Venous Thrombosis
Venous Thrombosis It occurs mainly in the deep veins of the leg (deep vein thrombosis, DVT), from which parts of the clot frequently embolize to the lungs (pulmonary embolism, PE). Fewer than 5% of all venous thromboses occur at other sites
Venous thrombosis is common and often occurs spontaneously, but it also frequently accompanies medical and surgical conditions, both in the community and the hospital
Major complications of thrombosis include a disabling post-thrombotic syndrome and death due to fatal PE
Many risk factors for thrombosis are known, all of them related either to immobilization or to hypercoagulability. While it has no utility to assess the risk factor status after thrombosis has occurred, several acquired risk factors are so strong that they warrant prophylactic anticoagulation, in both those with and without a history of thrombosis. Detailed guidelines for primary prevention are available.
The incidence of a first venous thrombosis is 1 3 per 1000 persons per year. Around two-thirds manifest as DVT of the leg, and one-third as PE. Up to half of patients with PE have no signs of DVT. From 1 10% of venous thromboses prove fatal,
The recurrence rate of venous thrombosis is 3 10% per year.
Venous thrombosis is a multicausal disease that occurs when several risk factors are present simultaneously in a particular combination
Acquired Orthopedic surgery Neurosurgery Major abdominal surgery Major trauma Central venous catheters Malignancy Antiphospholipid syndrome Puerperium Prolonged bed rest Pregnancy Obesity Plaster cast Oral contraceptives Hormonal replacement therapy Myeloproliferative disorders Polycythemia vera Long-haul travel Age
Inherited Antithrombin deficiency Protein C deficiency Protein S deficiency Factor V Leiden (FVL) Prothrombin 20210A Non-O blood group Dysfibrinogenemia Factor XIII 34val
Pathobiology Virchow's triad of hypercoagulability, venous stasis, and injury to the vessel wall provides a useful model for understanding many of the risk factors that lead to the formation of thrombosis.
Clinical Manifestations leg pain, tenderness, swelling palpable cord, discoloration, venous distention, prominence of the superficial veins, and cyanosis
In most patients in whom DVT is clinically suspected, the symptoms and signs are nonspecific; in more than 50% of these patients, the clinical suspicion of DVT is not confirmed by objective testing. Conversely, patients with relatively minor symptoms and signs may have extensive DVT.
In some patients, DVT may be asymptomatic, but the patient will present with pulmonary embolism. Conversely, pulmonary embolism occurs in 50% of patients with objectively documented proximal leg vein thrombosis, but many of the emboli are asymptomatic.
Usually, only part of the thrombus embolizes,
Clinical Characteristic Score Active cancer (treatment ongoing within previous 6 months or palliative) 1 Paralysis, paresis, or recent plaster immobilization of the lower extremities 1 Recent bedrest >3 days or major surgery within 3 months requiring anesthesia 1 Localized tenderness of the deep veins of the leg 1 Entire leg swollen 1 Calf swelling >3 cm larger than asymptomatic side measured 10 cm below tibial tuberosity 1 Pitting edema confined to the symptomatic leg 1 Collateral superficial veins (not varicosed) 1 Previously documented DVT 1 Alternative diagnosis as likely as or more likely than DVT -2
Lancet 1997;350:1795 1798. A score of 0 or less indicates low probability, 1 or 2 indicates moderate probability, and 3 or more indicates high probability.
Diagnostic algorithm for suspected deep venous thrombosis. This algorithm uses evaluation of pretest probability based on a clinical prediction rule (see Table 81-1 ) and D-dimer testing to complement compression ultrasonography (CUS). The asterisk indicates use of a highly sensitive (>95%) D-dimer.
Imaging Contrast Venography Ascending contrast venography remains the gold standard for diagnosis, but because of its expense, discomfort to the patient, and potential for adverse experiences, venography is currently indicated in symptomatic patients only when diagnostic uncertainty persists after noninvasive testing or if noninvasive testing is unavailable.
Imaging
Compression Ultrasonography Compression venous ultrasonography is currently the most widely used noninvasive test for suspected DVT because of its accuracy in detection of thrombus involving the popliteal or more proximal veins;
absence of compressibility of the proximal leg veins on ultrasonography has a sensitivity of 97% and a specificity of 96% for symptomatic patients with suspected DVT
Thus, the finding of a noncompressible venous segment, particularly in the popliteal or common femoral vein, has a high positive predictive value for DVT in symptomatic patients and is an indication for treatment.
Of patients with symptoms suggestive of DVT but with normal findings on initial ultrasound examination of the proximal veins, about 15% will have undetected isolated calf DVT
progression into the proximal veins occurs in a minority of patients, usually within a week of presentation
Isolated calf DVT that does not extend into the proximal veins is rarely if ever associated with clinically important pulmonary embolus. The sensitivity of ultrasonography for calf DVT is well below 90%, with a wide range of accuracies reported for different populations of patients.
Imaging of the calf veins is timeconsuming, potentially inaccurate, and generally not recommended.
two-point (common femoral and popliteal) or three-point (two-point plus the calf trifurcation ) ultrasonography should be performed and, if the results are normal, repeated in 1 week after the initial examination. This approach will identify the 20 to 25% of patients who have had proximal extension of distal clot in the calf veins. If the repeated ultrasound examination is normal, further investigation and therapy can be safely withheld.
In centers with highly skilled operators, however, normal ultrasonography of the proximal and calf veins at presentation may be sufficiently accurate to exclude clinically important DVT;
D-Dimer measurement of D-dimer levels is a sensitive test for recent DVT and pulmonary emboli. Unfortunately, numerous nonthrombotic conditions, including sepsis, pregnancy, surgery, and cardiac or renal failure, can also cause elevated levels. As a result of this nonspecificity, the role of Ddimer assays is limited to helping exclude VTE when levels are not raised.
Highly sensitive tests, consisting of new rapid ELISA or immunoturbidimetric assays, have sensitivities of 95 to 100% for acute VTE but in general have low specificities (20 to 50%).
but clinicians must be aware of the accuracy of the assay in their institution before using the D-dimer assay to make management decisions.
ALTERNATIVE DIAGNOSES Diagnosis Patients (%) Muscle strain 24 Direct twisting injury to the leg 10 Leg swelling in paralyzed limb 9 Lymphangitis, lymphatic obstruction 7 Venous reflux 7 Muscle tear 6 Baker's cyst 5 Cellulitis 3 Internal abnormality of the knee 2 Unknown 26
Patients with a high pretest probability require ultrasonography regardless of the D-dimer result. A normal D-dimer result with use of either a moderately or highly sensitive assay can safely obviate the need for repeated imaging in patients with normal findings on initial ultrasound examination
Recurrent Deep Venous Thrombosis Approximately 10% of patients with unprovoked VTE will experience recurrent thromboembolism in the first year after ceasing anticoagulant therapy. In addition, many patients will have positional leg swelling and pain early during treatment as a result of venous outflow obstruction of the post-thrombotic syndrome when venous valvar incompetence is manifested
comparison with previous ultrasound images is required in patients with suspected recurrence. A normal D-dimer test result is useful in excluding recurrent DVT.
Pregnancy objective testing is needed to diagnose VTE. As in nonpregnant patients, compression ultrasonography is the initial test of choice
Anticoagulant therapy, which is the treatment of choice in most patients with VTE, Coumarin derivatives (e.g., warfarin) are usually the drugs of choice for long-term anticoagulant therapy, but such drugs have a delayed onset of anticoagulant effect
Therefore, initial short-term therapy with a rapid-acting heparin or heparin derivative for approximately 1 week is necessary to provide an immediate antithrombotic effect and to reduce the risk of thrombus growth or embolization in patients with acute DVT
LMWH or fondaparinux is preferred to inpatient treatment with intravenous unfractionated heparin whenever feasible in patients with DVT
The reduced size of LMWH also decreases charge-related nonspecific protein binding, thereby resulting in improved subcutaneous bioavailability, more predictable anticoagulant response, and predominantly dose-independent renal clearance.
once-daily administration of LMWH is thought to be as safe and effective as twice-daily administration.
three populations of patients in whom anti factor Xa monitoring should be considered: (1) patients with renal insufficiency (calculated creatinine clearance of less than 30 ml/min); (2) obese patients, in whom the volume of distribution of LMWH might be different, so weight-adjusted dosing might not be appropriate; and (3) pregnant women, in whom it is unclear whether the dose should be adjusted according to the woman's weight change.
Fondaparinux is a synthetic analogue of the critical pentasaccharide sequence required for binding of heparin molecules to antithrombin fondaparinux demonstrates 100% bioavailability, with peak plasma concentrations occurring 1.7 hours after dosing. Once-daily subcutaneous administration of fondaparinux (5.0 mg daily if weight is less than 50 kg; 7.5 mg daily if weight is 50 to 100 kg; 10 mg daily if weight is more than 100 kg) is an effective and safe alternative to LMWH for the initial 5 to 10 days of treatment of DVT
Clearance is predominantly renal
Unfractionated Heparin Up to 25% of patients with acute VTE have resistance to heparin, defined as a requirement for greater than expected doses of unfractionated heparin to achieve a therapeutic aptt. If it is available, anti factor Xa monitoring is recommended in patients with heparin resistance.
Warfarin the drug should be started within 24 to 48 hours of initiation of heparin with a goal of achieving international normalized ratio (INR) results between 2.0 and 3.0
Warfarin The dose is empirical, but a starting dose of 5 to 10 mg is suitable for most patients doses are adjusted according to the prothrombin time, expressed as the INR, performed daily or every other day until the results are in the therapeutic range for at least 24 hours.
Side Effects of Anticoagulants Bleeding is the most common side effect of anticoagulant therapy in approximately 2% of patients Factors such as recent surgery, trauma, and concurrent aspirin or thrombolytic therapy increase the risk of bleeding.
The risk of major bleeding increases according to individual characteristics, such as older age, the presence of comorbid conditions (e.g., diabetes, hypertension, renal insufficiency, previous gastrointestinal bleeding, or cancer), and the use of concomitant drugs, in particular antiplatelet therapy.
Heparin-induced thrombocytopenia manifested typically with thrombocytopenia and new thrombosis Monitoring of the platelet count is recommended every other day until day 14 in patients receiving therapeutic unfractionated heparin but is not routinely recommended with LMWH or fondaparinux because of the extremely low risk with these newer medications
The decision to prolong or to stop anticoagulation should be individualized, and a patient's preferences should be considered
Three months of treatment is associated with a 10 to 27% risk of recurrence whereas 6 months,,the risk of recurrence in the first year after stopping = 10%
Indications VTE suspected Guidelines Obtain baseline aptt, PT, CBC Check for contraindication to heparin therapy Order imaging study; consider giving IV unfractionated heparin (5000 IU) or LMWH VTE confirmed Give LMWH (dalteparin,[*] enoxaparin,[ ] nadroparin,[ ] tinzaparin,[ ] fondaparinux[**]) Start warfarin therapy on day 1 at 5 mg and adjust the subsequent daily dose according to INR Check platelet count between days 3 and 5 Stop LMWH therapy after at least 4 or 5 days of combined therapy when the INR is >2 Anticoagulate with warfarin for at least 3 months at an INR of 2.5, range of 2 3
WEIGHT-BASED NOMOGRAM FOR INITIAL INTRAVENOUS HEPARIN THERAPY aptt Dose (IU/kg) Initial dose 80 bolus, then 18/hr <35 sec (<1.2 )[*] 80 bolus, then 4/hr 35 45 sec (1.2 1.5 ) 40 bolus, then 2/hr 46 70 sec (1.5 2.3 ) No change 71 90 sec (2.3 3 ) Decrease infusion rate by 2/hr >90 sec (>3 ) Hold infusion 1 hr, then decrease infusion rate by 3/hr
VTE in different populations of patients Management of Deep Venous Thrombosis in Pregnancy :
VTE in different populations of patients LMWH can simply be adjusted periodically on the basis of the woman's weight. Unfractionated heparin is less attractive than LMWH because it is associated with a greater reduction of bone density and a higher risk of heparin-induced thrombocytopenia.
Pregnant women with a DVT should probably be treated for the duration of pregnancy and for at least 6 weeks post partum. If the DVT occurs in the latter part of the third trimester, intravenous heparin should be administered by continuous infusion until approximately 6 hours before the expected time of delivery
Venous Thrombosis of the Upper Extremities Etiology : central venous catheters, acquired or hereditary thrombophilias, and anatomic (cervical rib) and physiologic (muscular individuals) impingement of the vein.
Upper extremity DVT can cause pulmonary emboli, although the exact frequency is not known.
anticoagulant therapy should be given in all patients with upper extremity DVT, with medications, doses, regimens, and durations identical to those for treatment of DVT of the leg
SUPERFICIAL THROMBOPHLEBITIS Superficial thrombophlebitis usually presents with pain, swelling, redness, and tenderness of superficial veins. Varicose veins can be red, warm, and clustered in a circumscribed area
SUPERFICIAL THROMBOPHLEBITIS it is reasonable to use moderate doses of LMWH for the initial treatment of acute, symptomatic superficial thrombophlebitis. Alternatively, and particularly for intravenous catheter induced superficial thrombophlebitis, a nonsteroidal antiinflammatory drug can be tried
Varicose veins are a risk factor for deep venous thrombosis and may result from it.
post-thrombotic syndrome develops in up to 50% of patients with proximal DVT, usually within the first 1 to 2 years after DVT. The syndrome is often a chronic, progressive disease with pain, swelling, and occasionally ulceration of the leg in patients with previous DVT.
Graduated compression stockings reduce the risk of the post-thrombotic syndrome by about 50%.