VTE Prophylaxis

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VTE Prophylaxis May-Thurner syndrome Thoracic outlet obstruction, Paget-Schroetter syndrome, Pancoast syndrome

Spectrum of conditions Deep vein thrombosis Phlegmasia (venous gangrene) Pulmonary embolism Superficial thrombophlebitis Post-thrombotic syndrome Recurrent VTE Chronic pulmonary hypertension Paradoxical embolism

DVT • consider unusual causes when this occurs in unusual sites

- mesenteric: thrombophilia, malignancy, pancreatitis - renal vein: tumour extension, nephrotic syndrome - ovarian vein: post-partum - cerebral

Phlegmasia • massive venous thrombosis with significantly compromised venous outflow • triggered by malignancy and hypercoagulable syndromes • limb feels warm despite gangrene

Pulmonary embolus • large emboli (5%)

- lodge in main pulmonary artery or astride the bifurcation (saddle embolus - leads to haemodynamic compromise, cardiac arrest and sudden death due to vascular

obstruction and reflex vasoconstriction • middle-sized emboli (20-35%)

- occlude moderate-sized peripheral PA branches usually inducing infarction • small emboli (60-80%)

- clinically silent - transient chest pain and sometimes haemoptysis due to intra-alveolar haemorrhage

• multiple small - over or covert produce chronic cor pulmonale and pulmonary hypertension

Superficial thrombophlebitis • can occur in:

- varicose veins: usually benign - non-varicose veins

‣ lines, malignancy (Trousseau’s sign) ‣ thrombophilia (~40%), Buerger’s disease

• no embolic risk if only superficial veins involved • 5-40% incidence of associated DVT

- direct extension in ~10% - non-contiguous: ipsilateral/contralateral

• STP extent more proximal than clinically apparent • monitor deep communications with duplex if not anticoagulated Treatment • symptomatic relief: compression, NSAIDs, local ointments, lance and express haematoma • anticoagulation • SFJ ligation • antibiotics if concerned re infection

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Post-thrombotic syndrome • long lag-phase to onset, although symptoms can arise early • symptoms: ache (bursting in character), oedema, pigmentation 2º to haemosiderin deposition,

venous eczema, lipodermatosclerosis, ulceration, inverted champagne bottle leg appearance, varices

• incidence following DVT - 30% of patients following DVT - 30% of these severe - more proximal DVT, more likely to develop PTS

‣ tibioperoneal <15% ‣ femoropopliteal 40% ‣ iliofemoral >60%

Chronic pulmonary hypertension • 0.1 to 0.5% of PE survivors, presents late • progressive exertional dyspnoea and exercise intolerance; then chest pain on exertion, presyncope

or syncope, bruits over lung fields • low survival, which is proportional to the degree of pulmonary hypertension at time of diagnosis

Paradoxical embolism • embolus arising from DVT to arterial circulation • represents 2% of arterial emboli • requires cardiac opening: ASD, VSD or PFO

VTE Risk factors • Virchow’s triad

• acute triggers: immobility, trauma, surgery, hormonal use • chronic acquired medical conditions: malignancy, obesity, age, APL syndrome • constitutional thrombophilia

• persistent - acquired: age, history of VTE, malignancy, APL antibodies - genetic: thrombophilia

• transient: surgery (highest in hip and knee replacement), immobilisation, pregnancy, oral contraceptives, HRT

Identifying the patient at risk of DVT

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Week number + TopicThrombophilia • consider in patients with:

- unexplained thrombotic episode at age <40 years - recurrent DVT or arterial reconstruction thrombosis - positive family history of DVT - non response to heparin (AT III deficiency) - prolonged APTT (lupus anticoagulant) - warfarin skin necrosis (protein C deficiency) - neonatal purpura fulminans (homozygous protein C deficiency)

Initiation of DVT • begins in valve sinuses, or at points of trauma e.g. THR • propagation • embolisation • lysis, organisation, recanalisation (most of it occurs in the first 6 weeks of thrombosis),

collateralisation - complete resolution +/- valve preservation or destruction - partial resolution with residual obstruction and valve destruction

PRINCIPLES OF MANAGEMENT FOR VTE • prevention - prophylaxis

- consider risks and benefits of prophylaxis - make the diagnosis - identify precipitants - risks and benefits of treatment options - initiate treatment and monitor patient - duration

NHMRC VTE Prevention CPG 1. pharmacological options: UFH, fondaparinux, danaparoid (a heparinoid), rivaroxaban, dabigatran,

aspirin, warfarin 2. mechanical options: GCS (knee length as effective as thigh length), pneumatic compression devices

and foot pumps

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Contraindications to mechanical prophylaxis 1. peripheral arterial disease ABI <0.7 2. peripheral neuropathy 3. severe leg oedema 4. severe lower limb deformity 5. fragile skin e.g. steroid use, elderly 6. inflammatory conditions of the lower leg 7. morbid obesity where correct fitting is not possible

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Clinical manifestations of DVT • due to blockage of vein and inflammation • swelling, warmth and suffusion/venous congestion • dilation of superficial veins • pain and tenderness • difficulty walking • fever and tachycardia • symptoms and signs of PE • phlegmasia and venous gangrene

Differential diagnosis • MSK: muscle tears, sprains, strains; haematoma; fracture • Baker’s cyst +/- rupture • cellulitis • lymphoedema • venous incompetence/PTS • tumours • systemic causes of oedema

- CCF - hypoproteinaemia (cirrhosis, nephrotic syndrome)

Investigation 1. duplex US 2. venography (gold standard, rarely used) 3. D-dimer 4. clinical probability scores (Wells score) 5. magnetic resonance venous imaging 6. CT venography

• scans must be bilateral • DVT scan should examine veins from ankle to IVC

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Week number + Topic• more proximal DVT can occur in isolation (hip replacement, trauma, pelvic surgery) • large proximal DVTs involving iliofemoral or caval segment should have a baseline CTPA (~50% will

have had PE by time of Dx)

Treatment • anticoagulation • compression stockings (class 1) • early mobilisation • caval interruption - filters

- contraindication to anticoagulation - failed anticoagulation - massive PE

• thrombolysis - catheter directed • thrombectomy (percutaneous/open) +/- angioplasty and stenting

Anticoagulation issues • heparin - minimum 5 days and until warfarin therapeutic

- need heparin cover while warfarinising - patients are hypercoagulable in the first 48 hours of warfarin therapy

• warfarin can be commenced on day 1 • beware of HITS - check platelets • ? duration of anticoagulation

- extent of DVT (distal/calf v proximal v iliofemoral/caval) - risk of recurrent VTE - idiopathic/spontaneous (40% of VTE) v secondary DVT (60% of VTE)

‣ consider identifiable triggers and persistent/transient risk factors - thrombophilia - near fatal VTE and unusual site DVT

Markers of recurrent VTE • increased D-dimer OR 2-3 • residual thrombus OR 2-3 • cancer • previous DVT • idiopathic DVT • outpatient presentation • outpatient presentation • proximal DVT • extensive DVT • short period of anticoagulation • thrombophilia (ACLA, ATIII, C, S, VIII, IX, XI) • male gender • younger age

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Pulmonary Embolism proximal DVT 50% calf DVT 5-20%

Differential Diagnosis • other causes of collapse, chest pain or dyspnoea • ACS, aortic dissection, cardiac tamponadfe, pneumonia, PTX, septicaemia

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Venous Thromboembolism

Arterial Thrombosis• Usually in association with atheroma• Areas of turbulent blood flow• White thrombus - platelet aggregation• Plaque rupture → tissue factor exposed to factor VIIa → blood coagulation → occlusion or

embolisation

Venous Thrombosis• Often occurs in normal vessels• Occur in the deep veins of the leg, around the valves• Red thrombus - red blood cells and fibrin• Chronic venous obstruction → swollen limb → ulceration (post-phlebitic syndrome)• May occur with changes in blood cells and with coagulation disorders

Thrombophilia• Inherited or acquired defects of haemostasis leading to a predisposition to venous or arterial thrombosis• Consider in patients with:

• Recurrent venous thrombosis• First venous thrombosis < 40 yo• Unusual venous thrombosis e.g. mesenteric or cerebral vein thrombosis• Unexplained neonatal thrombosis• Recurrent miscarriages• Arterial thrombosis in the absence of arterial disease

Coagulation abnormalities1. Factor V Leiden

• Factor V, cofactor for thrombin generation• Arg506Gln, less likely to be cleaved by protein C → impaired inactivation by protein C• Increased risk of (venous) thrombosis with OCs or in pregnancy

2. Prothrombin variant• 3’ untranslated region mutation, G20210A• Elevated levels of prothrombin• Increased risk of venous thrombosis

3. Antithrombin (AT) deficiency• Genetic (autosomal dominant) → recurrent thrombotic episodes, early onset• Acquired - trauma, surgery, contraceptive pill, severe proteinuria (e.g. nephrotic syndrome)• Resistant to heparin as AT is required for its action

4. Protein C and S deficiency• Autosomal dominant• Increased risk of venous thrombosis• Homozygous protein C or S deficiency → neonatal purpura fulminans

5. Antiphospholipid antibody/lupus anticoagulant

6. Hyperhomocysteinaemia• Elevated levels associated with both arterial and venous thromboembolism• Unknown mechanism• Folate, B12 and B6 helpful for reducing levels, but does not reduce risk of VTE


Prevention and Treatment of Arterial Thrombosis

1. Antiplatelet Drugs‣ Aspirin

• Irreversible COX inhibitor → reduced TXA2 production• LD, selective for COX-1 found within platelets (effective throughout life of platelet - 1 week)

‣ Dipyridamole• Inhibits platelet phosphodiesterase → increased cAMP → increased PGI2 actions

‣ Clopidogrel • Irreversible ADP (P2Y12) receptor antagonist → affects activation of GP IIb/IIIa complex

‣ Prasugrel• Novel thienopyridine• Similar to clopidogrel

‣ GP IIb/IIIa receptor antagonists• Block the platelet receptor for fibrinogen and vWF• 3 classes

• murine-human chimeric antibodies e.g. abciximab• synthetic peptides e.g. eptifibatide• synthetic non-peptides e.g. tirofiban

‣ Epoprostenol• Prostacyclin• Inhibits platelet aggregation• Used in renal dialysis and primary pulmonary hypertension

2. Thrombolytic therapy‣ Streptokinase

• From haemolytic streptococci• Forms a complex with plasminogen → plasmin activation → lysis of fibrin in clots AND free

fibrinogen• Risk of haemorrhage• Antigenic so precludes repeated use

‣ Plasminogen activators (alteplase (tPA), tenecteplase (TNK-tPA)• Non-antigenic, no allergic reactions• Relatively fibrin-specific, little systemic activity, short half-lives (5 minutes)


Venous Thromboembolism• Encompasses DVT and PE• VTE affects 1-2 per 1000 people per year• PE affects 0.5 - 1 per 1000 people per year, and is one of the most common preventable causes of hospital

death

Risk Factors for VTE• Classified into acute provoking vs chronic predisposing (see table)

Sequelae of Venous Thrombosis• Pulmonary, or systemic embolisation (through PFO or ASD)• Post-thrombotic syndrome (aka post-phlebitic or chronic venous insufficiency)• Recurrent VTE

Pathophysiology of VTE1. Hypoxaemia

• Increased anatomic dead space - breathed gas does not enter gas exchange units• Increased physiologic dead space - ventilation to gas exchange units exceeds venous blood flow

2. Increased pulmonary vascular resistance• Due to vascular obstruction• Platelet secretion of vasoconstricting neurohumoral agents e.g. serotonin

3. Impaired gas exchange• Increased alveolar dead space from vascular obstruction• Hypoxaemia from alveolar hypoventilation• Right to left shunting• Impaired carbon monoxide transfer due to loss of gas exchange surface

4. Alveolar hyperventilation due to reflux stimulation of irritant receptors5. Increased airway resistance due to constriction of airways distal to the bronchi6. Decreased pulmonary compliance due to lung oedema, lung haemorrhage, or loss of surfactant

Progressive RHF usual cause of death from PE• Increased pulmonary vascular resistance → increased RV wall tension → →


• RV dilation and dysfunction → IV septum bulges into and compresses LV → LV impairment during diastole → decreased LV distensibility and LV diastolic filling → decreased LV CO and MAP → myocardial ischaemia and RV infarction

• RCA compression → decreased subendocardial perfusion → myocardial ischaemia and RV infarction

Pulmonary Embolism• Result from embolisation of thrombi in the leg

or pelvic veins• Large emboli lodging at the bifurcation of the

pulmonary arteries → saddle embolus → circulatory failure or sudden death

• Most lodge in smaller pulmonary vessels• Only causes chest pain if there is involvement

of parietal pleura (lung has no pain fibres)

Natural History and Clinical Features• Determined by site of thrombosis

1. Distal (calf vein) DVT• Begins intra-operatively in surgical

patients• May resolve spontaneously within 72

hours or extend into proximal veins• Presence of symptoms and extent of

proximal progression indicates increased risk of PE

2. Proximal (popliteal and thigh) DVT• May develop PE, but often asymptomatic

3. Post-thrombotic syndrome• Chronic leg pain, swelling, venous

stasis, leg ulcers4. Recurrent VTE

• Higher risk of recurrent VTE in patients with an unprovoked event, and with a proximal DVT

Differential Diagnoses1. DVT

• Ruptured Baker’s cyst• Cellulitis• Post-phlebitic syndrome or venous

2. PE• Pneumonia, asthma, COPD• CHF• Pericarditis• Pleurisy: viral syndrome, costochondritis,

MSK discomfort

Diagnosis• VTE mimics other illnesses i.e. patients have a nonspecific clinical impression• Most common symptom for

• DVT - lower calf cramp that persists for several days• PE - breathlessness; fever is a common presentation

I. DVT1. Laboratory testing

• D-dimer, degradation product of cross-linked fibrin• Elevated D-dimer levels in 80% of VTE patients but not specific for VTE

• Malignancy


• Infection• Recent surgery• Trauma• Pregnancy

2. Diagnostic imaging• Ultrasonography

• DVT features• Lack of compressibility of vessel lumen (primary criterion)• Distended vessel• Lack of flow in the vessel

• Venography• Limited to patients with negative ultrasonography and unexplained swelling of the entire lower limb

e.g. isolated iliac vein thrombosis• Distinguishing acute recurrent DVT from chronic thrombus

II. PE

• ECG and CXR for excluding alternative diagnoses e.g. MI, pneumothorax

• ECG changes• S wave I• Q wave and T inversion in III• T wave inversion in V1 to V4

• CXR• Normal or enlarged pulmonary arteries,

atelectasis, vascular oligaemia, wedge-shaped density (→ pulmonary infarction)

• ABG of little role (but normal findings are hypoxaemia, hypocapnia, respiratory alkalosis)

Diagnostic Imaging

• Leg ultrasound


• Contrast pulmonary angiography• V/Q isotope scanning• CT pulmonary angiography

[PIOPED Article]

• Patients with suspected pulmonary embolism should have an objective clinical assessment (pretest probability)

• Obtain a D-dimer rapid ELISA if clinical assessment is low or intermediate probability• CT angiography/CT venography is recommended as first imaging tests• Discordant findings of clinical assessment and CT angiograms should prompt further evaluation• In pregnant women, and women of reproductive age, pulmonary scintigraphy may be the imaging test of

choice

Prognosis

Pulmonary Embolisms• 10% of symptomatic PE cases die within 1 hour of symptom onset• Determinants of clinical outcome

• Presence or absence and severity of haemodynamic compromise• Reduction in cardiac output• RV dysfunction

• Depends on:• Size and location of emboli• Presence of coexisting cardiopulmonary disease• Extent of neurohumoral activation in response to the embolus

Treatment


Aims (MJA) • Symptom relief• Reduce risk of PE or systemic embolism• Prevent post-thrombotic syndrome• Prevent recurrence of thrombosis

Rationale of Treatment (UpToDate)• Prevent further clot extension• Prevent acute PE• Reduce risk of recurrent thrombosis• Treat massive iliofemoral thrombosis with acute lower limb ischaemia and/or venous gangrene (i.e.

phlegmasia cerulea dolens)• Limit development of late complications e.g. post-thrombotic syndrome, CVI, chronic thromboembolic

pulmonary hypertension

1. Initial anticoagulation‣ Heparin (standard or unfractionated)

• Immediate binding to antithrombin → conformational change → increase inhibitory activity of antithrombin towards activated serine protease coagulation factors (thrombin, XIIa, XIa, Xa, IXa, VIIa)

• Requires a loading dose + continuous IV infusion• Requires APTT monitoring of anticoagulant response


• First choice in patients at high risk of bleeding or undergoing invasive procedures, and renal failure patients (due to shorter half-life; reversibility with protamine, extra-renal metabolism)

‣ LMW heparins e.g. enoxaparin, dalteparin• Greater activity against factor Xa than against IIa → lower risk of bleeding• Less inhibition of platelet function• Longer half-life than standard heparin → once-daily SC injection instead of every 8-12 hours• Little effect on tests of overall coagulation e.g APTT at prophylactic doses• Equally effective and safe as UFH but more convenient• 1-2x daily, SC without monitoring in most patients• Less likely to cause heparin-induced thrombocytopenia, but can’t be used to treat HIT because

antibodies to UFH cross-react with LMWH• Causes less osteoporosis

* Complications of heparin treatment* Bleeding* Osteoporosis* Heparin-induced thrombocytopenia

- Usually 14 days after first dose- Immune response against heparin/platelet factor 4 complexes- Associated with severe thrombosis

‣ Fondaparinux• Inhibits factor Xa• 1x daily SC injection, bridge to warfarin• Does not cause HIT• Metabolised by the kidneys so dose adjustment required for patients with renal dysfunction

‣ Direct thrombin inhibitors e.g. hirudin, lepirudin, bivalirudin• Hirudin

• Irreversible inhibitor of thrombin• Monitored by APTT• Excreted by the kidney


• Lepirudin - anticoagulation in patients with HIT• Bivalirudin - reversible thrombin inhibitor, less bleeding, shorter half-life, for PCI

‣ Oral anticoagulants• Act by interfering with vitamin K metabolism• Two types: coumarins and indanediones• Dosage controlled by prothrombin tests

2. Long term anticoagulation• Warfarin

• Prevents carboxylation activation of coagulation factors II, VII, IX and X• Target INR 2.0 to 3.0• Requires 5 to 7 days for therapeutic effect• When used as monotherapy, has procoagulant effect so overlap use with UFH, LMWH or

fondaparinux• May cause major bleeding and intracranial bleeding• Bleeding risk increases with age and INR, comorbid conditions, concomitant platelet therapy and

genetic factors (e.g. CYP450 polymorphisms)

3. Maintaining Adequate Circulation• For patients with massive PE and hypotension• May exacerbate RV wall stress, RV ischaemia and worsen LV compliance and filling (due to septal

shift)

4. Fibrinolysis• May cause major bleeding and intracranial haemorrhage

5. Pulmonary Embolectomy• Percutaneous transcatheter or surgical embolectomy• Patients who are haemodynamically unstable or shocked, and have contraindications or do not

response to thrombolytics

6. Pulmonary Thromboendarterectomy

7. Inferior Vena Cava Filter• Prevent PE in DVT patients ineligible for anticoagulants or who experience embolism even with

anticoagulation therapy• May fail by permitting small- to medium-sized clots• Large thrombi may embolise to pulmonary arteries via collateral veins• Complication: caval thrombosis with marked bilateral leg swelling

8. Graduated Compression Stockings• Reduce the risk of post-thrombotic syndrome• Contraindications: pre-existing leg ulceration and extensive varicosities

Thromboprophylaxis


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References:K&CHarrison’sVTE Dx Mx DVTVTE Dx Mx PEPIOPED Acute PE

VTE Prophylaxis

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