatory bowel disease
Connective tissuedisease

Intravascular devices

Pacemaker or implantable cardioverter-defibrillator leads
Indwelling venous catheters

Pregnancy/postpartum period

Atherosclerotic cardiovascular disease

Congestive heart failure

Cerebrovascular accident

Previous venous thromboembolism

Varicose veins/venous stasis

Acquired hypercoagulability

Nephrotic syndrome
Lupus anticoagulant
Antiphospholipid antibody syndrome
Hyperhomocysteinemia
Heparin-induced thrombocytopenia

Surgery and Trauma

The risk of VTE among surgical patients can be stratified by patient age, type of surgery, and comorbid conditions. The incidence of VTE in surgical patients is highest for those aged 65 years or older. High-risk procedures include orthopedic surgery; neurosurgery; thoracic, abdominal, or pelvic surgery for malignancy; renal transplantation; and cardiovascular surgery. The risks from surgery may be less with neuraxial anesthesia than with general anesthesia.

The association between trauma and VTE has long been recognized. As with surgical risks, the risk of VTE after trauma is related to predisposing host factors; the location, nature, and extent of injuries; and the use of prophylaxis. The risk of VTE in trauma victims is highest with advancing age. Injuries involving the lower extremities or pelvis confer the highest VTE risk. Other VTE risk factors associated with trauma include spinal cord injuries with paralysis, head injuries, vascular injuries, circulatory shock on hospital admission, requirement for mechanical ventilation for longer than 3 days, and the need for a major surgical procedure.

Age

The incidence of VTE increases significantly with advancing age for both idiopathic and secondary forms of the condition, suggesting that the biology of aging and not simply an increased accumulation of VTE risk factors may be involved. In one study, the annual incidence rates for VTE increased from 17 per 100,000 persons for patients 40 to 49 years of age to 232 per 100,000 persons for patients 70 to 79 years of age.

Pregnancy

Pregnancy is associated with increased risk for VTE as a consequence of the hypercoagulability associated with this condition, as well as the increased resistance to venous return by compression from the gravid uterus. VTE will develop in approximately 1 in 2000 women during pregnancy. Age-adjusted estimates of the risk of VTE range from 5 to 50 times higher in pregnant than in nonpregnant women. The risk in the postpartum period is approximately five times higher than during pregnancy. Previous superficial vein thrombosis is an independent risk factor for the occurrence of venous thrombosis during pregnancy and in the postpartum period.

Hormone Replacement Therapy

Hormone therapy is associated with a two- to four-fold increased risk of VTE. The risk of thrombosis increases within 4 months of the initiation of therapy and is unaffected by the duration of use. The VTE risk decreases to baseline levels within 3 months of discontinuation of hormone therapy. First- and third-generation oral contraceptives carry a higher risk for VTE than that reported with second-generation agents. Therapy with selective estrogen receptor modulators, including tamoxifen and raloxifene, has been associated with increased rates of VTE.

Cancer

Malignancy accounts for approximately 20% of cases of incident VTE in the community. Many primary malignancies are associated with VTE. Risk for VTE in patients with cancer seems highest among those with pancreatic cancer, lymphoma, malignant brain tumors, hepatocellular carcinoma, leukemia, colorectalcarcinoma, and other digestive cancers. Furthermore, the use of certain chemotherapy regimens in patients with cancer, including thalidomide, tamoxifen, and L-asparaginase, is associated with higher VTE risk.

Obesity

Emerging evidence supports obesity as an independent risk factor for VTE. The relative risk of VTE for obese people is greater in women than in men, with the greatest effect being noted before the age of 40 years. In addition to its role as an independent risk factor in the context of VTE, obesity is a common contributing factor for VTE occurring in people undergoing long-duration air travel and in women concomitantly taking oral contraceptives or hormone replacement agents.

Previous Venous Thromboembolism

Previous VTE is a major risk factor for recurrence. The magnitude of the risk depends on host factors. Persons with reversible risk factors such as immobility or surgery exhibit a lower rate of recurrence than that noted for those with nonmodifiable risk factors, such as malignancy or inherited thrombophilia.

Heparin-Induced Thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is a life-threatening disorder that follows exposure to unfractionated (UF) or, less commonly, low-molecular-weight heparin (LMWH). HIT classically manifests with a low platelet count (less than 150,000/μL) or a relative decrease in platelet count by 50% from baseline typically within 5 to 10 days of the initiation of heparin or LMWH therapy. The incidence of HIT among patients treated with UF heparin is 10 times higher than among those receiving LMWH. In patients with HIT, the risk of thrombosis is more than 30 times that in the control population. The risk of thrombosis remains high for days to weeks after discontinuation of heparin, even after the platelet counts return to normal.

HIT is caused by antibodies against complexes of platelet factor 4 (PF4) and heparin. The heparin-PF4–antibody complex binds to the platelet surface, where it is recognized by circulating IgA, IgG, and IgM antibodies. Immunoglobulin recognition leads to further platelet activation and release of PF4, thus creating a positive feedback loop. The activated platelets aggregate, resulting in thrombocytopenia and thrombosis. Early-onset HIT, defined as that with onset within hours after initiation of heparin therapy, may be seen in approximately 30% of patients with persistent antibodies to heparin if such therapy is given within the previous 3 months. Diagnosis of HIT is based on recognition of the clinical syndrome and specific serologic testing. Serologic assays can detect circulating IgG, IgA, and IgM heparin-dependent antibodies with high sensitivity (97%) but modest specificity (74% to 86%). Therefore, positive results on serologic assays must be confirmed by more specific tests, including serotonin release assays, heparin-induced platelet aggregation assays, or solid phase immunoassays.

The first intervention in a patient with suspected HIT is immediate cessation of all exposure to heparin, including heparin-bonded catheters and heparin flushes. LMWH should be avoided, because it may cross-react with heparin-induced antibodies. In addition to heparin cessation, patients with suspected HIT should be started on alternative anticoagulation because of high risk of thrombosis. In patients with suspected HIT and/or the need for alternative anticoagulation, direct thrombin inhibitors such as lepirudin or argatroban may be used. The duration of alternative anticoagulant therapy and the subsequent use of oral anticoagulants will depend on whether the patient has had a thrombotic event or requires continued anticoagulation. For patients with HIT without evidence of thrombus, therapeutic doses of alternative anticoagulation should be continued until the platelet counts return to normal. Consideration should be given to continuing anticoagulation therapy with alternative anticoagulation or warfarin for 2 to 4 weeks after the diagnosis of HIT, because of persistent high risks of thrombosis over this period. For a patient with HIT and thrombosis, therapeutic doses of alternative anticoagulation should be continued until the platelet count has normalized; then the patient should be transferred to warfarin therapy with at least a 5-day overlap until the international normalized ratio (INR) is in the therapeutic range for at least 48 hours. Skin necrosis and warfarin-induced venous gangrene of the limbs have been reported during shorter periods of overlap or shorter duration of therapeutic INR.

Pathogenesis

Between 60% and 90% of pulmonary emboli arise from the deep veins of the lower extremity and pelvis. Other sources of thrombi include the renal veins, upper extremities, or right side of the heart. Iliofemoral thrombi are the most frequently clinically recognized causes of PE. Thrombi dislodge and embolize to the pulmonary arteries, where they cause hemodynamic abnormalities and impair gas exchange. The hemodynamic response to PE is determined by the embolic burden in association with the host’s hemodynamic reserve and compensatory adaptive response. After traveling through the right heart, large thrombi may lodge and obstruct the main pulmonary arteries or travel distally within the pulmonary vascular tree, leading to hemodynamic alterations. In addition to the physical obstruction to flow, acute PE triggers the release of vasoactive substances, resulting in further increase in pulmonary vascular resistance and right ventricular afterload. Because right ventricular afterload increases, increased right ventricular wall tension may lead to right ventricular dilatation and hypokinesis with further right ventricular dysfunction, tricuspid regurgitation, and right ventricular failure. Right ventricular pressure overload can lead to flattening or bowing of the interventricular septum toward the left ventricle with resulting impairment of left ventricular filling, systemic arterial hypotension, and cardiac arrest. Increased right ventricular wall stress caused by right ventricular pressure overload may also lead to right-sided stress-induced ischemia.

Impaired gas exchange may result from impaired ventilation-perfusion matching, increased alveolar dead space, or right-to-left shunting through a patent foramen ovale. Stimulation of pulmonary irritant receptors results in hyperventilation, contributing to the observed hypocapnia and respiratory alkalosis. The presence of hypercapnia in acute PE suggests a large amount of physiologic dead space and impaired minute ventilation, which can result from massive PE.

Clinical Features

The clinical consequences of PE range from incidental and clinically unimportant to circulatory collapse and sudden death. Equally challenging, the clinical signs and symptoms related to PE are diverse and nonspecific. Therefore, clinicians use a combination of history and examination findings in association with clinical prediction tools to determine appropriate diagnostic tests and the need for therapeutic interventions. Considerations in the differential diagnosis for acute PE are listed in Box 57-2.

Box 57-2

Differential Diagnosis for Acute Pulmonary Embolism

Pneumonia or bronchitis

Asthma or exacerbation of chronic obstructive lung disease

Pleuritis

Pericarditis/cardiac tamponade

Pneumothorax

Musculoskeletal pain

Costochondritis

Rib fracture

Pulmonary edema/congestive heart failure

Thoracic malignancy

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