GENERAL PRINCIPLES
Thrombotic disease refers to the inappropriate formation of a clot in the venous or arterial circulation. Arterial and venous thrombi form in the presence of Virchow triad: hypercoagulability, stasis, and endothelial damage. Embolism of these clots can occur, causing a pulmonary embolism (PE) when arising from the venous circulation or a systemic embolus when arising from the arterial circulation. Risk factors for venous thrombosis include immobility, surgery, increasing age, obesity, pregnancy, and an inherited or acquired hypercoagulable state (Table 6-1).1 Thrombotic disease often results from an interaction of genetic predisposition and environmental factors. Evaluation of patients presenting with thrombosis includes identification of risk factors, recommendations on appropriate anticoagulant management and duration of therapy, and in carefully selected cases, workup for thrombophilia or hypercoagulable state.
DEEP VENOUS THROMBOSIS AND PULMONARY EMBOLUS
General Principles
Definition
The term venous thromboembolism (VTE) encompasses both deep venous thrombosis (DVT) and PE.
Epidemiology1
The annual incidence of DVT is approximately 100 per 100,000 persons per year. About 40% to 50% of people with a symptomatic DVT will have a silent PE, and 1% to 8% of patients with a PE will die of its complications.
Prevention
Primary prevention of VTE in the hospitalized patient with risk factors is essential. These risk factors include an acute infectious disease, congestive heart failure, malignancy, stroke, acute pulmonary disease, acute rheumatic disease, inflammatory bowel disease, and critical illness. Expert opinion recommends that all medical patients older than 40, who are expected to have at least 3 days of inpatient stay and have one risk factor, should be provided with DVT prophylaxis. Prophylaxis can be nonpharmacologic, with compression stockings or pneumatic compression devices. However, there are no large, blinded trials proving that these interventions prevent VTE in medical patients. For patients without a contraindication to low-dose anticoagulation who need prophylaxis, pharmacologic agents are recommended. Subcutaneous heparin three times a day, low-molecular-weight heparin (LMWH) once daily, and fondaparinux once daily have been shown to have equal efficacy in preventing VTE with minimal increased bleeding risk and have been wildly used as DVT prophylaxis in hospitalized patients.2
Diagnosis3,4
Clinical Presentation
History
Symptoms of acute DVT and PE can be variable; however, common symptoms include
· DVT—acute onset of pain, swelling, and pain at a unilateral extremity
· PE—dyspnea, pleuritic chest pain, cough, anxiety, and hemoptysis
Physical Examination
· DVT—unilateral extremity tenderness, erythema, and unequal circumference of extremities
· PE—tachypnea, tachycardia, and inspiratory crackles
Diagnostic Testing
Laboratories
D-dimer is a cheap and fast initial screening test, particularly in patients with low suspicion of VTE. D-dimer is the result of fibrin breakdown and is generated in many other circumstances, including infections, tumors, surgery, trauma, extensive burning, bruises, ischemic heart disease, stroke, peripheral artery disease, aneurysms, inflammatory disease, and pregnancy. The sensitivity of the D-dimer test in clinical trials ranges from 93% to 100%; however, the specificity ranges from 35% to 75%. Therefore, it is effective for ruling out the diagnosis if negative, but a positive D-dimer assay is not specific and requires additional workup. In cases of very high clinical suspicion, testing should be pursued despite a negative D-dimer.
Electrocardiography
The most common finding in PE is sinus tachycardia. The classic ECG changes associated with PE are S wave in lead I, Q wave in lead III, and inverted T wave in lead III (SI, QIII, TIII). However, these findings are neither sensitive nor specific for PE (present in 13.5% of patients with PE). New right axis deviation is another clue for right-sided heart strain from PE.
Imaging
Doppler ultrasonography is the test of choice for diagnosing DVT.3
Sensitivity and specificity for DVT are > 97%, with venography considered the gold standard.
A positive Doppler study should lead one to treat the patient.
A negative study largely rules out the diagnosis, and alternative diagnoses should be considered.
In cases of very high suspicion and negative Doppler study, venography or CT (or MR) venography can be considered.
The most commonly used tests for the diagnosis of PE are CT angiography (CTA) of the lungs or ventilation/perfusion scans (V/Q scans), although the most useful algorithms and radiographic tests used to diagnose acute PE are still debatable and the subject of ongoing trials.4,5
Determining a clinical pretest probability of PE is necessary before performing any diagnostic tests. Objective criteria such as the Wells Criteria (Table 6-2) are commonly used to determine the pretest probability.
The PIOPED trial used V/Q scans in the diagnosis of acute PE (Table 6-3).6
The PIOPED II trial published in 2006 used CTA of the lungs and CT venography of the lower extremities to diagnose PE (Table 6-3).7 As shown in Table 6-3, in patients with a high pretest probability and negative CTA, PE is still present in 40% of cases; therefore, these patients should undergo further testing such as venous compression ultrasonography of the lower extremities or CT venogram of lower extremities.
Based on the results of these trials, an algorithm for the diagnosis of PE has been recommended (Fig. 6-1).8
In special cases such as patients with renal failure, patients with allergy to contrast dye, women of childbearing age, and pregnant women, the recommendations are guided by expert opinion. In these patients, the algorithm should begin with D-dimer testing followed by venous ultrasonography in the majority of cases. Patients with a positive D-dimer and a negative ultrasound will then need additional testing. Ventilation/perfusion scanning can then be used, with the realization that the testing may be nondiagnostic.
Treatment9
Treatment of VTE with unfractionated heparin or LMWH should begin promptly after the diagnosis is established or, in situations of high clinical suspicion, while awaiting confirmatory studies. Thrombolytics may be considered in selected patients with hemodynamically significant PE. Individuals who are actively bleeding or at high risk for bleeding should be considered for inferior vena cava (IVC) filter placement.
Medications
Most common medications used in the treatment of VTE are summarized in Table 6-4.
Low-molecular-weight heparin
A recent meta-analysis concluded that LMWH is superior to unfractionated heparin for the treatment of DVT, with a lower overall mortality over the first 3 to 6 months and a reduced incidence of major bleeding during initial therapy.
In patients with cancer, LMWH for the duration of therapy is superior to oral coumarins in reducing the risk of recurrent thromboembolism without increasing the bleeding risk.10
The duration of anticoagulation is variable and depends on a number of factors, including underlying thrombotic risk and risk of bleeding.11
Current recommendations suggest that 3 months of treatment is adequate for provoked DVT (i.e., an identifiable and reversible risk factor, such as trauma) and most suggest longer treatment, such as 6 months, for PE.
FIGURE 6-1. Algorithm for the diagnosis of PE. (Adapted from Writing Group for the Christopher Study Investigators. Effectiveness of managing suspected pulmonary embolism using an algorithm combining clinical probability, D-dimer testing, and computed tomography. JAMA. 2006;295:172–179.)
Unprovoked VTE or a recurrent episode should be treated for an extended duration. The precise length of treatment is still debated. Many trials have treated patients for 3 months to 1 year after an initial unprovoked VTE. However, recurrent events occurred in similar numbers after treatment was stopped, regardless of the initial length of treatment. Therefore, most experts recommend treatment for 3 to 6 months for unprovoked VTE, with the realization that after completion of therapy there may be a recurrence.
For patients with recurrent VTE, the recommendation is lifelong anticoagulation.
Thrombolytics12
The role of thrombolytics in the management of VTE has not been fully elucidated. Thrombolytics dissolve clot faster than conventional anticoagulation; however, the risk of bleeding is significantly increased.
A recent meta-analysis suggested that thrombolytics should be reserved for patients with PE and circulatory shock, as there are data demonstrating a survival advantage in these patients.
Thrombolytics can be used for DVT to decrease symptoms and postthrombotic syndrome.
Prior to treatment with thrombolytics, clinicians must carefully evaluate the patient for any contraindications to thrombolytic therapy, including recent surgery, bleeding diathesis, recent stroke, active intracranial disease (including neoplasm, aneurysm), pregnancy, and uncontrolled hypertension. A careful risk/benefit analysis is warranted in every patient.
Other Nonpharmacologic Therapies
Inferior Vena Cava Filters13
The use of IVC filters has increased significantly in the past 10 to 20 years, even as evidence supporting their use remains insufficient. Only one randomized controlled trial has compared the use of IVC filters with anticoagulation to the use of anticoagulation alone. At 2 years of follow-up, there was a mild increase in PEs (largely asymptomatic) in those without the filters and an increase in DVT and postthrombotic syndrome in those with the filters. There was no difference in mortality. Retrievable IVC filters have recently been studied with some encouraging results for patients with temporary contraindications to anticoagulation. These filters can be retrieved up to 2 months after initial placement with minimal adverse effects.
The only currently recommended indication for IVC filter placement is in patients with an absolute contraindication to anticoagulation. Potential indications that require additional study include the following:
Patients who developed new VTE on therapeutic anticoagulation
Patients undergoing pulmonary thromboembolectomy
Prophylaxis in high-risk trauma patients
Patients with extensive free-floating iliofemoral thrombus
Patients undergoing thrombolysis of an iliocaval thrombus
Special Considerations
Acute Recurrent Thrombosis
The diagnosis of recurrent venous thrombosis in the same vein can be difficult. Diagnostic tests currently available have difficulty differentiating between a venous occlusion caused by the initial venous thrombosis and a recurrence. The diagnosis of recurrent DVT commonly can only be made with certainty if there is a clot in an area that was documented to be free of thrombus on prior studies. The risk of new thrombosis in adequately anticoagulated patients is very low, but recurrence can occur, particularly in patients with cancer, heparin-induced thrombocytopenia, and the antiphospholipid antibody syndrome.
Venous Thrombosis During Pregnancy
The risk of VTE is five times higher in pregnant women than nonpregnant women. As warfarin is teratogenic and can cause fetal hemorrhage, heparins have been the mainstay of therapy. Currently, the general recommendation is to use LMWH for the duration of pregnancy and then continue therapy with warfarin after delivery.
Thrombosis of Cerebral Veins and Sinuses14
Although rare, the thrombosis of cerebral veins and sinuses is important to identify because, with appropriate treatment, patients often have a good neurologic outcome. Occlusion of cerebral veins leads to localized brain edema and venous infarction, whereas occlusion of the venous sinuses leads to intracranial hypertension. About 85% of patients have an identifiable risk factor, including a thrombophilia, oral contraceptive use, recent trauma (including lumbar puncture), and infection. The most common presenting symptom is unrelenting headache.
The diagnosis can be difficult to make, with an average delay of 7 days from initial presentation to diagnosis. Venography is the current recommended diagnostic modality.
Even with the theoretical risk of causing cerebral hemorrhage, the limited evidence suggests a benefit of rapid initiation of anticoagulation, with therapy continuing for at least 6 months. Endovascular thrombolysis has been attempted in some patients. In patients who develop intracranial hypertension, therapy including repeated lumbar punctures, acetazolamide, and possibly surgical creation of a lumboperitoneal shunt may be warranted. More than 80% of patients have a good neurologic outcome if appropriately treated.
A search for a thrombophilia should be pursued in these patients.
Budd–Chiari Syndrome
Budd–Chiari syndrome encompasses various disease states that result in hepatic vein occlusion. Thrombosis of the hepatic veins leads to hepatomegaly, right-upper quadrant pain, and other sequelae of acute or chronic liver disease. The most common causes of Budd–Chiari syndrome in the Western world are the myeloproliferative disorders. All patients should undergo screening for thrombophilia and age-appropriate malignancy including myeloproliferative disorders. The decision to use anticoagulation should be based on the extent of liver disease and subsequent risk of bleeding. In certain cases, liver transplantation is the treatment of choice.
Mesenteric and Portal Venous Thrombosis
Portal vein thrombosis often presents after the disease has caused splenomegaly and both esophageal and gastric varices. The main risk factors include local causes (pancreatitis, tumor, infection) as well as thrombophilic states such as myeloproliferative disorders. Treatment involves anticoagulation, assuming that the degree of thrombocytopenia related to splenomegaly and the extent of varices are minimal.
Mesenteric venous thrombosis presents acutely, with a mortality rate ranging from 20% to 50%. The usual presentation is severe abdominal pain and bloody diarrhea. Risk factors include intra-abdominal inflammation and thrombophilias. Myeloproliferative disorders are only rarely associated with thrombosis of the mesenteric veins. Treatment includes anticoagulation and surgery if the bowel becomes necrotic.
Renal Vein Thrombosis
Renal vein thrombosis is frequently asymptomatic and incidentally discovered. These patients should be evaluated for nephrotic syndrome as well as other more common thrombophilias. Treatment involves anticoagulation, with thrombolysis reserved for patients with acute and marked deterioration in renal function due to the thrombosis.
Upper Extremity DVT
DVTs occur in the upper extremity in 10% of cases. Risk factors specific to upper extremity DVT include indwelling central venous catheters and local trauma. Patients usually have unilateral upper extremity edema. Diagnosis is by ultrasonography or venography. Approximately one-third of upper extremity DVTs will cause PE, so treatment is essential. While there are limited studies guiding treatment, it is generally recommended to fully anticoagulate patients for at least 3 months. The use of thrombolytics is controversial.
Anticoagulation in Patients with Brain Metastases or Primary Brain Tumors
The use of anticoagulation for patients with either primary brain malignancies or metastases to the brain has been controversial. In the past, it was thought that due to the risk of hemorrhage, anticoagulation should be absolutely contraindicated in these patients. However, the limited evidence currently available suggests that anticoagulation is preferable to IVC filters in the majority of cases. Highly vascular tumors such as melanoma, thyroid, and renal cell metastases are still felt to be contraindications to anticoagulation.
Cancer
Patients with cancer have an increased risk of thrombotic events. In a recent cohort study, the incidence of VTE within the first 6 months of diagnosis was ~12%; the risk increased with chemotherapy and metastatic disease. Cancer of the ovary, pancreas, and lung, and hematologic cancers are associated with a high rate of VTE in the year prior to diagnosis. Thus, occult malignancy as a cause of VTE should always be a consideration in the appropriate clinical scenario.
Trousseau syndrome is a hypercoagulable state associated with malignancy and is characterized by DIC and recurrent arterial or venous thrombotic events. Multiple studies have shown that LMWH is superior to oral coumarins in the treatment of VTE in patients with cancer, with the main benefit in decreasing the recurrence of DVT, with similar overall mortality.
Complications
Chronic PEs can result in pulmonary hypertension leading to right-sided heart failure.
Symptoms vary from venous stasis pigment changes and/or slight pain and swelling to more severe manifestations such as chronic pain, intractable edema, and leg ulcers. Symptoms can be similar to acute DVT; however, image studies showed no DVT. Symptoms can be profound and affect quality of life.
Treatment of the syndrome is largely supportive and often inadequate. Therefore, prevention by appropriately treating initial DVT is important.
Incidence of postthrombotic syndrome can be reduced with prompt anticoagulation and the use of compression stockings. Two trials have suggested that the use of compression stockings for 2 years after the diagnosis of DVT can decrease the incidence of postthrombotic syndrome by half.
THROMBOPHILIA
General Principles
The presence of inherited thrombotic disorders (thrombophilia) has been appreciated for only a few decades. Inherited causes of thrombophilia can be either gain-of-function disorders, in which mutations lead to prothrombotic activity (activated protein C resistance/factor V Leiden, prothrombin G20210A), or loss-of-function disorders, which result in deficiencies of endogenous anticoagulants (antithrombin, protein C, and protein S). Common mutations include factor V Leiden and prothrombin G20210A mutations, while other thrombophilias, such as antithrombin, protein C, and protein S deficiencies, are rare.
Etiology16,17
Activated Protein C Resistance/Factor V Leiden
This is the most common hereditary thrombophilia in the Caucasian population (Table 6-5). More than 90% of patients with activated protein C resistance have the G1691A mutation in the factor V gene (factor V Leiden), which decreases the rate of proteolytic cleavage by activated protein C. Activated protein C resistance test should be used for screening before obtaining factor V Leiden mutation genotype. This test is performed by a clotting assay in which patient plasma is diluted in factor V-deficient plasma; in a positive test, the addition of activated protein C fails to cleave factor V, resulting in prolongation of PTT. Diagnosis is often confirmed by detection of the factor V Leiden mutation by a DNA-based assay. The risk for VTE in heterozygous patients who use oral contraceptives is increased 35-fold.
Prothrombin G20210A Mutation
The prothrombin G20210A mutation is a substitution mutation that results in increased levels of plasma prothrombin, leading to increased generation of thrombin. Assays of prothrombin time or prothrombin antigen are neither specific nor sensitive enough for diagnosis; therefore, diagnosis is made by genotype analysis.
Antithrombin Deficiency
Antithrombin is a plasma protease inhibitor that irreversibly binds and neutralizes thrombin and factors Xa, IXa, and XIa, resulting in reversal of coagulation cascade. This reaction is accelerated by heparin. Therefore, antithrombin deficiency increases risk of thrombosis. Antithrombin deficiency is relatively rare but is considered one of the more severe thrombophilias.
Type I antithrombin deficiency is characterized by both decreased levels and decreased activity, whereas type II is characterized by decreased protease activity, with defects in either the active center or the heparin-binding site. Thus, resistance to the anticoagulant effects of heparin is seen in some patients. There is no difference in clinical severity between type I and type II.
Antithrombin activity assays and antigen levels are used to make the diagnosis. Acute thrombosis, heparin, liver disease, DIC, nephrotic syndrome, and preeclampsia can all decrease antithrombin levels; therefore, diagnosis should not be made on the basis of levels obtained under these conditions.
Prospective studies indicate that the incidence of VTE in these patients is 4% per year. Nearly 70% of patients present with the first thrombotic event before age 35 years.
Protein C and S Deficiency
Proteins C and S are vitamin K-dependent endogenous anticoagulants. Homozygous protein C deficiency can cause neonatal purpura fulminans. Patients with either protein C or protein S deficiency can present with warfarin skin necrosis at the initiation of anticoagulation due to a transient hypercoagulable state.
Protein C deficiency is diagnosed by an assay to detect activity followed by immunoassays to differentiate type I (reduced antigen and activity) and type II (reduced activity) defects. Protein S binds to a plasma protein so that free protein S antigen and activity are used to screen for protein S deficiency and differentiate among type I (decreased antigen and activity), type II (decreased activity), and type III (low free protein S). DNA-based assays are not practical in both protein C and protein S deficiency, given that >150 mutations in the protein C gene have been described. Protein C and S levels are affected by liver disease, anticoagulation with warfarin, nephrotic syndrome, DIC, vitamin K deficiency, oral contraceptives, pregnancy, and hormone replacement therapy.
Elevated Factor VIII Levels
Increased factor VIII levels have been associated with an increased risk of thrombosis (relative risk = 4.8). Elevated levels are found with increased age, obesity, pregnancy, surgery, inflammation, liver disease, hyperthyroidism, and diabetes. No gene alteration has been found, although familial clustering of increased factor VIII levels is noted. It is unclear how increased factor VIII levels lead to increased thrombotic risk and how elevated factor VIII levels may affect treatment of thromboembolism.
Hereditary Thrombotic Dysfibrinogenemia
Dysfibrinogenemias are qualitative defects in the fibrin molecule. Multiple genetic defects have been described. These defects lead to VTE in 20% of patients and bleeding tendency in 25% of patients, but they are asymptomatic in 55%. Normal or low levels of fibrinogen and a prolonged thrombin time may be observed. This disorder is rare, and testing for it in patients with suspected thrombophilia is considered low priority.
Diagnosis
Screening for thrombophilia should be done only in a carefully selected population rather than all patients with first onset of VTE. There are few clinical trial data available to guide the management of symptomatic or asymptomatic thrombophilic patients in different clinical scenarios. Consequently, there is debate about which patients should be screened. Screening symptomatic and asymptomatic individuals and their family members for the presence of thrombophilia has both benefits and drawbacks. Benefits include a focus on prophylaxis with anticoagulant therapy during high-risk situations, such as surgery, immobilization, and pregnancy to prevent a first-time event and an awareness of increased risk associated with oral contraceptive use, pregnancy, and hormone replacement therapy. Drawbacks may include difficul-ties in obtaining life insurance coverage and overanticoagulation, with exposure to unnecessary bleeding risk. Universal screening, even for women considering hormonal therapy, oral contraceptives, or pregnancy, is not currently recommended, as it is not cost-effective and may deny women birth control options.
Consideration of a hypercoagulable workup is usually recommended in patients with
Recurrent VTE, especially unprovoked thrombosis
Thrombosis at a young age (< 50 years)
Thrombosis at unusual sites (cerebral sinus, mesenteric vein, portal vein, hepatic vein)
Recurrent second or third trimester fetal loss, placental abruption, or severe preeclampsia
The optimal time for testing patients for hereditary defects is not well defined, but performing the thrombophilic evaluation at the time of thrombosis is not advised because it often leads to misleading results. As discussed above, acute thrombosis can cause low levels of antithrombin, protein C, and protein S. Therapy with heparin reduces antithrombin levels, and warfarin reduces protein C and S levels. Therefore, it is usually recommended to test (if needed) at the time when patient is off anticoagulation for several weeks without recent thrombosis.
Treatment
There are few clinical trial data to provide evidence-based recommendations for the duration of anticoagulation in patients with hereditary thrombophilia.
Many experts would recommend a longer duration of anticoagulation in patients with
Active cancer
Multiple allelic abnormalities
Antithrombin deficiency
Protein C or S deficiency
More then one thrombotic event
Antiphospholipid antibody syndrome
Some experts recommend lifelong anticoagulation for ptients with
Two or more unprovoked VTEs
Unprovoked VTE with antithrombin deficiency
Multiple genetic abnormalities
One life-threatening VTE
In all patients with a history of a thromboembolic event, regardless of the presence or absence of hereditary thrombophilias, prophylaxis should be pursued with unfractionated heparin or LMWH during high-risk situations, including surgery, trauma, and immobilization. Women should also be advised of the increased risk of recurrent thrombotic events with oral contraceptives, hormone replacement therapy, and pregnancy.
ARTERIAL THROMBOEMBOLISM
General Principles
Definition
Arterial thromboses are those that lodge in the arterial side of the circulatory system. There are two types:
In situ thrombosis due to a damaged artery (e.g., by trauma, vasculitis, or foreign body)
Embolization from a proximal source (e.g., from the atria in atrial fibrillation, a ventricular or arterial aneurysm, a proximal clot formed in an area of damaged artery, or a venous clot that passes into the arterial circulation through a heart defect)
Etiology
Possible hypercoagulable states leading to arterial thrombosis include hyperhomocysteinemia, antiphospholipid syndrome, HIT, myeloproliferative disorders, and paroxysmal nocturnal hemoglobinuria. Of note, these disorders may present with either venous or arterial thrombosis.
Risk Factors
moking
Hypertension
Atherosclerosis
Turbulent blood flow
Diabetes
Chronic inflammation
Hyperlipidemia
Hypercoagulable state
Diagnosis
Clinical Presentation
The symptoms are typically related to the acute ischemia of the organ in which the clot forms or lodges.
Treatment
The initial management of an arterial thrombus includes a search for either its source as an embolus from a distant site or its origin as a clot that formed in situ. The presence of a hypercoagulable state as the etiology of the arterial thrombus may be considered if there are no readily identifiable risk factors.
Special Considerations
Hyperhomocysteinemia18
General Principles
Homocysteine is an intermediate formed in the metabolism of methionine. Elevated levels of homocysteine are associated with arterial and venous thrombosis. Hyperhomocysteinemia can be due to inheritance of enzyme defects involved in the homocysteine metabolic pathways or can be acquired. Severe hyperhomocysteinemia (plasma levels > 100 μmol/L) is most commonly due to defects in cystathionine B-synthase, which results in homocystinuria, mental retardation, and thromboses at a young age. The most common genetic defect in mild homocysteinemia (plasma levels, 15 to 40 μmol/L) results in reduced activity of the enzyme methylenetetrahydrofolate reductase. Prospective studies show that the relative risk for VTE in patients with hyperhomocysteinemia is 3.4.
Acquired causes
Vitamin B 12, vitamin B 6, and folate deficiencies
Chronic renal failure
Hypothyroidism
Cancer
Increasing age
Smoking
Inflammatory bowel disease
Psoriasis
Rheumatoid arthritis
Methotrexate, phenytoin, and theophylline
The diagnosis is made by measuring fasting homocysteine plasma levels.
Treatment
Patients deficient in folate, vitamin B6, or vitamin B12 can be supplemented with these vitamins at sufficient doses to achieve normal levels. In the absence of specific deficiencies, plasma homocysteine levels can be reduced by up to 50% by administration of folate at doses of 1 to 2 mg/d, although it is uncertain whether this ultimately leads to a decreased frequency of adverse events. In patients with severe hyperhomocysteinemia due to cystathionine B-synthase deficiency, treatment with vitamin B supplements improves homocysteine levels and delays thrombotic events. In several recent studies, patients with first-time events, either arterial (stroke, myocardial infarction [MI]) or VTE, treated with vitamin supplementation had reductions in homocysteine levels but no protection from recurrent MI, recurrent venous thrombosis, or progression of peripheral vascular disease. Therefore, the role of homocysteine in thrombosis is still debated.
Antiphospholipid Syndrome19
General Principles
Antiphospholipid syndrome is characterized by recurrent venous or arterial thrombosis and/or recurrent pregnancy morbidity/fetal loss and the presence of antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulants, anti-B2-glycoprotein 1). Antiphospholipid antibodies are autoantibodies that recognize phospholipids and/or phospholipid-binding proteins. Lupus anticoagulants are IgG or IgM antibodies that react with negatively charged phospholipids. In vitro they act as anticoagulants and interfere with membrane surfaces in clotting assays, resulting in false prolongation of the aPTT and, rarely, the PT. The pathogenesis of antiphospholipid antibodies is thought to involve the binding and subsequent activation of endothelial cells, platelets, and complement to promote thrombosis and the inhibition of the fibrinolytic pathway.
The syndrome is considered primary if there is no accompanying autoimmune disease and secondary if the patient has systemic lupus erythematosus (SLE).
Clinical Presentation
Approximately 30% to 50% of patients develop DVT of the legs within 6 years of follow-up. Although venous thrombosis is more common, patients may present with arterial occlusions, the most frequent involving the brain, followed by coronary occlusions. Any vessel or vascular bed may be involved and diverse presentations, such as intestinal, pancreatic, or splenic infarction; ARDS; retinitis; and acute renal failure, may occur. Other features occasionally seen include thrombocytopenia, hemolytic anemia, and livedo reticularis. Catastrophic antiphospholipid syndrome, characterized by multiple simultaneous thromboses, occurs in <1% of patients and is associated with multiorgan failure and death.
Diagnosis relies on meeting at least one of the clinical and one of the laboratory criteria as below.
Clinical
One or more episodes of venous, arterial, or small vessel thrombosis
Pregnancy morbidity—at least one unexplained death of a morphologically normal fetus beyond the 10th week of gestation; at least three unexplained spontaneous abortions before the 10th week of gestation; or one or more premature births secondary to eclampsia, preeclampsia, or placental insufficiency before the 34th week of gestation
Laboratory
Lupus anticoagulant present on two or more occasions at least 12 weeks apart. The presence of the lupus anticoagulant may be confirmed with the dilute Russell’s viper venom assay or phospholipid neutralization assay.
Anticardiolipin antibody of IgG or IgM isotype presents at medium or high titer on two or more occasions at least 12 weeks apart.
Anti-B2 - glycoprotein 1 of IgG or IgM isotype presents on two or more occasions at least 12 weeks apart. Anticardiolipin and anti-B2 -glycoprotein 1 are detected by immunologic assays.
Treatment
The treatment of antiphospholipid syndrome is lifelong anticoagulation, typically with warfarin, with the goal INR 2.0 to 3.0. Hydroxychloroquine and ASA may be used as adjunct therapy. Plasma exchange and rituximab have been used to treat patients with catastrophic antiphospholipid syndrome, although these approaches are based on case studies and not on clinical trials.
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