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Hypercoagulability Syndromes REVIEW ARTICLE Hypercoagulability Syndromes Robert H. Thomas, MD ypercoagulability can be defined as the tendency to have thrombosis as a result of certain inherited and/or acquired molecular defects. Clinical manifestations of hy- percoagulability can be devastating and even lethal. In the past 20 years, the origin of most of these diverse hypercoagulability syndromes has been elucidated. Cur- Hrently, hypercoagulability disorders can be correctly diagnosed in approximately 80% to 90% of patients. Defining the cause of hypercoagulability may determine the type and duration of treat- ment for the associated thrombosis. The discovery of an occult carcinoma allows for the possibil- ity of early and possibly curative treatment. Finding a genetic defect in coagulation allows for test- ing of asymptomatic family members as well. The purpose of this review is to provide internists with a logical approach to the identification and treatment of hypercoagulability syndromes. Arch Intern Med. 2001;161:2433-2439 Most commonly, thrombosis is the result depending on the ethnic backgrounds of of more than one “hit.” For example, pa- persons in a particular geographic area. tients with the factor V Leiden defect may be asymptomatic until they start taking oral Disorder Incidence, % contraceptives. Patients with antithrom- Antiphospholipid antibody 28 syndrome bin deficiency may go on without inci- Activated protein C resistance 25 dent until they undergo a hernia repair. Elevated coagulation factor VIII 25 Also, multiple genetic defects predispose levels one to thrombosis much more than does Malignancy 15 a single defect.1,2 Some defects are known Sticky platelet syndrome 14 to be more powerful predictors than oth- Protein C deficiency 10 ers. Therefore, hypercoagulability is not Protein S deficiency 10 Homocystinemia 10 a uniform disease process but rather a host Prothrombin G20210A 5-10 of predisposing conditions that may or may Plasminogen deficiency 2-3 not be expressed as thrombosis, depend- Dysfibrinogenemia 1.5 ing on environmental insults and the Plasminogen activator inhibitor 1-3 strength and number of predisposing fac- increase tors. Tissue plasminogen 1 activator deficiency INDIVIDUAL SYNDROMES Antiphospholipid Antibody Syndrome The following is a list of the disorders that cause hypercoagulability and their ap- The antiphospholipid antibody syn- proximate incidences. Since these were de- drome is probably the most common of the rived from different studies, percentages hypercoagulable disorders. It is caused by cannot be exact. Also, incidences may vary, a heterogeneous family of immunoglobu- lins that bind to plasma proteins that have From the Department of General Medicine, University of Miami School of Medicine, an affinity for phospholipid surfaces. These Miami, Fla. antigens include B2 glycoprotein I, pro- (REPRINTED) ARCH INTERN MED/ VOL 161, NOV 12, 2001 WWW.ARCHINTERNMED.COM 2433 ©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 thrombin, high- and low-molecular- clude valvular abnormalities, livedo 80-fold.17 Heterozygous factor V weight kininogens, annexin V, ac- reticularis, superficial thrombophle- Leiden is, therefore, a relatively mild tivated protein C, and activated pro- bitis, ulcers, adrenal hemorrhage, fe- risk factor for thrombosis.15,18 The an- tein S. It is usually acquired and can tal wastage, chorea, transverse my- nual rate of thrombosis is 0.28%.19 Six be divided into the lupus anticoagu- elopathy, and thrombocytopenia. percent of patients will have a throm- lant syndrome and the anticardio- The treatment of patients with bosis by the age of 65 years.20 Sixty lipin antibody syndrome. Both of antiphospholipid antibody syn- percent of patients who experience these syndromes may be associated drome who have had thrombosis is thrombosis have a predisposing event, with other disorders, such as colla- long-term anticoagulation until the such as oral contraceptive use or preg- gen vascular diseases or infections, antibody has been absent for at least nancy.21 The presence of this muta- but are more often primary. Anti- 6 months.8 The drug of choice is low- tion does not appear to affect life ex- phospholipid antibody syndrome molecular-weight heparin sodium pectancy, and many patients will can also be associated with use of the since in 65% of patients warfarin so- remain asymptomatic. Therefore, pa- following medications: phenytoin, dium therapy fails8 and the interna- tients with no history of thrombosis quinidine, hydralazine, procain- tional normalized ratio is unreliable should not be treated prophylacti- amide hydrochloride, phenothi- in monitoring the intensity of therapy. cally with long-term anticoagula- azines, interferon, cocaine, qui- If warfarin must be used, an interna- tion.22 Functional tests for activated nine, and the combination product tional normalized ratio target range protein C resistance should be used of pyrimethamine and sulfadoxine. of 3 to 4 should be sought.9 The treat- to screen for the disorder, and posi- Usually, a patient will have one syn- ment of fetal wastage syndrome is be- tive results should be confirmed with drome or the other but not both. yond the scope of this review. There polymerase chain reaction for the ge- Multiple mechanisms as to the rea- is no clear indication for therapy in netic mutation. However, patients son for hypercoagulability have been asymptomatic persons; however, as- with phenotypic resistance to acti- postulated, but the exact cause is un- pirin therapy would be reasonable in vated protein C have an increased risk known at this time. The risk of this population because the risk of of thrombosis even if it is not due to thrombosis is 5.5% per year for thrombosis is higher than normal. factor V Leiden.20 Functional tests symptomatic patients.3 Other treatments, such as corticoste- may still be performed while pa- The lupus anticoagulant is di- roids, cyclophosphamide, and plasma tients undergo anticoagulation. rected against phospholipids, which exchange, have been used for se- then causes an in vivo prolongation verely symptomatic disease, but their Elevated Coagulation in the prothrombin time (PT), par- roles in routine management are not Factor VIII Levels tial thromboplastin time (PTT), or the well established. Russell viper venom time. These val- Elevated coagulation factor VIII lev- ues do not correct with normal Activated Protein C Resistance els appear to be nearly as common a plasma. However, the addition of risk factor for thrombosis as factor V phospholipids will correct the ab- Activated protein C resistance (eg, fac- Leiden. The Leiden Thrombophilia normality. Despite the prolonged co- tor V Leiden) is the most common in- Study found an 11% incidence in agulation times, thrombosis is the herited disorder that causes hyper- healthy controls and a 25% inci- predominant feature of this syn- coagulability. Factor V Leiden is dence in patients with venous throm- drome. The PT and PTT are not sen- present in 5% of whites but virtually bosis. The odds ratio for thrombosis sitive enough to be used as a screen- absent in Africans and Asians. How- was 4.8 for subjects with levels greater ing tool for the lupus anticoagulant. ever, 1% of African Americans have than 150 IU/dL vs those with levels Instead, the Russell viper venom time the mutation, reflecting racial mix- less than 100 IU/dL.23,24 For every 10- must be used. Venous thrombosis is ing.10 It results from a point muta- IU/dL rise in levels, the risk for a single much more common than arterial tion in the factor V gene, which causes episode of deep venous thrombosis thrombosis in these patients.4 the substitution of glutamine for ar- (DVT) increases 10% and the risk for The anticardiolipin antibody ginine at position 506.11 (Several other recurrent DVT increases 24%.25 Lev- syndrome is 5 times more common rare factor V gene mutations that can els of coagulation factor VIII are not than the lupus anticoagulant syn- lead to activated protein C resis- elevated because of the acute-phase drome.5 Antibodies can be detected tance have also been described.12-14) reaction but appear to be constitu- by enzyme-linked immunosorbent as- Consequently, 1 of 3 activated pro- tively increased in most patients with say. Both IgG and IgM are associated tein C cleavage sites is lost. The re- thrombosis, since coagulation factor with thrombosis.4,5 A total of 1% to sult is an impaired inactivation of fac- VIII levels are elevated indepen- 7% of asymptomatic individuals have tor V by activated protein C. Venous dently of C-reactive protein and fi- low titers of these antibodies.6 Even thromboses and fetal wastage may oc- brinogen, and 94% of patients con- asymptomatic persons have a 1% risk cur. It is not an important risk factor tinue to have high levels throughout per year of thrombosis. This in- for arterial disease except in the pres- long-term follow-up.26,27 Pregnancy creases to 6% in those with high ti- ence of smoking or other known risk and oral contraceptive use may also ters.7 This contrasts with a 0.1% risk factors.15,16 Those with factor V Leiden raise levels. The use of oral contra- per year in the general population. Ve- have a 2- to 3-fold risk for venous ceptives in patients with increased co- nous and arterial thrombi are equally thrombosis compared with healthy agulation factor VIII levels raises the common.4 Other manifestations in- subjects. The risk in homozygotes is risk of thrombosis 10-fold over pa- (REPRINTED) ARCH INTERN MED/ VOL 161, NOV 12, 2001 WWW.ARCHINTERNMED.COM 2434 ©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 tients with neither risk factor.28 The should be continued indefinitely un- function. Deficiency of protein C oc- genetic basis for increased coagula- til the patient is cured of the malig- curs in 1 of 250 controls.35 Protein tion factor VIII levels is not well un- nancy and is no longer receiving che- C is made in the liver and is vita- derstood at this time; however, one motherapy.
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