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THROMBOSISFatimah Eliana

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Intrinsic Clotting PathwayBlood or collagen contactXII

XIIa (H)XIXIa (H)(W) IXIXa (H)CA++PF 3VIII (W)Extrinsic Clotting PathwayTissue traumaTissue factor(W) VII VIIaCommon Pathway(W) XXa (H)

(Next slide)The Clotting Cascade

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Common PathwayXa (H)Ca++PF 3V (W)(W) ProthrombinThrombinCa++FibrinogenFibrin (soluble)CA++XIIIaXIIIFibrin (insoluble)

(H)(H) (F)

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Coagulation CascadeA series of conversions of inactive proenzymes to activated enzymes, culminating in the formation of thrombinThrombin then coverts the soluble plasma protein fibrinogen to insoluble fibrous protein fibrin

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Coagulation CascadeIntrinsicSurface contactExtrinsicTissue injury

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Factors that favor or inhibit thrombosis

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Control of cascade to prevent clotting elsewhereAntithrombinsactivated by heparin like molecules on endothelial cellsClinical administration of heparin minimizes thrombosisProteins C and SVitamin K dependentInactivate cofactors Va and VIIIaPlasminogen-plasmin systemBreaks down fibrin and inhibits its polymerizationProducts of split fibrin are anticoagulants

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Clot is a thrombus formed in an arterial or venous vessel Thrombophlebitis - both inflammation and clots are presentSome thrombus can be superficial but its the DVT thats a concern embolism to lungsThrombus Formation

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Begins with platelet adhesion to arterial vessel wall Adenosine diphosphate (ADP) released from platelets more platelet aggregation blood flow inhibited fibrin, platelets and erythrocite surround clot build up of size structure occludes blood vessels tissue ischemiaThe result of arterial thrombus is localized tissue injury from lack of perfusionAntiplatelet drugs primarily act by preventing arterial thrombosis

Arterial Thrombus

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Usually from slow blood flowStagnation of the blood flow initiate the coagulation cascadeproduction of fibrin enmeshes erythrocyte andplatelets to form the thrombus. Venous thrombus has a long tail that can break off to produce an embolus. These travel to faraway sites then lodge in lung (capillary level) inadequate O2 and CO2 exchange occur (pulmonary and cerebral embolism)Anticoagulants (heparin/warfarin) primarily act by preventing venous thrombosis

Venous Thrombus

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Arterial Venous NeuropathicTypes of foot ulcers

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Arterial VenousNeuropathic

DistalMedial Pressuremalleoluspoint

YesNoNo

NoYesYes (maybe)

NoYesNo

MaybeNoYesLocationArterial diseaseand risk factors foratherosclerosis

Contra-lateral pulses

Skin changes ofvenous HTN

Neuropathy Foot ulcers

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DEEP VENOUS THROMBOSIS

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Deep vein thrombosis is the formation of a blood clot in one of the deep veins of the body, usually in the leg

Definition

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DVT usually originates in the lower extremity venous level Starting at the calf vein level and progressing proximally to involve popliteal, femoral or iliac system. 80 -90 % pulmonary emboli originates hereEtiology

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Virchow triad More than 100 years ago, Virchow described a triad of factors:Venous stasisHypercoagulable stateEndothelial damage

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Venous stasis Prolonged bed rest (4 days or more) A cast on the leg Limb paralysis from stroke or spinal cord injury Extended travel in a vehicle

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Hypercoagulability Surgery and trauma responsible for up to 40% of all thromboembolic disease Malignancy Increased estrogen (fall in protein S):all stages of pregnancythe first three months postpartum, after elective abortionduring treatment with oral contraceptive pills

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deficiency of protein Sdeficiency protein Cdeficiency antithrombin III.

Inherited disorders of coagulation

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Acquired disorders of coagulation Nephrotic syndrome urinary loss of antithrombin III (should be considered in children presenting with thromboembolic disease)Autoimmune disorder accelerate coagulation:Antiphospholipid syndrome (APS): antiphospholipid antibody, anticardiolipin antibody systemic lupus erythematosus (SLE): lupus anticoagulant

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Inflammatory processes, such as:sickle cell diseaseinflammatory bowel disease (IBD),

also predispose to thrombosis, presumably due to hypercoagulability

Acquired disorders of coagulation

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Endothelial Injury Trauma, surgery and invasive procedure may disrupt venous integrity.Iatrogenic causes of venous thrombosis are increasing due to the widespread use of central venous catheters, particularly subclavian and internal jugular lines. These lines are an important cause of upper extremity DVT, particularly in children.

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Clinical Pathophysiology The nidus for a clot is often an intimal defect When a clot forms on an intimal defect, the coagulation cascade promotes clot growth proximally. Thrombus can extend from the superficial veins into the deep system from which it can embolize to the lungs.

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Clinical Pathophysiology Opposing the coagulation cascade is the endogenous fibrinolytic system. After the clot organizes or dissolves, most veins will recanalize in several weeks. Residual clots retract as fibroblasts and capillary development lead to intimal thickening.

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Presentation and Physical Examination Calf pain or tenderness, or both Swelling with pitting oedema Swelling below knee in distal deep vein thrombosis and up to groin in proximal deep vein thrombosis Increased skin temperature Superficial venous dilatation Cyanosis can occur with severe obstruction

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Presentation and Physical Examination Palpate distal pulses and evaluate capillary refill to assess limb perfusion. Move and palpate all joints to detect acute arthritis or other joint pathology. Neurologic evaluation may detect nerve root irritation; sensory, motor, and reflex deficits should be noted Homans' sign: pain in the posterior calf or knee with forced dorsiflexion of the foot

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Presentation and Physical Examination Search for stigmata of PE such as tachycardia (common), tachypnea or chest findings (rare)Exam for signs suggestive of underlying predisposing factors.

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SCOREActive cancer (treatment ongoing, or within 6 months or palliative)1Paralysis or recent plaster immobilization1Recently bedridden for >3 days or major surgery 3 cm compared to the asymptomatic leg1Pitting edema (greater in the symptomatic leg)1Collateral superficial veins (nonvaricose)1Alternative diagnosis (as likely or > that of DVT)1

Wells Clinical Prediction Guide

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Wells Clinical Prediction GuideTotal of Above Score

High probability: Score > 3Moderate probability: Score = 1 or 2Low probability: Score 0

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Diagnostic Studies Clinical examination alone is able to confirm only 20-30% of cases of DVT Blood Tests D-dimer: predictive value for DVT INR: useful for guiding the management of patients with known DVT who are on warfarin (Coumadin)

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D-dimer D-dimer is a specific degradation product of cross-linked fibrin. Because concurrent production and breakdown of clot characterize thrombosis, patients with thromboembolic disease have elevated levels of D-dimer Three major approaches for measuring D-dimer ELISA Latex agglutination Blood agglutination test (SimpliRED)

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D-dimer False-positive D-dimers occur in patients:recent (within 10 days) surgery or trauma,recent myocardial infarction or stroke,acute infection,disseminated intravascular coagulation,pregnancy or recent delivery, active collagen vascular disease, metastatic cancer

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Imaging Studies InvasiveVenographyRadiolabeled fibrinogen. Noninvasive Ultrasound with DopplerPlethysmographyMRI techniques

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VenographyGold standard modality for the diagnosis Advantages:useful if the patient has a high clinical probability of thrombosis and a negative ultrasoundvaluable in symptomatic patients with a history of prior thrombosis in whom the ultrasound is non-diagnostic. Side Effects:phlebitis anaphylaxis

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Venography

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Nuclear Medicine Studies Because the radioactive isotope incorporates into a growing thrombus, this test can distinguish new clot from an old clot

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PlethysmographyPlethysmography measures change in lower extremity volume in response to certain stimuli.

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Ultrasonography Color-flow Duplex scanning is the imaging test of choice for suspected DVT Advantages:inexpensive, noninvasive, widely available can also distinguish other causes of leg swelling, such as tumor, popliteal cyst, abscess, aneurysm, or hematoma.

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Ultrasonography Clinical limitations Reader dependent Duplex scans are less likely to detect non-occluding thrombi. During the second half of pregnancy, US becomes less specific, because the gravid uterus compresses the inferior vena cava, thereby changing Doppler flow in the lower extremities

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Magnetic Resonance Imaging It detects leg, pelvis, and pulmonary thrombi 97% sensitive and 95% specific for DVT It distinguishes a mature from an immature clot. MRI is safe in all stages of pregnancy.

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CellulitisThrombophlebitisArthritisAsymmetric peripheral edema secondary to CHF, liver disease, renal failure, or nephrotic syndromeLymphangitis, LymphedemaExtrinsic compression of iliac vein secondary to tumor, hematoma, or abscessDifferential Diagnosis

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HematomaMuscle or soft tissue injuryNeurogenic painPostphlebitic syndrome Prolonged immobilization or limb paralysisRuptured Baker cystStress fractures or other bony lesionsVaricose veins

Differential Diagnosis

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ManagementUsing the pretest probability from the Wells Clinical Prediction rule: high, moderate, or low risk. The results from duplex ultrasound are incorporated as follows: If the patient is high or moderate risk and the duplex ultrasound study is positive, treat for DVT.If the patient is low risk and the duplex study is negative, DVT has been ruled out. If the patient is high risk but the ultrasound study was negative, the patient still has a significant probability of DVT

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ManagementWhen discordance exists between the pretest probability and the duplex study result, further evaluation is required. If the patient is low risk but the ultrasound study is positive, some authors recommend a second confirmatory study such as a venogram before treating for DVT Results of D-dimer assay to guide management

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ManagementAnticoagulationThrombolytic therapy for DVTSurgery for DVTFilters for DVT Compression stockings

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AnticoagulationHeparin prevents extension of the thrombus Heparin's anticoagulant effect is related directly to its activation of antithrombin III. Antithrombin III, the body's primary anticoagulant, inactivates thrombin and inhibits the activity of activated factor X in the coagulation process.

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AnticoagulationThe optimal regimen for the treatment of DVT is anticoagulation with heparin or an low molecular weight heparin (LMWH) followed by full anticoagulation with oral warfarin for 3-6 months Warfarin therapy is overlapped with heparin for 4-5 days until the INR is therapeutically elevated to between 2-3.

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AnticoagulationAfter an initial bolus of 80 U/kg, a constant maintenance infusion of 18 U/kg is initiated. The aPTT is checked 6 hours after the bolus and adjusted accordingly. The aPTT is repeated every 6 hours until 2 successive aPTTs are therapeutic. Thereafter, the aPTT is monitored every 24 hours as well as the hematocrit and platelet count.

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The hemorrhagic complications attributed to heparin are thought to arise from the larger higher molecular weight fragments.

Anticoagulation

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Advantages of Low-Molecular-Weight Heparin Over Standard Unfractionated HeparinSuperior bioavailabilitySuperior or equivalent safety and efficacySubcutaneous once- or twice-daily dosingNo laboratory monitoringLess thrombocytopenia

Anticoagulation

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Low-Molecular-Weight HeparinAt the present time, 3 LMWH preparations:Enoxaparin,Dalteparin, andArdeparin

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Warfarin Interferes with hepatic synthesis of vitamin K-dependent coagulation factors Dose must be individualized and adjusted to maintain INR between 2-3 2-10 mg/d PO Caution in active tuberculosis or diabetes; patients with protein C or S deficiency are at risk of developing skin necrosis

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Thrombolytic therapy for DVTAdvantages include:prompt resolution of symptoms, prevention of pulmonary embolism, restoration of normal venous circulation, preservation of venous valvular function, prevention of postphlebitic syndrome.

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Thrombolytic therapyThrombolytic therapy does not prevent clot propagation,rethrombosis, orsubsequent embolization. Heparin therapy and oral anticoagulant therapy always must follow a course of thrombolysis.

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Thrombolytic therapy is also not effective once the thrombus is adherent and begins to organize The hemorrhagic complications of thrombolytic therapy are formidable (about 3 times higher), including the small but potentially fatal risk of intracerebral hemorrhage. Thrombolytic therapy

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Indication:when anticoagulant therapy is ineffective, unsafe, contraindicated. The major surgical procedures for DVT are clot removal and partial interruption of the inferior vena cava to prevent pulmonary embolismSurgery for DVT

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These pulmonary emboli removed at autopsy look like casts of the deep veins of the leg where they originated.

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This patient underwent a thrombectomy. The thrombus has been laid over the approximate location in the leg veins where it developed.

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Filters for DVT Indications for insertion of an inferior vena cava filter: Pulmonary embolism with contraindication to anticoagulation Recurrent pulmonary embolism despite adequate anticoagulation

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Filters for DVT Controversial indications:DVT with contraindication to anticoagulation DVT in patients with pre-existing pulmonary hypertension Free floating thrombus in proximal vein Failure of existing filter device Post pulmonary embolectomy

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Filters for DVT Inferior vena cava filters reduce the rate of pulmonary embolism but have no effect on the other complications of deep vein thrombosis. Thrombolysis should be considered in patients with major proximal vein thrombosis and threatened venous infarction

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Compression stockings (routinely recommended

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Complications Acute pulmonary embolismHemorrhagic complications Chronic venous insufficiency

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Progression of Chronic Venous InsufficiencyFrom UpToDate 2006

Identify any patient who is at risk.Prevent dehydration.During operation avoid prolonged calf compression.Passive leg exercises should be encourged whilst patient on bed.Foot of bed should be elevated to increase venous return.Early mobilization should be rule for all surgical patients.

Prophylaxis

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ARTERY THROMBOSIS

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Begins with platelet adhesion to arterial vessel wall Adenosine diphosphate (ADP) released from platelets more platelet aggregation blood flow inhibited fibrin, platelets and erythrocite surround clot build up of size structure occludes blood vessels tissue ischemiaThe result of arterial thrombus is localized tissue injury from lack of perfusionAntiplatelet drugs primarily act by preventing arterial thrombosis

Arterial Thrombus

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Arterial thrombosis angiographic picture

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Severe arterial thrombosis

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Thrombus in left atrium

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Clot on bicuspid aortic valve

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Bacterial endocarditis

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Severe internal carotid stenosis

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Multi-level peripheral vascular disease External iliac Superficial femoral Tibial

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Aspirin, Dipyridamole (Persantine), Ticlopidine (Ticlid) abciximab (ReoPro), tirofiban (Aggrastat)Action: prevent thrombosis in the arteries by suppressing platelet aggregationUse: Prevention of MI, stroke for patient with family history, DMPrevention of repeat MI, stroke in patient having TIA

Antiplatelet Drugs

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Persantine,Ticlid = similar to ASA but more expensiveReoPro, Aggrastat = mainly for acute coronary syndromes. Route = IV

Antiplatelet Drugs

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.Thrombolytics promote fibrinolytic mechanism (convert plasminogen to plasmin and destroys the fibrin in the clot)Administering a thrombolytic drug clot disintegratesSide effects: hemorrhage, allergic reactionsOnset and peak are immediate and rapidDuration can be 12 hour.

Thrombolytic

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Use :Acute MI - within 4 hrs to dissolve clot and unblock artery, so decrease necrosis to myocardium.Other uses: pulmonary embolismDVTnoncoronary arterial occlusion

Thrombolytic

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Streptokinase, Urokinase, Tissue plasminogen activator (t-PA), anisoylated plasminogen streptokinase activator complex (APSAC)Streptokinase and Urokinase: enzymes that act to convert plasminogen to plasmint-PA and APSAC: activate plasminogen by acting specifically on clot.

Thrombolytic

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Aorto-bifemoral bypass

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VEIN THROMBOSIASARTERY THROMBOSISSimilar nameRed thrombiWhite thrombiContainRich in fibrin and trapped RBCHigher concentration of platetelts, lower concentration of RBCPreventionMedication that interrupt cloting cascade (anticoagulant)Medication that block platelet activation (antiagregation)Anticoagulant also used because thrombin is potent activator of platelets and arterial clots contain fibrin

CONCLUSION

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