The model in this slide provides a simplified explanation for the antagonism of clotting factor biosynthesis by warfarin. The cyclic interconversion of vitamin K from its vitamin K epoxide (KO) back to its hydroquinone (KH 2 ) form, which occurs under normal physiological and dietary conditions, is disrupted in the presence of pharmacologically effective doses of warfarin. This metabolic disruption of the cycle results in decreased availability of the active cofactor form of vitamin K, vitamin K hydroquinone (KH 2 ). The result is decreased presence of -carboxyglutamic acid in the vitamin K-dependent clotting factors. Warfarin inhibits the enzymatic conversion (by reductases) of KO to its active cofactor form, KH 2 . This inhibition decreases the amount of KH 2 available to participate in the conversion of prothrombin to its biologically active form. In order for prothrombin to have normal biological activity, between 10-13 glutamic acid (glu) residues must be converted to -carboxyglutamic acid (gla) residues. This reaction requires the addition of a second carboxyl group (-COOH) to glutamic acid residues. Bovill EG, Mann KG, Lawson JH, Sadowski, J. Biochemistry of vitamin K: implications of warfarin therapy. In: Ezekowitz MD, ed. Systemic cardiac embolism. New York:Marcel Dekker, 1994 pp 31-54. Hirsh J, Ginsberg JS, Marder VJ. Anticoagulant therapy with coumarin agents. In: Colman RW, Hirsh J, Marder VJ, Salzman EW, eds. Hemostasis and thrombosis, 3rd ed. Philadelphia: J.B. Lippincott, 1994 pp 1567-1581.
DEEP VEINTHROMBOSISGuide – Dr. Prof. P. M. Luka(MS)Presented by – Dr. Abhinandan Patil
DEFINITIONDeep vein thrombosis is the formation of a blood clot in one of the deep veins of the body, usually in the leg.
IT IS LIKE ICEBERG DISEASE Symptomatic deep vein thrombosis is "tip of the iceberg"
EPIDEMIOLOGY Venous ThromboEmbolism related deaths 3,00,000/anum 7% diagnosed and treated 34% sudden pulmonary embolism 59% as undected
INCIDENCE An annual incidence of symptomatic Venous ThromboEmbolism as 117 per 100,000 persons . Venous ThromboEmbolism in hospitalized patients has increased from 0.8% to 1.3% over a period of 20 years (reported in 2005).
Without prophylaxis the incidence of deep vein thrombosis is about – 14% in gynaecological surgery 22% in neurosurgery 26% in abdominal surgery 45%-60% in patients undergoing hip and knee surgeries. 15% to 40% Urologic surgery.
Virchows triad describesthree factors that are thought to contribute to thrombosis
VIRCHOW TRIAD More than 100 years ago, Rudolf Virchow described a triad of factors of -
VENOUS STASIS prolonged bed rest (4 days or more) A cast on the leg Limb paralysis from stroke spinal cord injury extended travel in a vehicle
HYPERCOAGULABILITY Surgery and trauma - 40% of all thrombo embolic disease Malignancy increased estrogen Inherited disorders of coagulation -Deficiencies of protein-S, protein-C, anti-thrombin III. Acquired disorders of coagulation- Nephrotic syndrome, Anti-phospholipid antibodies
ENDOTHELIAL INJURY Trauma Surgery Invasive procedure Iatrogenic causes –central venous catheters Subclavian Internal jugular lines These lines cause of upper extremity DVT.
HYPERCOAGULABLE STATE OFMALIGNANCY Up to 15% of cancer patients presents with VTE VTE is not equally common in all types of cancer. The highest incidence is found in mucin- producing adenocarcinomas, pancreas and gastrointestinal tract, lung cancer, and ovarian cancer.
Cancer Site Prevalence (% )Pancreas 28Lung 27Stomach 13Colon 13Breast premenopausal 1 –2Breast postmenopausal 3 –8Prostate 2Unknown primary tumor 1
PATHOPHYSIOLOGY Vessel trauma stimulates the clotting cascade. Platelets aggregate at the site particularly when venous stasis present Platelets and fibrin form the initial clot RBC are trapped in the fibrin meshwork
The thrombus propagates in the direction of the blood flow. Inflammation is triggered, causing tenderness, swelling, and erythema. Pieces of thrombus may break loose and travel through circulation- emboli. Fibroblasts eventually invade the thrombus, scarring vein wall and destroying valves. Patency may be restored valve damage is permanent, affecting directional flow.
Thrombophlebitis - a thrombus accompanied by inflammation of the vein (phlebitis). Phlebothrombosis - refers to a thrombus with minimal inflammation. Dislodgment and migration of a thrombus are known as thromboembolism. Which is common in phlebothrombosis.
PRESENTATION ANDPHYSICAL EXAMINATION Calf pain or tenderness, or both Swelling with pitting oedema Increased skin temperature and fever Superficial venous dilatation Cyanosis can occur with severe obstruction
Less frequent manifestations of venous thrombosis include Phlegmasia alba dolens, Phlegmasia cerulea dolens, and Venous gangrene. These are clinical spectrum of the same disorder.
PHLEGMASIA ALBA DOLENSThrombosis in only major deep venous channels sparing collateral veins Causing painful congestion and oedema of leg, with lymphangitis Which further increases Oedema
40-60% also have capillary involvement irreversible venous gangrenehydrostatic pressure in arterial and venous capillaries exceeds the oncotic pressure fluid sequestration in the interstitiumCirculatory shock, and arterial insufficiency which causes gangrene.
c/f sudden severe pain , swelling, cyanosis and edema of the affected limb. There is a high risk of massive pulmonary embolism, even under anticoagulation. Foot gangrene may also occur. An underlying malignancy is found in 50% of cases. Usually, it occurs in those afflicted by a life-threatening illness.
CLINICAL 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.
Moses sign Gentle squeezing of the lower part of the calf from side to side. Neuhofs sign Thickening and deep tenderness elicited while palpating deep in calf muscles. Lintons sign After applying torniquet at saphenofemoral junction patient made to walk , then limb is elevated in supine posation prominent superficial veins will be observed.
Search for stigmata of PE such astachycardia (common)tachypneachest findings (rare), exam for signs suggestive of underlying predisposing factors.
WELLS CLINICAL PREDICTIONGUIDE It pre-test probability score Helpsin early risk stratification and appropriate use of laboratory tests and imaging modalities. wellscriteria is an additional tool to diagnosis rather than being a stand-alone test.
Variable WellsActive cancer (rx within last 6 months or palliative) 1Calf swelling >3 cm compared to other calf 1Collateral superficial veins (non-varicose) 1Pitting edema 1Swelling of entire leg 1Localized pain along distribution of deep venous system 1Paralysis, paresis, or recent cast immobilization of lower extremities 1Recently bedridden > 3 days, or major surgery requiring regional or 1general anesthetic in past 12 weeksPreviously documented DVT 1 -2Alternative diagnosis at least as likely deep vein thrombosis
Interpretation High probability: ≥ 3 (Prevalence of DVT - 53%) Moderate probability: 1-2 (Prevalence of DVT - 17%) Low probability: ≤ 0 (Prevalence of DVT - 5%) Adapted from Anand SS, et al. JAMA. 1998; 279 ;1094
LIMITATIONS OF WELLS SCORE It useful in secondary and tertiary care centers, has not been properly validated for use in primary care centers patients with the suspicion of DVT. The performance of Wells score was decreased when evaluating elderly patients or those with a prior DVT or having those having other comorbidities, which might be equivalent to what is found in a primary care setting.
DIAGNOSTIC STUDIES Clinical examination alone is able to confirm only 20-30% of cases of DVT Blood Tests The D-dimer Imaging Studies
D-DIMER It 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
S OF FIBRIN,PLASMINCLEAVESFACTORXIIIA–CROSS-LINKEDFIBRIN INTOAN ARRAY OFINTERMEDIATE FORMS.THE D-DIMERAND EFRAGMENTSARE THERESULT OFTERMINALFIBRINDEGRADATION
Various kits have a 93-95% sensitivity and about 50% specificity in the diagnosis of thrombotic disease. False-positive D-dimers occur in patients with 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, or metastatic cancer
It should be noted that since D-dimer assays present a low specificity for DVT, the value of this test should be limited to ruling out rather than confirming the diagnosis of a DVT.
VENOGRAPHYIt detects thrombi in both calf and thigh It can conclude and exclude the diagnosis of DVT when other objective testings are not conclusive. Advantages It is useful if the patient has a high clinical probability of thrombosis and a negative ultrasound. It is also valuable in symptomatic patients with a history of prior thrombosis in whom the ultrasound is non-diagnostic.
DISADVANTAGE It can primary cause of DVT in 3% of patients who undergo this diagnostic procedure. An invasive and expensive. Although Venography was once considered the gold standard for diagnosis of DVT, today it is more commonly used in research environments and less frequently utilized in clinical practice.
NUCLEAR MEDICINE STUDIES Because the radioactive isotope incorporates into a growing thrombus, this test can distinguish new clot from an old clot. Nuclear medicine studies done with I125-labeled fibrinogen . More commonly used in research.
PLETHYSMOGRAPHY Plethysmography measures change in lower extremity volume in response to certain stimuli.
IMPEDANCE PLETHYSMOGRAPHY Principle- Blood volume changes in the leg lead to changes in electrical resistance. Venous return in the lower extremity is occluded by inflation of a thigh cuff, and then the cuff is released, resulting in a decrease in calf blood volume. Any obstruction of the proximal veins diminishes the volume change, which is detected by measuring changes in electrical resistance (impedance) over the calf.
ULTRASONOGRAPHY color-flow Duplex scanning is the imaging test of choice for patients with suspected DVT inexpensive, noninvasive, widely available Ultrasound can also distinguish other causes of leg swelling, such as tumor, popliteal cyst, abscess, aneurysm, or hematoma.
CLINICAL LIMITATIONS Reader dependent Duplex scans are less likely to detect non- occluding thrombi. During the second half of pregnancy, ultrasound becomes less specific, because the gravid uterus compresses the inferior vena cava, thereby changing Doppler flow in the lower extremities. An inability to distinguish old clots from a newly forming clot
Lack of accuracy in detecting DVT in the pelvis or the small vessels of the calf Lack of accuracy in detecting DVT in the presence of obesity or significant edema
MAGNETIC RESONANCE IMAGING It detects leg, pelvis, and pulmonary thrombi and is 97% sensitive and 95% specific for DVT. It distinguishes a mature from an immature clot. MRI is safe in all stages of pregnancy. Test may not be appropriate for patients with pacemakers or other metallic implants, it can be an effective diagnostic option for some patients.
DIFFERENTIAL DIAGNOSISo Cellulitis Thrombophlebitiso Arthritis Asymmetric peripheral edema secondary to CHF, liver disease, renal failure, or nephrotic syndrome lymphangitis Extrinsic compression of iliac vein secondary to tumor, hematoma, or abscess Hematoma Lymphedema
Muscle or soft tissue injury Neurogenic pain Postphlebitic syndrome Ruptured Baker cyst Stress fractures or other bony lesions Superficial thrombophlebitis
MANAGEMENT Using the pretest probability score calculated from the Wells Clinical Prediction rule, patients are stratified into 3 risk groups—high, moderate, or low. 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 duplex study is negative and the patient is low risk, DVT has been ruled out.• When discordance exists between the pretest probability and the duplex study result, further evaluation is required. If the patient is high risk but the ultrasound study was negative, the patient still has a significant probability of DVT
a venogram to rule out a calf vein DVT surveillance with repeat clinical evaluation and ultrasound in 1 week. results of a D-dimer assay to guide management 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
EMERGENCY DEPARTMANTCARE The primary objectives of the treatment of DVT are to - prevent pulmonary embolism, reduce morbidity, and prevent or minimize the risk of developing the postphlebitic syndrome.
GENERAL THERAPEUTICMEASURES : Bed rest . Encourage the patient to perform gentle foot & leg exercises every hour. Increase fluid intake upto 2 l/day unless contraindicated. Avoid deep palpation .
SPECIFIC TREATMENT : Anticoagulation Thrombolytic therapy for DVT Surgery for DVT Filters for DVT Compression stockings
Initialtreatment of DVT is with low- molecular-weight heparin or unfractionated heparin for at least 5 days, followed by warfarin (target INR, 2.0–3.0) for at least 3 months.
ANTICOAGULATION Heparin prevents extension of the thrombus It is a heterogeneous mixture of polysaccharide fragments with varying molecular weights but with similar biological activity.
MECHANISM OF ACTION Heparins anticoagulant effect is related directly to its activation of antithrombin III. Antithrombin III, the bodys primary anticoagulant, inactivates thrombin and inhibits the activity of activated factor X, factor IX in the coagulation process.
Heparin: Mechanism of ActionAccelerates antithrombin III activity Antithrombin III (Heparin) Factor X Factor IXa Ca2+, PL Factor VIIIa Factor Xa Prothrombin Thrombin Factor Va Ca2+, PL
Side effects• Bleeding• Osteoporosis• Thrombocytopenia• Skins lesions- urticaria, papules, necrosis• Hypoaldosteronism, hyperkalemia CONTRAINDICATIONS-• Bleeding disorders,• Severe hypertension, threatened abortion, piles,• large malignancies, tuberculosis’• Ocular surgery and neurosurgery,• Chronic alcoholics, cirrhosis, renal failure
DOSE IV bolus dose of 5,000 to 10,000 units followed by an infusion of 1,000 units per hour. Other method of initiating therapy is to begin with Loading dose of 50-100 units/kg of heparin followed by a constant infusion of 15-25 units/kg/hr.
LOW MOLECULAR WEIGHTHEPARIN Selectively inhibit factor Xa . Superior bioavailability Superior or equivalent safety and efficacy Subcutaneous once- or twice-daily dosing No laboratory monitoring Less phlebotomy (no monitoring/no intravenous line) Less thrombocytopenia
The optimal regimen for the treatment of DVT is anticoagulation with heparin or an 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.
WARFARIN Interferes with hepatic synthesis of vitamin K- dependent coagulation factors Dose must be individualized and adjusted to maintain INR between 2-3 Oral dose of 2-10 mg/d caution in active tuberculosis or diabetes; patients with protein C or S deficiency are at risk of developing skin necrosis
WARFARIN—MECHANISM OF ACTIONVitamin K VII Synthesis of IX Dysfunctiona X l Coagulation Factors IIWarfarin
DRAWBACKS OF WARFARINTHERAPY Delayed onset and offset of action. Frequent blood test monitoring required: - the dose response is unpredictable, - has a narrow therapeutic range Reversibility of anticoagulant affect is slow. Requires labor-intensive follow up, Expert dose management, Frequent patient communication.
THROMBOLYTIC THERAPY FORDVT Advantages include Prompt resolution of symptoms, Prevention of pulmonary embolism, Restoration of normal venous circulation, Preservation of venous valvular function, Prevention of postphlebitic syndrome.
DISADVANTAGEThrombolytic therapy does not preventclot propagation, rethrombosis, or subsequent embolization. Heparin therapy and oral anticoagulant therapy always must followed after a course of thrombolysis.
Thrombolytic therapy is also not effective once the thrombus is adherent and begins to organize The hemorrhagic complications of thrombolytic therapy are about 3 times higher, including the small but potentially fatal risk of intra-cerebral hemorrhage. At present, therefore, thrombo-lysis should be reserved for exceptional circumstances, such as patients with limb-threatening ischemia caused by phlegmasia cerulea dolens.
SURGERY FOR DVT Indications 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 embolism.
These pulmonary emboli removed at autopsy look like casts of the deep veins of the leg where they originated.
THIS PATIENT UNDERWENT A THROMBECTOMY. THETHROMBUS HAS BEEN LAID OVER THE APPROXIMATELOCATION IN THE LEG VEINS WHERE IT DEVELOPED.
FILTERS FOR DVT Indications Contraindication to anticoagulation. Significant bleeding complication of anticoagulation therapy. Pulmonary embolism with contraindication to anticoagulation. Recurrent thrombo-embolic complication despite adequate anticoagulation therapy.
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
PROPHYLAXIS Indicated in who underwent major abdominal trauma or orthopaedic surgery or patient having prolonged immobolization (> 3 days). Benefits of VTE Prophylaxis Improved patient outcomes Reduced costs
METHODS OF VTE PROPHYLAXIS Mechanical: Graduated Compression Stockings (GCS) Intermittent Pneumatic Compression Devices (IPC) Pharmacologic Low molecular weight Heparin.(5000u sc 8hourly ) It inhibits factor Xa and IIA activity.