Pulmonary Embolism

ByEman mahmoud

M.D of chest diseases

Pulmonary Embolism

• Embolism : Impaction of a thrombus or foreign matter in the pulmonary vascular bed.

Epidemiology

• 2nd most common cause of unexpected death in most age groups.

• present in 60-80% of patients with DVT, more than 50 % them are asymptomatic.

• Account for 15 % of all postoperative deaths

• it is estimated that in the USA .100 000 people• die each year of pulmonary embolism.

• .

• Thrombotic

• Non-thrombotic : Fat, Air, Tumour , Amniotic fluid.

EMBOLUS

RISK FACTORS• Bed rest• Post-operative• After severe blood

loss and trauma• COPD• CHF• Varicose veins• Advancing age

• Obesity• Post-partum• Malignancy• Travel of 4 hours or

more • Smoking• 1ry polycythemia• Oral contraceptives

THROMBOPHILIA

• Acquired thrombophilia•• Inherited thrombophilias

Hereditary factors

• Antithrombin III deficiency• Protein C deficiency• Protein S deficiency• Factor V Leiden (most common genetic

risk factor for thrombophilia)• Plasminogen abnormality• Plasminogen activator abnormality• Fibrinogen abnormality• Resistance to activated protein C

Acquired thrombophilia

• This is mostly associated with the antiphospholipid syndrome (APS).

• APS is the combination of (LAC) with or without, (ACA), with a history of recurrent miscarriage and or thrombosis.

Pathophysiology

Clinical Features• Size of the embolus and blood vessel occluded.

• State of the lung.

• Associated disease(s).

PE, Clinical Features

•dyspnea (75–85%)

• Pleuritic chest pain (57–87%)

• cough (40–53% )

• Hemoptysis

• Syncope.

Massive Pulmonary Embolism MPE

•collapse/hypotension

•unexplained hypoxia

•engorged neck veins

•Acut right heart failure

Physical Signs• Normal• Tachypnea (respiratory rate >16/min) - 96%• Rales - 58%• Accentuated second heart sound - 53%• Tachycardia (heart rate >100/min) - 44%• Fever (temperature >37.8°C) - 43%• Diaphoresis - 36%• S3 or S4 gallop - 34%• Clinical signs and symptoms suggesting thrombophlebitis -

32%• Lower extremity edema - 24%• Cardiac murmur - 23%• Cyanosis - 19%

Clinical Probability of PE

D-Dimer• Degradation product produced by plasmin-mediated

proteases of cross-linked fibrin.

• Blood D-dimer assay should only be considered following assessment of clinical probability.

• D-dimer assay should not be performed in those with high clinical probability of PE.

D-dimer

.Highly sensitive assays, such rapid ELISA assays, have high false positive rates but safely rule out VTE in outpatients presenting with a low clinical probability of PE. • A negative D-dimer test reliably excludes PE in

patients with low clinical probability; such patients do not require imaging for VTE.

Ischemia-Modified Albumin levels

• A potential alternative to D-dimer testing is assessment of the ischemia-modified albumin (IMA) level.

• 93% sensitive and 75% specific for pulmonary embolism

•  The positive predictive value of IMA, in particular, is better than D-dimer. However, it should not be used alone.

Chest x-ray

• 14% Normal • 68% Atelectasis • 48% Pleural Effusion • 35% Pleural based opacity • 24% Elevated diaphragm • 15% Prominent central pulmonary artery • 7% Westermark’s sign • 7% Cardiomegaly • 5% Pulmonary edema

Elevated L H.Diaph

Decreased vascularity (Westermark sign)

(Hampton hump)

• The classic radiographic findings of pulmonary infarction

• a wedge-shaped, pleura-based triangular opacity with an apex pointing toward the hilus

Atelectic band

cardiac troponins

• Recently, cardiac troponins I and T have been shown to be associated with early mortality and a complicated hospital course in patients with PE.

The assessment of cardiac plasma troponin levels revealed ventricular injury, especially in patients with massive PE who had hypotensionor shock.

B Natriuretic Peptide (BNP)

• BNP is a neurohormone secreted from the cardiac ventricles in response to dilatation or an increase of pressure.

• BNP levels may increase with right ventricle dysfunction when the patients is in bed and decrease with treatment.

• Serum brain natriuretic peptide levels of > 90 pg/mL have a sensitivity of 85% and a specificity of 75% for predicting adverse clinical outcomes

Arterial blood gases

• Blood gases may increase the suspicion and

contribute to the clinical assessment, but they are insufficient to permit proof or exclusion of PE.

ECG

• In minor pulmonary embolism, the only finding is sinus tachycardia.

• In massive pulmonary embolism, evidence of right heart strain may be seen (rightward shift of the QRS axis, transient RBBB, T-wave inversion, SIQIIITIII pattern, P- pulmonale), but these signs are non-specific.

The main value of ECG is exclusion other diagnoses, such as MI or pericarditis.

S1 Q3 T3 Pattern

Echocardiography

•RV dilatation •RV size does not change from diastole to systole = hypokinesis •D-shaped LV •40% of pts have RV abnormalities seen by ECHO

Echocardiography

• Transthoracic echocardiography rarely enables direct visualisation of the pulmonary embolus but may reveal thrombus floating in the right atrium or ventricle.

• Transoesophageal echocardiography, it is possible to visualise massive emboli in the central pulmonary arteries.

Lower extremity venous ultrasonography

Advantages Portability May avoid further diagnostic imaging if positive

Limitations Low sensitivity and risk of false positives No consistent protocol for technique Operator dependant

Venous Ultrasonography

Recommendations of Use •First-line if radiographic imaging contraindicated or not readily available

•Not likely required in patient with negative CT-PA.

•Helpful to rule out DVT in patient with non-diagnostic V/Q scan.

Lung scintigraphy

• The lung scan is an indirect method of diagnosis since it does not detect the embolus itself but only its consequence, the perfusion abnormality.

• Used when CT scanning is not available or if the patient has a contraindication to CT scanning or intravenous contrast material.

The Lung Scan Perfusion Perfusion

• IV injection of human serum albumin labelled w/ technetium-99m •Particles are same size as pulmonary capillaries and become trapped •Lung peripheral to a clot is not perfused and will show defect

Ventilation: •Inhalation of xenon-133 radioactive gas •Degree of ventilation of all lung areas can be assesed •Pneumonia, emphysema, tumors can cause defects •Pulmonary embolism does not cause ventilation defect

Patients w/ a perfusion defect w/out a ventilation defect is suggestive of a pulmonary embolus.

Presence of several large focal perfusion defects not matched by ventilation defects indicates a high probability of PE !!!!!

Normal scan basically excludes PE and indicates for other explanations for the pts condition.

High probability – start Rx.

Low probability – withhold Rx – can do CT / angiogram. Intermediate probability – can do CT / angio

VQ Scan results

V/Q Scan

Advantages Excellent negative predictive value (97%) Can be used in patients with contraindication to contrast medium Limitations 30-50% of patients have non-diagnostic scan necessitating further investigation

CTPA• CTPA studies using the multislice technique

showed a high sensitivity (96 to 100%) and specificity (97 to 98%),

• CTPA is now the recommended initial lung imaging modality for non-massive PE.

• Patients with a good quality negative CTPA do not require further invest. or ttt for PE.

BTS (2003)

Multidetector helical CT pulmonary angiography

Diagnosis of alternative disease entities

Coverage of entire chest with high spatial resolution in one breath hold Availability

Improved depiction of small peripheral emboli

Advantages

Multidetector helical CT pulmonary angiography – Limitations

Reader expertise required Expense Requires precise timing of contrast bolus Radiation exposure Not portable Contraindications to contrast Renal insufficiency the radiation dose from 3 to 5 mSv, with an estimated cancer risk of 150 excess cancer deaths per million

Multidetector-CT Findings

Partial or complete filling defects in lumen of pulmonary arteries Most reliable sign is filling defect forming acute angle with vessel wall with defect outlined by contrast material “polo mint” sign “Tram-track sign” Parallel lines of contrast surrounding thrombus in vessel that travels in transverse plane “Rim sign” Contrast surrounding thrombus in vessel that travels orthogonal to transverse plane a right-to-left ventricular dimensional ratio of 0.9 or more at MDCTA, had 92% sensitivity for right ventricular dysfunction

“railway track” sign on longitudinal images of the vessel 

Arterial occlusion with failure to enhance the entire lumen due to a large filling defect

A peripheral intraluminal filling defect that forms acute angles with the arterial wall

A partial filling defect surrounded by contrast material, producing the “polo mint” sign on images acquired perpendicular to the long axis of a vessel

a peripheral, crescent-shaped intraluminal defect that forms obtuse angles with the vessel wall 

Pulmonary Angiography• Was traditionally regarded as the reference test for PE. • Due to the invasive character, including right heart

catheterization and injection of contrast material.

• The current availability of noninvasive diagnostic imaging catheter pulmonary angiography now has an insignificant role.

Magnetic resonance angiography (MRA)

MRA appears promising & avoids ionising radiation but has poor sensitivity for subsegmental clot.

Further Alternative Imaging Tests

• Dual-energy CTPA

• Electrocardiographically gated CTPA

• Three-dimensional images acquired by single-photon emission computed tomography (SPECT) using a gamma-emitting radioisotope may improve V/Q scintigraphy and has a lower radiation dose.

Dual-energy CTPA

Provides functional and anatomic lung imaging Demonstrates perfusion defects beyond obstructive and non-obstructive clots Diagnostic accuracy requires further research Advantages Indirect evaluation of peripheral pulmonary arterial bed Disadvantages Longer data acquisition time Increased radiation exposure

Dual-energy CTPA

[A] Axial reconstruction with color-coded dual energy perfusion information. Note the large perfusion defects in both lungs.

[B] Coronal reconstruction. Only the apical parts show a normal perfusion.

Electrocardiographically gated CTPA

• can differentiate between cardiac events and PE • may be of use in patients presenting with thoracic pain and

suspected PE, cardiac events, or aorta dissection.

• More contrast material is needed, and the radiation dose is higher compared with CTPA.

Three-dimensional images

• Single-photon emission computed tomography (SPECT) using a gamma-emitting radioisotope may improve V/Q scintigraphy

• lower radiation dose.

Low dose MDCT

using ultra high pitch technique Useful in patients who are unable to hold their breath

Treatment

• For acute PE, the ACCP guidelines recommend starting low–molecular weight heparin (LMWH) or fondaparinux, preferred over unfractionated heparin (UFH) or subcutaneous heparin

• Patients should have an oral anticoagulant (warfarin) initiated at the time of diagnosis, and they should have UFH, LMWH, or fondaparinux discontinued only after the international normalized ratio (INR) is 2.0 for at least 24 hours but no sooner than 5 days after warfarin therapy has been started

Heparin

• The initial treatment of PE is LMWH or UHF for at least 5 days, followed by warfarin.

• Dose of UFH: 80 U/kg/h bolus followed by18 U/kg. Monitoring by APTT(1.5-3)times normal.

• It binds to endogenous antithrombin, This heparin - antithrombin complex catalyzes the inactivation of factor Xa and IIa (thrombin).

Heparin

• Adverse drug reactions include bleeding, heparin-induced thrombocytopenia, and osteoporosis .with prolonged use .

• A platelet count should be obtained weekly for the first month. If there is an abrupt decrease in the platelet count (approx. 50%) or by skin lesions at heparin injection sites or acute systemic reactions (eg, chills, cardiorespiratory distress) after IV heparin bolus administration consideration must be given to the possibility of (HIT).

LMWH

.

• It should be used whenever possible for the initial inpatient treatment of DVT & PE.

• Outpatient ttt of DVT, and possibly PE,is safe and cost-effective for carefully selected patients.

Oral anticoagulant

Warfarin inhibits gamma-carboxylation of the vitamin K-dependent coagulation factors II, VII, IX, and X.

Warfarin and heparin can be started on the same day, but concomitant administration of these drugs for 4 or 5 days is recommended.

Oral anticoagulant

• Warfarin also inhibits carboxylation of natural anticoagulant proteins C and S resulting in a rapid decline of their levels. This poses a theoretical risk for a venous thromboembolic events.

• Starting the patient on the expected daily dose (eg, 5mg) rather than administering a loading dose can minimize potential bleeding and avoid an extreme decline in protein C.

• Target international normalised ratio [INR], 2.0–3.0) for at least 3–6 months.

Factor Xa inhibitors

• Rivaroxaban (Xarelto) is an oral factor Xa inhibitor approved by the FDA in November 2012 for the treatment of DVT or PE.

• Reduce risk of recurrent DVT and PE following initial treatment.

• Associated with less bleeding, particularly in elderly patients and those with moderate renal impairment.

Factor Xa inhibitors

• Apixaban was approved for treatment of PE in August 2014.

• This advance thus offers the prospect of a safe and effective regimen of anticoagulation for patients with the advantages of simplicity and cost-effectiveness in comparison to current management strategies.

Fondaparinux

• In patients with acute PE, favored over IV UFH and over SC UFH

• Once-daily fondaparinux was found to be similar as IV UFH.

• Synthetic polysaccharide derived from the antithrombin binding region of heparin. Catalyzes factor Xa inactivation by antithrombin without inhibiting thrombin.

Direct Thrombin Inhibitors

Argatroban (Novastan

approved in 2000: Anticoagulant for pts with HIT needing prophylaxis or treatment for thrombosis

Ximelagatran (Exanta) • have shown benefit over warfarin or LMWH

)

Duration of anticoagulation • A patient with a first thromboembolic event occurring in the

setting of reversible risk factors, should receive warfarin therapy for at least 3 months.

• The current ACCP guidelines recommend that all patients with unprovoked PE receive three months of treatment with anticoagulation and have an assessment of the risk-benefit ratio of extended therapy at the end of three months .

patients with a second unprovoked episode of venous thromboembolism and low or moderate risk of bleeding, extended anticoagulant therapy is recommended

Patients who have pulmonary embolism and preexisting irreversible risk factors should be placed on long-term anticoagulation.

Heparin-induced thrombocytopenia (HIT)

• Transient prothrombotic disorder initiated by heparin.

• The main features of HIT are (1) thrombocytopenia (2) increased risk of venous and arterial thrombosis.

• The highest frequency , 5%, has been reported in post–orthopedic surgery patients receiving up to 2 weeks of unfractionated heparin

Heparin-induced thrombocytopenia (HIT)

• should be suspected whenever the patient's platelet count falls to less than 100,000/µL or less than 50% of the baseline value

• The treatment stop all heparin products, initiate an alternative, nonheparin anticoagulant, even when thrombosis is not clinically apparent. the use of lepirudin, argatroban, or danaparoid is preferred over continued use of heparin, LMWH, or either initiation or continuation of a vitamin K antagonist

Thrombolytic Therapy

Thrombolytic Therapy • The ACCP guidelines recommend that thrombolytic therapy

should be used in • patients with acute PE associated with hypotension (systolic

BP< 90 mm HG) who do not have a high bleeding risk .

• select patients with acute PE not associated with hypotension and with a low bleeding risk whose initial clinical presentation or clinical course after starting anticoagulation suggests a high risk of developing hypotension

• Tissue plasminogen activator (tPA) has a short infusion time and has been recommended as the best agent for this reason.

Major contraindications

•A history of intracranial hemorrhage •Known intracranial aneurysm or arteriovenous malformation •Significant head trauma •Active internal bleeding •Known bleeding diathesis •Intracranial or intraspinal surgery within 3 months •A cerebrovascular accident within 2 months.

Relative contraindications :

•Recent internal bleeding •Recent surgery or organ biopsy •Uncontrolled hypertension •Pregnancy •Age 75 years

Pulmonary Embolectomy

Surgical embolectomy rarely done. It should be reserved for pts with hemodynamic instability despite heparin and cardiopulmonary support, who either fail thrombolytic therapy or have a contraindication to it.

Catheter-Based Thrombus Removal for the Initial Treatment of Patients

With PE

In patients with acute PE associated with hypotension and who have (i) contraindications to thrombolysis, (ii) failed thrombolysis, (iii) shock that is likely to cause death before systemic thrombolysis can take effect (eg, within hours).

if appropriate expertise and resources are available, we suggest catheter-assisted thrombus removal over no such intervention

Vena Cava Filters

indicated in the following settings:

• Patients with acute venous thromboembolism who have an absolute contraindication to anticoagulant therapy

• Patients with massive PE who survived but in whom recurrent embolism invariably will be fatal

IVC filter

• Pregnancy increases the risk of VTE 4-fold to 5-fold over the nonpregnant state.

• Overall, the prevalence of VTE in pregnancy is 0.5-2.0 per 1,000 pregnancies .

• PE is one of the commenest cause of maternal death in pregnancy

• accounts for 1.1 deaths per 100,000 pregnancies.

Pulmonary embolism In Pregnancy

Pulmonary embolism In Pregnancy

AETIOLOGY• Increase in the levels of coagulation factors

VII, VIII, IX, and X.• Increased fibrinogen levels.• Increased platelet activation.• increases resistance to the anti-thrombotic

factors such as protein C and protein S. 

• Venous stasis in the lower limbs due to pressure by the gravid uterus

Risk factors for DVT / PE during pregnancy

• Maternal age > 35 years. • Pre-pregnancy weight > 80 kg.• Pre-existing Thrombophilia. • Previous DVT. • Severe varicose veins (V.Vs). • Prolonged bed rest.• Multi foetal pregnancies. • Severe pre-eclampsia.• Caesarean section delivery.

Laboratory Evaluation D-dimer

• Pregnancy limits the usefulness of this test.

• Studies indicate that d-dimer values increase with gestational age, making the d-dimer test less specific.

•  Nonetheless, it remains a test with good negative predictive value in pregnancy.

Imaging for PE• If at initial presentation a patient has

concomitant symptoms or signs consistent with DVT and PE, compression ultrasonography may be considered first.

• A negative compression ultrasonography of lower extremity veins however does not exclude PE.

• If clinical suspicion still exists, further chest imaging is necessary.

A chest radiograph

•Recommended prior to the evaluation for PE to define other etiologies that may explain the symptoms (eg, pneumonia, atelectasis) and define the appropriate next imaging test.

• Two alternative radiologic modalities exist for diagnosis of PE are spiral CT pulmonary angiography (CT-PA) and ventilation-perfusion (V/Q) scan.

• In the pregnant patient with no known pulmonary disease and a normal chest radiograph,ventilation-perfusion scan is the recommended study to evaluate for PE.

• If the patient has an abnormal chest radiograph or known pulmonary disease, spiral CT pulmonary angiography is recommended.

CTPA versus V/Q scan • Spiral CT scanning and V/Q lung/can be safely performed in all

trimesters. • Fetal radiation exposure for CTPA varies from 0.03

mGy to 1.3 mGy; increased with gestation and enlarged gravid uterus

• - Fetal radiation dose for V/Q scanning is estimated as 1–3.7 mGy

• The risk of abnormality is considered to be negligible at ≤ 5 rads (50 mGy) and the risk of malformations is increased at doses > 15 rads (150 mGy).

•British Journal of Radiology,2006 (79):441-444

• - ESC (2008): Guidelines on the diagnosis and management of acute pulmonary embolism

CTPA versus V/Q scan CTPA •More sensitive and specific •Short acquisition time, easy access and interpretation • Lower radiation dose to the fetus (<10% of that with V/Q scanning) • Identify other pathology: aortic dissection.• Iodinated contrast medium can potentially alter fetal or neonatal

thyroid function.V/Q scan - Not suitable if there is X-ray abnormalities or other chest disease as asthma or COPD - High incidence of indeterminate scans - Advantage over CTPA: Less radiation to maternal breast

Treatment• Heparin, both low molecular weight and unfractionated does not

cross the placenta or the breast. It is therefore safe for the fetus and for the breast-fed infant.

• warfarin, cross the placenta In the first trimester warfarin

• UFH, LMWHs, and warfarin are not secreted in breast milk in clinically significant amounts, and so are safe for use in breast-feeding patients. So after labour oral anticoagulant can be introduced

Duration of therapy•A pregnant patient with a DVT or PE should be anticoagulated for the duration of the pregnancy and at least six weeks postpartum, or for six months, whichever is longer

• Subcutaneous LMWH is preferred over IV UFH or SC UFH in most patients .

• UFH (either IV or SC) is preferred over SC LMWH in patients who have severe renal failure.

Labor and delivery

• Treatment with SC LMWH should be discontinued at least 24 hourPrior to delivery if the delivery time is predictable .

• A period of 24 to 36 hours without anticoagulant therapy may be undesirable in pregnant women who are at high risk for recurrent VTE (eg, those with an acute PE or proximal DVT that developed within the past month).

• Such patients may benefit from having their SC LMWH or SC UFH switched to IV UFH, which can be discontinued 4 to 6 hours prior to delivery .

Postpartum

• Anticoagulation may be restarted with UFH or LMWH 4-6 hours following vaginal delivery or 6-12 hours following cesarean delivery.

•  If neuraxial blockade was used, prophylactic anti-coagulation should not be restarted any sooner than 2 hours following epidural removal.

•  Although the ideal time to restart therapeutic anticoagulation following epidural removal is unclear, waiting 12 hours after removal of the epidural may be a reasonable approach

. Streptokinase (and probably other thrombolytic drugs) does not cross the placenta because of its high molecular weight.

• However in the mother, bleeding is the major side effect, usually from the genital tract and often severe.incidence of bleeding is about 8%.

• Because of the risk of bleeding, thrombolysis should not be used routinely in pregnancy,

• Should not be used at the time of delivery unless it appears that the patient is likely to die

Thrombolytic agents in pregnancy

Malignancy• Four- to sevenfold higher risk of thrombosis compared with

patients without cancer,

• caused by prothrombotic effects of the tumor and also because of treatment, particularly with surgery, use of a central venous catheter, and chemotherapy.

• ~20% of patients presenting with VTE have active cancer, associated with reduced survival.

• Value (specificity) of D-dimer testing is reduced, leading to an increased need for imaging.

Malignancy• initial treatment with heparin and warfarin is given in the

standard manner.

• The relative risk of recurrence is 3 and of bleeding is 6 compared with other

• Duration of treatment is arbitrary.

• For those with recurrence in spite of adequate anticoagulation,options include: (a) aiming for a higher INR of 3.0–3.5 (which further increases the risks of bleeding)(b) switching to longterm LMWH while continuing anticoagulation, (c) insertingan IVC filter, the value of which is questionable.307

Patients with liver cirrhosis

• Characterized by decreased synthesis of both pro- and anticoagulant factors.

• Although bleeding is the most common clinical manifestation as a result of decreased platelet function and number, diminished clotting factors and excessive fibrinolysis,

• Hypercoagulability may play an under recognized but important role in many aspects of chronic liver disease.

• Particular patients with cirrhosis appear to have a higher incidence of DVT and pulmonary embolism(PE) compared with the general population.

• The incidence of DVT/PE ranges from 0.5% to 1.9%, similar to patients without comorbidities, but lower than patients with other chronic diseases (i.e, renal or heart disease).

• Serum albumin level was independently associated with the occurrence of thrombosis

• Cirrhotic patient should not be considered as an auto-anticoagulated patient.

Liver disease as a risk DVT/PE

• Patients w autoimmune liver disease have a higher incidence of portal vein thrombosis

• Cholestatic liver disease are characterized by a hypercoagulable state .

• patients with non-cirrhotic liver disease are at greater risk of DVT/PE.

• Non-alcoholic fatty liver disease have been associated with a great risk of atherosclerosis and endothelial dysfunction

•

Liver disease as a risk DVT/PE

• Patients with hepatocellular carcinoma are known to be at greater risk of thrombo embolic complications (i.e. portal vein thrombosis and PE), and increased levels of thrombin–antithrombin complexes have been demonstrated.

Risk factors for DVT/PE

• Same risk factors as other non-cirrhotic patients such as venous stasis, infection, congestive heart failure, acute respiratory disease and immobilization.Surgery .

• liver resection such as for hepatocellular carcinoma has been shown to correlate with a higher incidence of thrombotic complications.

Thrombotic prophylaxis

• Current American College of Chest Physicians (ACCP) guidelines for thrombo prophylaxis in patients with important risk factors for bleedings state: ‘for medical patients with risk factors for VTE, and for whom there is a contraindication to anticoagulant thromboprophylaxis, we recommend the optimal use of

mechanical thromboprophylaxis with graduated compressionstockings or intermittent pneumatic compression.

• The statement has the maximum grade of evidence and strength of recommendation,

• Current guidelines on antithrombotic prophylaxis do not specifically comment on the cirrhotic population as a result of the perceived risk of bleeding complications

• Thromboprophylaxis should be recommended in patients with liver cirrhosis at least when exposed to high-risk conditions for thrombotic complications.

• Low molecular weight heparins (LWMHs) seem to be

relatively safe in this group of patients.

• when important risk factors for bleeding are present, graduated compression stockings or intermittent pneumatic compression should be considered.

• Disadvantage of the use of LMWH and fondaparinux inpatients with cirrhosis, is the unpredictable efficacy, as these drugs require antithrombin to exert its anticoagulant function, and antithrombin levels are frequently decreased in these patients.

• The use of antithrombotic agents, directly inhibiting factor (F)Xa or thrombin, will need very careful evaluation in this subset of patients due to the risk of haemorrhagic complications.

• The FXa inhibitors rivaroxaban and apixaban are metabolized in the liver and they are contraindicated in severe hepatic disease

• Idraparinux, an antithrombin dependent FXa inhibitor, has no hepatic clearance,but its long half-life (approximately 80 h) and the lack of antidote do represent major problems if bleeding occurs.

• Finally, all these drugs must be used with caution or are contraindicated in the presence of renal failure.