2.2. Bases Teóricas
2.2.1 ARTICULACION TEMPOROMANDIBULAR
Patients with TTP-HUS develop consumptive thrombocytope- nia and microangiopathic hemolysis from platelet thrombi that form throughout the microvasculature. The multi-system nature
156 • Hematology
Table 2. Laboratory Tests to Support the Diagnosis of Idiopathic Thrombocytopenic Purpura (ITP)
Test Notes
CBC Low platelet count with normal hemoglobin/hematocrit and leukocyte count is evidence for the diagnosis of ITP. Peripheral blood smear Exclude platelet clumping (pseudothrombocytopenia). Myeloid and erythroid morphology should be normal. Platelets
should appear normal or large in size. Abnormal or immature leukocytes should be absent. The presence of schistocytes is associated with TTP and is evidence against ITP. The presence of polychromatophilia, poikilocytosis, and spherocytes suggests hemolytic anemia. Nucleated erythrocytes should be absent.
Bone marrow aspiration Consider bone marrow aspiration and biopsy to establish the diagnosis in patients with atypical or nondiagnostic findings or with additional abnormalities on the peripheral blood smear; ITP will show normal or increased numbers of
megakaryocytes, normal myeloid and erythroid morphology, and no malignant cells. HIV antibodies Indicated in patients with risk factors for HIV.
PT/PTT Coagulation testing is not recommended for routine diagnosis; however, an abnormal PT or PTT is evidence against ITP. ANA and other serologic tests ANA not recommended for routine diagnosis; however, consider ANA and other serologic tests such as rheumatoid factor,
complement levels, and anti-DNA in patients with rash, synovitis, arthralgias, or other signs of rheumatologic disease.
of this syndrome is unpredictable. Fever, renal disease, and fluc- tuating neurological abnormalities are parts of the syndrome but are seldom all present during earlier phases of the illness. TTP- HUS is a syndrome with diverse triggers and pathophysiology, including abnormal von Willebrand’s factor metabolism and very high-molecular-weight polymers that predispose to platelet microthrombi. Some patients with TTP have an autoantibody that inhibits a metalloproteinase (ADAMTS13) that normally cleaves unusually large von Willebrand’s factor multimers into smaller fragments. Pregnant women, HIV-infected patients, and patients receiving cancer chemotherapy or immunosuppression following organ transplantation are at increased risk.
Children develop the hemolytic uremic syndrome with promi- nent gastrointestinal symptoms from Shiga-toxin–producing enteric bacteria such as E. coli 0157-H7.
Laboratory findings of a microangiopathic hemolysis, includ- ing prominent schistocytes on peripheral blood smear (Plate 32), decreased haptoglobin, and elevated serum lactate dehydrogenase along with thrombocytopenia suggest TTP-HUS syndrome. Assays for ADAMTS13 activity may help to confirm the diagno- sis, but the test is neither uniformly standardized nor easily avail- able, and therapy should not be withheld while awaiting test results. Malignant hypertension, disseminated intravascular coagulation, and prosthetic heart valves can be associated with
microangiopathic hemolysis, although the additional presence of thrombocytopenia, fever, renal, and neurological findings strongly supports the diagnosis of TTP-HUS.
Treatment consists of plasma exchange and corticosteroids. Platelet transfusions in patients with untreated TTP-HUS are associated with acute renal failure, stroke, and sudden death and are contraindicated.
Book Enhancement
Go to www.acponline.org/essentials/hematology-section.html to view images of petechiae and peripheral blood smears show- ing platelet clumping and schistocytes, and to access a systematic review on drug causes of thrombocytopenia. In MKSAP for
Students 4, assess yourself with items 18-22 in the Hematology
section.
Bibliography
Sekhon SS, Roy V.Thrombocytopenia in adults: A practical approach to evaluation and management. South Med J. 2006;99:491-8; [PMID: 16711312]
Simantov R.Idiopathic Thrombocytopenic Purpura. http://pier.acponline .org/physicians/diseases/d340. [Date accessed: 2008 Jan 11] In: PIER [online database]. Philadelphia: American College of Physicians; 2008. Thrombocytopenia • 157
158
T
hrombosis can represent a normal response to injury or an unwanted response to an inciting factor. Factors limiting thrombosis include rapid blood flow and dilution of acti- vated factors, a non-thrombogenic endothelium, inhibitors to coagulation factors, and a fibrinolytic system that degrades fibrin clots. Venous stasis limits blood flow and allows activated factors to accumulate, vascular injury disrupts the endothelium and exposes platelet and coagulation active surfaces, and a defect or deficiency of inhibitors or lytic factors allows coagulation activa- tion to go unchecked. Thrombophilia refers to patients with an increased risk of thrombosis. Thrombophilia risk factors can be congenital or acquired, permanent or transient. They act by dis- rupting the blood flow, the blood vessel, or the procoagulant/ anticoagulant regulatory pathways. In the normally function- ing anticoagulant pathway, thrombin bound to thrombomodulin on the endothelial cell surface activates protein C which binds to cofactor protein S on the platelet surface resulting in the degra- dation of factors V and VII. Antithrombin is another major reg- ulatory protein of the coagulation cascade. It irreversibly binds and neutralizes activated factors II, IX, and X. Genetic amino acid defects or vitamin B12and B6deficiency may result in an elevated homocystine concentration, which in turn may result in throm- botic and atherosclerotic reactions. Thrombophilia may also be due to abnormally elevated levels of prothrombin, deficienciesof antithrombin, protein C, the cofactor protein S, thrombo- modulin, or an abnormal factor V that cannot be degraded by activated protein C. The evaluation of thrombophilia begins by establishing which risk factors are present (Table 1). A family his- tory is a particularly strong indicator of risk and prompts consid- eration of congenital disorders.
Until 1993, a genetic cause of thrombophilia was detected in only 5%-15% of patients and was limited to deficiencies of antithrombin, protein C, and protein S. The discovery of two prothrombotic mutations, the factor V-Arg506Gln (factor V Leiden) mutation and the prothrombin G20210A mutation, has greatly increased the percentage of patients in whom a hereditary risk factor is identifiable. The total incidence of an inherited thrombophilia in patients with deep venous thrombosis is approx- imately 30% compared with about 10% in patients without deep venous thrombosis. The pathogenesis of venous thromboem- bolism, however, is multifactorial, and more than 90% of persons with the factor V Leiden or the prothrombin G20210A mutations never have a venous thromboembolism (VTE).
Screening
A family history of thrombosis in a first-degree relative has a pos- itive predictive value of only 14% for factor V Leiden, the most
Chapter 42
Thrombophilia
Patrick C. Alguire, MD
Table 1. Risk Factors For Venous Thromboembolism (VTE)
Disease Notes
Immobility Prolonged immobilization (>72 hours) increases the risk for VTE. High risk includes recent stroke with paresis, MI, HF, and pulmonary disease.
Inherited thrombophilia Family history of thrombosis or thrombophilia; personal history of VTE under age 45, recurrent thrombosis, or thrombosis at an unusual site; personal history of arterial thrombosis under age 50 (MI, stroke); personal history of pregnancy complications (fetal demise, abruption).
Malignancy Includes solid and hematologic cancers, especially myeloproliferative disorders. Ongoing treatment, palliation, or a diagnosis within the prior 6 months all increase risk. Screen all patients with VTE for malignancy with age- and sex-appropriate screening (e.g., mammograms for women over age 50 and Pap smears for women over age 18); CBC and liver tests; chest x-ray for all smokers. The utility of screening for malignancies, with regard to morbidity and survival, is not known. Previous thrombosis Even in the absence of a recognized thrombophilic condition, the risk for VTE increases in any patient with a history of
thrombosis.
Surgery All but minor procedures in the last month represent an increased risk for VTE. Hip, knee, and pelvic surgeries are highest risk. Trauma Trauma (especially of the lower limb, with or without plaster immobilization) within the last month increases risk for VTE,
especially spinal injuries.
Erythropoiesis stimulating When administered to patients with cancer to treat chemotherapy-associated anemia, erythropoietin and darbepoietin are agents associated with increased risks of VTE and mortality.
Thrombophilia • 159
common of the thrombophilias; therefore the clinical utility of thrombophilia screening has been questioned. Nevertheless, some experts believe that the benefits of screening family mem- bers of patients with documented hereditary defect can be clini- cally important to the individual patient, particularly if they are exposed to high-risk situations such as use of birth control pills or initiating hormone replacement therapy.
Diagnosis
Strongly consider the diagnosis of an inherited thrombophilia in: • VTE in the absence of obvious risk factors (e.g., cancer,
prolonged immobility, recent trauma, surgery)
• VTE at age <50 years or in patients who have a positive family history for thrombophilia
• Women with VTE while receiving oral contraceptive pills or hormone replacement therapy, or during pregnancy • Women who develop myocardial infarction at age <45 years,
particularly if cigarette smokers (look specifically for factor V Leiden mutation)
• Women with unexplained complications of pregnancy (e.g., unexplained recurrent miscarriages, stillbirth, intrauterine growth retardation, abruptio placenta, severe preeclampsia) • Patients at age <50 years with unexplained cerebrovascular
accident, ischemic heart disease, or peripheral vascular disease (look specifically for anticardiolipin antibodies, lupus anticoagulant, and hyperhomocystinemia)
Factor V Leiden, prothrombin gene mutations, and hyperho- mocystinemia are by far the most common defects; factor V Leiden and prothrombin gene mutations are found almost exclu- sively in persons of European heritage. The presence of a lupus anticoagulant is suggested by the paradoxical finding of throm- bosis associated with a prolonged partial thromboplastin time test.
Avoid testing during an acute episode of thrombosis, because protein levels may be transiently low as a result of consumption. Avoid testing while a patient is taking anticoagulants. In particu- lar, heparin may decrease antithrombin levels or mimic a lupus anticoagulant, and warfarin will decrease protein C and protein S levels. Finally, confirm all test results before assigning a specific diagnosis; laboratory abnormalities can be transient and a single positive test may be unreliable (Table 2).
Therapy
Certain thrombophilias (hyperhomocystinemia, lupus anticoagu- lant, anticardiolipin antibodies) are associated with increased arte- rial vascular disease. The combination of smoking and these con- ditions may increase vascular risk. Dehydration and prolonged immobility are additional risk factors for VTE. Advise all patients to stop smoking and patients at risk to avoid dehydration and pro- longed immobility.
Patients with VTE and certain thrombophilias are at especial- ly high risk for recurrent VTE. The benefit of long-term antico- agulation in these high-risk patients may outweigh the risk of bleeding complications. Recommend lifelong therapeutic antico- agulation in patients with VTE and any of the following throm- bophilias: lupus anticoagulant, anticardiolipin antibodies, homo- zygosity for the factor V Leiden mutation, homozygosity for prothrombin gene defect, combined heterozygosity for factor V Leiden mutation and prothrombin gene defect, and antithrombin III deficiency. Provide only temporary prophylactic anticoagula- tion in all other patients with documented thrombophilias during high-risk situations such as surgery, prolonged immobilization, and pregnancy.
Consider the use of folic acid supplementation, vitamin B6
supplementation, and oral vitamin B12 supplementation in
patients with VTE or arterial thrombosis who also have high
Table 2. Laboratory and Other Studies for Thrombophilia
Condition Test
Activated protein C resistance 95% of activated protein C resistance is due to the factor V Leiden gene mutation; thus, the activated protein C resistance assay is a good screen. False-positive results in pregnancy and oral contraceptive pill use. Confirmed positive test result with testing for the factor V Leiden gene mutation.
Factor V Leiden gene mutation A direct PCR gene test. Test of choice for activated protein C resistance in patients who are pregnant or receiving estrogen or oral contraceptive pills.
Prothrombin gene mutation A direct PCR gene test.
Protein C deficiency Select both antigenic and functional assay. Active thrombosis and use of warfarin may cause false-positive results. Protein S deficiency Select both antigenic and functional assay. Active thrombosis, use of warfarin, and pregnancy may cause
false-positive results.
Antithrombin III deficiency Select both antigenic and functional assay. Active thrombosis and use of heparin may cause false-positive results. Fasting plasma homocysteine level The risk for thrombosis increases as levels exceed 10 µmol/L. Renal failure and vitamin deficiencies can cause
false-positive results. Pregnancy may artificially lower levels.
Lupus anticoagulant Test with partial thromboplastin time. If prolonged, perform mixing study; mixing with normal plasma will not correct study if lupus anticoagulant is present.
Anticardiolipin antibodies ELISA testing. Levels fluctuate; thus, positive tests should be repeated several weeks apart. (immunoglobulin G, immunoglobulin M)
plasma homocysteine levels. Hyperhomocystinemia has been implicated in the development of VTE and arterial thrombosis, which may be associated with defects in pathways using these fac- tors or low levels of these vitamins.
Follow-Up
Follow patients with thrombophilias closely for the development of thrombotic events. Do not obtain regular laboratory studies once the diagnosis of a thrombophilia has been established, except in patients who require monitoring of anticoagulant therapy. Do not repeat thrombophilia testing or regular routine blood work in patients in whom a diagnosis of a thrombophilia has already been established. Periodically check platelet levels in patients with anti- cardiolipin antibodies or lupus anticoagulant, because these indi- viduals may have thrombocytopenia as part of their clinical picture.
Book Enhancement
Go to www.acponline.org/essentials/hematology-section.html to review common sites of thrombosis and recommendations for the duration of anticoagulation therapy for inherited throm- bophilias. In MKSAP for Students 4, assess yourself with items 23- 24 in the Hematology section.
Bibliography
Bick RL. Hereditary and acquired thrombophilic disorders. Clin Appl Thromb Hemost. 2006;12:125-35. [PMID: 16708115]
Karovitch A, Rodger M. Thrombophilia. http://pier.acponline.org/ physicians/diseases/d647. [Date accessed: 2008 Jan 18] In: PIER [online database]. Philadelphia: American College of Physicians; 2008. 160 • Hematology