Antithrombin deficiency, congenital

* Objectives.-To review of the state of the art relating to congenital heparin cofactor II deficiency as a potential risk factor for thrombosis, as reflected by the medical literature and the consensus opinion of recognized experts in the field, and to make recommendations for the use of laboratory assays for assessing this thrombotic risk in individual patients.

Data Sources.-Review of the medical literature, primarily from the last 10 years.

Data Extraction and Synthesis.-After an initial assessment of the literature, including review of clinical study

design and laboratory methods, a draft manuscript was prepared and circulated to participants in the College of American Pathologists Conference XXXVI: Diagnostic Issues in Thrombophilia. Recommendations were accepted if a consensus of experts attending the conference was reached. The results of the discussion were used to revise the manuscript into its final form.

Conclusions.-Consensus was reached that there is insufficient evidence to recommend testing for heparin cofactor II deficiency in patients with thromboembolic disease.

(Arch Pathol Lab Med. 2002;126:1394-1400)

Heparin cofactor II (HCII) is a serine protease inhibitor (serpin that is synthesized bv the liver and circufates in plasma at a concentration of ~1(mu)M.1 Heparin cofactor II inhibits thrombin but has no activity against other proteases involved in coagulation or fibrinolysis. The rate at which HCII inhibits thrombin increases more than 1000-fold in the presence of heparin, heparan sulfate, or dermatan sulfate. Heparin cofactor II is unique among serpins in its ability to be stimulated by dermatan sulfate, and it binds to a minor subpopulation of dermatan sulfate oligosaccharides. Turnover studies of labeled HCII in humans suggest that ~40% of the protein equilibrates with an extravascular compartment,2 but the distribution of HCII in various tissues has not been thoroughly investigated. Heparin cofactor II has been detected in the intima of normal human arteries, and the ability of dermatan sulfate in the arterial wall to stimulate HCII is decreased in atherosclerotic lesions.3 Whether decreased HCII activity in these lesions contributes to thrombosis or restenosis after angioplasty remains to be determined.

PATHOPHYSIOLOGY

Although the presence of thrombin-HCII complexes in human plasma suggests that HCII inhibits thrombin in vivo,4,5 the physiologic function of this serpin is unknown. Indirect evidence suggests that HCII activity increases during pregnancy. During the third trimester, plasma HCII levels are ~140% of normal,6-8 thrombin-HCII complexes are elevated -fourfold,4 and both maternal and fetal plasma contain trace amounts of a dermatan sulfate proteoglycan that stimulates thrombin inhibition by HCII.9 The placenta is rich in dermatan sulfate and may be the source of this proteoglycan. Conversely, HCII levels are ~50% of normal in women with severe preeclampsia in whom antithrombin levels are near normal,7 suggesting that decreased HCII activity may be associated with placental dysfunction.

Knockout mice have recently been developed as a tool to investigate the physiologic function of HCII.10 Unlike antithrombin-deficient mice, which die in utero with extensive fibrinogen) deposition in the liver and myocardium,11 HCII-deficient mice undergo normal fetal development and are born at the expected mendelian frequency. Their subsequent growth and survival is normal up to at least 1 year of age, and they do not appear to have spontaneous thrombosis or other morphologic abnormalities. Blood tests also indicate normal hematopoiesis, as well as normal liver and kidney function. Crosses in which both parents are HCII-deficient produce litters similar in size to those from heterozygous matings, suggesting that HCII is not required for normal gestation in mice. In comparison with wild-type animals, however, HCII-deficient mice demonstrate a significantly shorter time to thrombotic occlusion of the carotid artery after photochemically induced damage to the endothelium.10 These observations suggest that HCII might inhibit thrombosis following arterial injury.

TEST METHODS

Heparin cofactor II activity is conveniently assayed by measuring the inhibition of human thrombin in the presence of (heparin-free) dermatan sulfate.12 Addition of polybrene permits determination of HCII activity in samples containing

Heparin cofactor II assays are usually standardized with normal pooled plasma containing 100% or 1 U/mL HCII by definition. The absolute amount of HCII in normal human plasma has been estimated to be ~1.2 +/0.4(mu)M (mean +/- SD).12 An Italian study of 4000 unselected people aged 18 to 65 years reported HCII activities of 93.0% +/- 16.2% (mean +/- 1 SD), which deviated significantly from the normal distribution.15 Positive correlations were found between the HCII level and several other variables, including plasma fibrinogen, serum cholesterol and triglycerides, and oral contraceptive use.16,17 No correlation was found between HCII levels and either sex or age in this adult population, although smaller studies suggested that mean HCII levels increase ~30% between the third and the fifth or sixth decades of life and decrease thereafter.13,18,19 Heparin cofactor II levels are low at birth (~50% in healthy, full-term infants; ~30% in healthy, premature infants) but approach adult levels by 6 months of age.20-23 The mean HCII level appears to remain ~10% below the normal adult mean until the age of 16 years.24

During episodes of venous thrombosis, HCII levels may be transiently elevated (10%-20% above normal) as part of the acute phase response.25 However, HCII levels do not appear to be affected by the administration of heparin or oral anticoagulants.13,25-27 Heparin cofactor II levels are normal in the vast majority of patients with antithrombin deficiency26,28-34 and in most patients with the lupus anti-- coagulant.35-37 Normal HCII levels are found in women with subclinical hypothyroidism.38 Moderately elevated levels of HCII (20%-40% above normal) have been reported in some,13,39-41 but not all,33,42-45 patients with nephrotic syndrome and in some patients with pneumonia or hemorrhagic stroke.46

Two groups reported that HCII levels are elevated (~40% above normal) during the third trimester of pregnancy and return to normal within 72 hours postpartum6-8; however, this increase was not observed in 2 smaller studies.26,47 Heparin cofactor II levels appear to be depressed in women with severe preeclampsia.7,47 Heparin cofactor II levels are moderately increased (15%-40% above normal) in women taking oral contraceptives,6,31,48,49 but may be slightly depressed in postmenopausal women receiving hormone replacement therapy.49

INHERITED HCII DEFICIENCY

Inherited deficiency of HCII has been documented in at least 15 families (Table 1).13,32,50-60 In most cases, the defect was transmitted from one generation to the next as an autosomal dominant trait in which affected individuals had reduced plasma levels of both HCII activity and antigen (~50% of normal). Several frameshift and missense mutations in the HCII gene (designated SERPIND1 on chromosomal band 22q11.21) have been identified in these individuals with "type 1" deficiency (Table 2).58,60-62 Two unrelated probands with "type 2" deficiency have been identified52; both had normal HCII antigen levels but ~50% activity as determined by assays of thrombin inhibition in the presence of dermatan sulfate. The abnormal variant in both cases bound heparin normally but failed to bind dermatan sulfate as demonstrated by crossed immunoelectrophoresis. This variant, designated HCII Oslo, contained a missense mutation (Arg189 -> His) in the glycosaminoglycan-binding site.63 In the only reported occurrence of homozygous HCII deficiency, the proband and her sister each had 10% to 15% of normal plasma HCII activity and 2% to 5% antigen, while their heterozygous relatives had activity and antigen levels in the range of 33% to 58%.59 The proband was homozygous for a missense mutation (Glu428 -> Lys) near the reactive site that may impair, but not completely eliminate, hepatic secretion of the protein.62

In 7 of the 15 families with HCII deficiency, the proband had a history of deep vein thrombosis and/or pulmonary embolism (see Table 1).13,50,53,55,57-59 However, 3 of the symptomatic probands, including the woman with homozygous HCII deficiency, had another risk factor for thrombosis (ie, antithrombin deficiency,59 protein S deficiency,57 or factor V Leiden58). In the remaining families, the HCII-deficient proband was a normal blood donor,52 had a questionable history of deep vein thrombosis,13 or had a history of arterial disease51,56,60 or spontaneous abortion.53 Among the 58 family members who were found to have HCII deficiency (probands not included), 10 (17%) had histories of thrombotic disease (6 venous and 4 arterial) and 1 had a history of spontaneous abortion. The sister of the proband who was homozygous for HCII deficiency, as well as 12 heterozygous HCII-deficient family members, had no history of thrombosis.59 An additional 74 members of the 15 families were found to have normal levels of HCII; 3 of these individuals (4%) had histories of thrombotic disease. Based on these case reports, most authors have concluded that inherited HCII deficiency is not a strong risk factor for thrombosis or that it contributes to thrombotic risk only when combined with other deficiencies. In a large family with multiple risk factors for venous thromboembolism, however, 4 individuals with HCII deficiency combined with other abnormalities (ie, protein S deficiency, protein C deficiency, or both antithrombin and protein S deficiency) were asymptomatic.32

PREVALENCE OF HCII DEFICIENCY

At least 16 groups have estimated the prevalence of HCII deficiency in patients with venous thromboembolism, retinal vein thrombosis, cerebral venous sinus thrombosis, or arterial thrombosis (including stroke and transient ischemic attacks) (Table 3).* These studies were heterogeneous in terms of assay methodology and criteria for deficiency. Overall, among 4891 patients tested, 54 (1.1%) were considered to have HCII deficiency. By comparison, 9 (1.0%) of 868 healthy volunteers were HCII deficient. Thus, heterozygous deficiency of HCII may be a coincidental finding in ~1% of patients with thrombosis, and most authors believe that HCII deficiency is not a strong risk factor for development of disease. In 5 studies, the prevalence of HCII deficiency in patients was compared directly with that of a healthy control group.13,33,52,68,71 Only 1 of these studies reported a significantly higher prevalence of HCII deficiency in thrombotic patients (7 [5.7%] of 122) than in controls (1 [0.9%] of 114)68; this study examined patients with deep vein thrombosis whose first episode occurred before 45 years of age. Another study reported 1 case (0.4%) of HCII deficiency among 285 pediatric patients with venous or arterial thrombosis and none among 185 healthy control subjects71; this study defined HCII deficiency as a value

ACQUIRED HCH DEFICIENCY

Plasma HCII is decreased to a variable degree in many patients with acute or chronic liver disease,12,13,26,28,73 and patients with fulminant hepatic failure may have very low HCII levels (~10%).74 Heparin cofactor II remains ~30% below normal after orthotopic liver transplantation, perhaps because of immunosuppressive therapy.75,76 Many patients with disseminated intravascular coagulation have reduced HCII levels.^ The reduction may be due, at least in part, to consumption, since elevated levels of HCII-- thrombin complex may be present.77 In some cases of disseminated intravascular coagulation, HCII is decreased to a much greater degree than is antithrombin13,29,71; the significance of this finding is unclear. The mean HCII level in patients with chronic renal failure on dialysis is ~80% of normal,79 and the level remains low after renal transplantation.80 Although ~20% of renal allograft recipients have HCII levels below the lower limit of normal, they do not appear to be at increased risk for thrombotic complications.80 Two groups reported a slight decrease in HCII activity (10%-15% below normal) with normal HCII antigen in patients with type 1 diabetes mellitus.81,82 The decreased activity may be caused by nonenzymatic glycation of HCII.83 Other groups, however, reported normal84,85 or slightly increased86 levels of HCII activity in diabetic patients. Reduced levels of HCII (60%-70% of normal) have been reported in patients with chronic hemolytic anemias (ie, sickle cell anemia, hemoglobin SC disease, thalassemia intermedia, and pyruvate kinase deficiency).87-89 In some thalassemic patients, the HCII level normalized after the anemia was corrected by red blood cell transfusions.88 Decreased plasma HCII activity relative to HCII antigen was found in patients with acute pancreatitis.90 Interestingly, HCII-chymotrypsin complexes were detected in plasma from these patients. Acquired HCII deficiency has also been reported in patients with adult respiratory distress syndrome,31 heparin-induced thrombocytopenia,91 Hunter syndrome,92 and gastric or pancreatic cancer.93,94 Transient decreases in HCII levels were observed in patients after elective surgery95,96 and during cardiopulmonary bypass.97-99 Heparin cofactor IT deficiency was found in 37 (38.5%) of 96 patients infected with human immunodeficiency virus and correlated best with depression of the CD4+ lymphocyte count.100 Whether acquired HCII deficiency contributes to the thrombotic complications that occur in some of the conditions listed remains to be determined.

RECOMMENDATION

Routinely testing patients with thromboembolic disease for HCII deficiency is not recommended at the present time.13,52 Level 1

For an explanation of the levels cited in this article, refer to Olson.101

References

1. Tollefsen DM. Antithrombin deficiency. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York, NY: McGraw-Hill; 2001:4455-4471,

2. Sie P, Dupouy D, Pichon , Boneu B. Turnover study of heparin cofactor II in healthy man. Thromb Haemost. 1985;54:635-638.

3. Shirk RA, Parthasarathy N, San Antonio JD, Church FC, Wagner WD. Altered dermatan sulfate structure and reduced heparin cofactor II-stimulating activity of biglycan and decorin from human atherosclerotic plaque. J Biol Chem. 2000; 275:18085-18092.

4. Liu L, Dewar L, Song Y, et al. Inhibition of thrombin by antithrombin III and heparin cofactor 11 in vivo. Thromb Haemost. 1995;73:405-412.

5. Andersson T, Lorentzen B, Hogdahl H, Clausen T, Mowinckel MC, Abildgaard U. Thrombin-inhibitor complexes in the blood during and after delivery. Thromb Res. 1996;82:109-117.

6. Massouh M, Jatoi A, Gordon EM, Ratnoff OD. Heparin cofactor II activity in plasma during pregnancy and oral contraceptive use. J Lab Clin Med. 1989; 114:697-699.

7. Bellart J, Gilabert R, Cabero L, Fontcuberta J, Monasterio J, Miralles RM. Heparin cofactor II: a new marker for pre-eclampsia. Blood Coagul Fibrinolysis. 1998;9:205-208.

8. Bellart J, Gilabert R, Fontcuberta J, Cameras E, Miralles RM, Cabero L. Coagulation and fibrinolytic parameters in normal pregnancy and in pregnancy complicated by intrauterine growth retardation. Am J Perinatol. 1998;15:81-85.

9. Andrew M, Mitchell L, Berry L, et al. An anticoagulant dermatan sulfate proteoglycan circulates in the pregnant woman and her fetus. J Clin Invest. 1992; 89:321-326.

10. He L, Vicente CP, Westrick RJ, Eitzman DT, Tollefsen DM. Heparin cofactor II inhibits arterial thrombosis after endothelial injury. J Clin Invest. 2002;109:213219.

11. Ishiguro K, Kojima T, Kadomatsu K, et al. Complete antithrombin deficiency in mice results in embryonic lethality. ] Clin Invest. 2000;106:873-878.

12. Tollefsen DM, Pestka CA. Heparin cofactor II activity in patients with disseminated intravascular coagulation and hepatic failure. Blood. 1985;66:769774.

13. Bertina RM, van der Linden IK, Engesser L, Muller HP, Brommer EJ. Hereditary heparin cofactor 11 deficiency and the risk of development of thrombosis. Thromb Haemost. 1987;57:196-200.

14. Toulon P, Costa JM, Amiral J. An enzyme-linked immunosorbent assay for heparin cofactor 11 (HCII): application to the measurement of HCII in clinical materials. Clin Chim Acta. 1992;205:65-73.

15. Rodeghiero F, Tosetto A. The VITA Project: population-based distributions of protein C, antithrombin III, heparin-cofactor II and plasminogen: relationship with physiological variables and establishment of reference ranges. Thromb Haemost. 1996;76:226-233.

16. Tosetto A, Ruggeri M, Castaman G, Rodeghiero F Inherited abnormalities of blood coagulation in juvenile stroke: a case-control study. Blood Coagul Fibrinolysis. 1997;8:397-402.

17. Tosetto A, Gatto E, Rodeghiero F. Influence of cholesterol, triglycerides and fibrinogen on AT III, PC, HC-11 and plasminogen measurement. Thromb Haemost. 1997;77:804.

18. Andersson TR, Larsen ML, Handeland GF, Abildgaard U. Heparin cofactor II activity in plasma: application of an automated assay method to the study of a normal adult population. Scand] Haematol. 1986;36:96-102.

19. Kario K, Matsuo T, Kobayashi H. Heparin cofactor II deficiency in the elderly: comparison with antithrombin III. Thromb Res. 1992;66:489-498.

20. Andrew M, Paes B, Milner R, et al. Development of the human coagulation system in the full-term infant. Blood. 1987;70:165-172.

21. Andrew M, Paes B, Milner R, et al. Development of the human coagulation system in the healthy premature infant. Blood. 1988;72:1651-1657.

22. Chuansumrit A, Manco-Johnson MJ, Hathaway WE. Heparin cofactor II in adults and infants with thrombosis and DIC. Am J Hematol. 1989;31:109-113. 23. Manco-Johnson MJ, Abshire TC, Jacobson LJ, Marlar RA. Severe neonatal

protein C deficiency: prevalence and thrombotic risk. J Pediatr. 1991;119:793798.

24. Andrew M, Vegh P, Johnston M, Bowker J, Ofosu F, Mitchell L. Maturation of the hemostatic system during childhood. Blood. 1992;80:1998-2005.

25. Toulon P, Vitoux JF, Fiessinger JN, Sicard D, Aiach M. Heparin cofactor II: an acute phase reactant in patients with deep vein thrombosis. Blood Coagul Fibrinolysis. 1991;2:435-439.

26. Ezenagu LC, Brandt JT Laboratory determination of heparin cofactor II. Arch Pathol Lab Med. 1986;110:1149-1151.

27. Toulon P Vitoux IF, Capron L, Roncato M, Fiessinger JN, Aiach M. Heparin cofactor 11 in patients with deep venous thrombosis under heparin and oral anticoagulant therapy. Thromb Res. 1988;49:497-500.

28. Abildgaard U, Larsen ML. Assay of dermatan sulfate cofactor (heparin cofactor II) activity in human plasma. Thromb Res. 1984;35:257-266.

29. Tran TH, Duckett F. Heparin cofactor It determination: levels in normals and patients with hereditary antithrombin III deficiency and disseminated intravascular coagulation. Thromb Haemost. 1984;52:112-116.

30. Conard, Bara L, Horellou MH, Samama MM. Bovine or human thrombin in amidolytic at III assays: influence of heparin cofactor II. Thromb Res. 1986;41: 873-878.

31. Mackie IJ, Segal H, Burren T, et al. Heparin cofactor II levels are increased by the use of combined oral contraceptives. Blood Coagul Fibrinolysis. 1990;1: 647-651.

32. Jobin F, Vu L, Lessard M. Two cases of inherited triple deficiency in a large kindred with thrombotic diathesis and deficiencies of antithrombin III, heparin cofactor II, protein C and protein S. Thromb Haemost. 1991;66:295-299.

33. Vinazzer H, Stocker K. Heparin cofactor II: experimental approach to a new assay and clinical results. Thromb Res. 1991;61:235-241.

34. Demers C, Henderson P, Blajchman MA, et al. An antithrombin III assay based on factor Xa inhibition provides a more reliable test to identify congenital antithrombin III deficiency than an assay based on thrombin inhibition. Thromb Haemost. 1993;69:231-235.

35. Tsakiris DA, Marbet GA, Makris PE, Settas L, Duckert F. Impaired fibrinolysis as an essential contribution to thrombosis in patients with lupus anticoagulant. Thromb Haemost. 1989;61:175-177.

36. Lo SC, Salem HH, Howard MA, Oldmeadow MI, Firkin BG. Studies of natural anticoagulant proteins and anticardiolipin antibodies in patients with the lupus anticoagulant. BrJ Haematol. 1990;76:380-386.

37. Keeling DM, Campbell SJ, Mackie IJ, Machin SI, Isenberg DA. The fibrinolytic response to venous occlusion and the natural anticoagulants in patients with antiphospholipid antibodies both with and without systemic lupus erythematosus. BrJ Haematol. 1991;77:354-359.

38. Muller B, Tsakiris DA, Roth CB, Guglielmetti M, Staub JJ, Marbet GA. Haemostatic profile in hypothyroidism as potential risk factor for vascular or thrombotic disease. Eur Clin Invest. 2001;31:131-137.

39. Sie P, Meguira B, Bouissou F, Boneu B, Barthe P. Plasma levels of heparin cofactor II in nephrotic syndrome of children. Nephron. 1988;48:175-176.

40. Toulon P, Gandrille S, Remy P, Chadeuf G, Jouvin MH, Aiach M. Significance of high levels of heparin cofactor II in the plasma and urine of adult patients with nephrotic syndrome. Nephron. 1992;60:176-180.

41. Ruggeri M, Milan M, La Greca G, Castaman G, Rodeghiero F. Adult patients with the nephrotic syndrome: really at high risk for deep venous thromboembolism? Report of a series and review of the literature. Haematologica. 1993;78:47-51.

42. Hannedouche T, Fischer AM, Blanche P, Tapon-Bretaudiere J, Ganeval D. Plasma heparin cofactor II and antithrombin III concentrations in adult nephrotic syndrome. Clin Nephrol. 1987;28:305-306.

43. Vermylen CG, Levin M, Lanham JG, Hardisty RM, Barratt TM. Decreased sensitivity to heparin in vitro in steroid-responsive nephrotic syndrome. Kidney Int. 1987;31:1396-1401.

44. Grau E, Oliver A, Felez J, et al. Plasma and urinary heparin cofactor II levels in patients with nephrotic syndrome. Thromb Haemost. 1988;60:137-140. 45. Pech MA, Rostoker G, Soria C, et al. Heparin cofactor 11 in adult glomerulopathy and nephrotic syndrome. Am J Nephrol. 1991; 11:74-75.

46. Sandset PM, Andersson TR. Coagulation inhibitor levels in pneumonia and stroke: changes due to consumption and acute phase reaction. J Intern Med. 1989;225:311-316.

47. Sandset PM, Hellgren M, Uvebrandt M, Bergstrom H. Extrinsic coagulation pathway inhibitor and heparin cofactor II during normal and hypertensive pregnancy. Thromb Res. 1989;55:665-670.

48. Toulon P, Bardin JM, Blumenfeld N. Increased heparin cofactor II levels in women taking oral contraceptives. Thromb Haemost. 1990;64:365-368.

49. Cortellaro M, Boschetti C, Crosignani PG. Effects on haemostasis of hormone replacement therapy with transdermal estradiol and oral sequential medroxyprogesterone acetate: a 1-year, double-blind, placebo-controlled study. The Writing Group for the Estradiol Clotting Factors Study. Thromb Haemost. 1996; 75:476-480.

50. Sie P, Dupouy D, Pichon J, Boneu B. Constitutional heparin co-factor II deficiency associated with recurrent thrombosis. Lancet. 1985;2:414-416.

51. Tran TH, Marbet GA, Duckert F. Association of hereditary heparin co-factor It deficiency with thrombosis. Lancet. 1985;2:413-414.

52. Andersson TR, Larsen ML, Abildgaard U. Low heparin cofactor II associated with abnormal crossed immunoelectrophoresis pattern in two Norwegian families. Thromb Res. 1987;47:243-248.

53. Simioni P, Lazzaro AR, Coser E, Salmistraro G, Girolami A. Hereditary heparin cofactor II deficiency and thrombosis: report of six patients belonging to two separate kindreds. Blood Coagul Fibrinolysis. 1990;1:351-356.

54. jobin F, Vu L, Biogonesse JM. Follow-up: a young man with three defi

ciencies of antithrombotic proteins, asymptomatic until now, spontaneously develops pulmonary embolism. Thromb Haemost. 1992;67:730.

55. Weisdorf DJ, Edson JR. Recurrent venous thrombosis associated with inherited deficiency of heparin cofactor II. BrJ Haematol. 1991;77:125-126.

56. Matsuo T, Kario K, Sakamoto S, et al. Hereditary heparin cofactor If deficiency and coronary artery disease. Thromb Res. 1992;65:495-505.

57. Simioni P, Zanardi S, Prandoni P, Girolami A. Combined inherited protein S and heparin co-factor II deficiency in a patient with upper limb thrombosis: a family study. Thromb Res. 1992;67:23-30.

58. Bernardi F, Legnani C, Micheletti F, et al. A heparin cofactor 11 mutation (HCII Rimini) combined with factor V Leiden or type I protein C deficiency in two unrelated thrombophilic subjects. Thromb Haemost. 1996;76:505-509.

59. Villa P, Aznar J, Vaya A, et al. Hereditary homozygous heparin cofactor II deficiency and the risk of developing venous thrombosis. Thromb Haemost.1999; 82:1011-1014.

60. Kanagawa Y, Shigekiyo TL Aihara K, Akaike M, Azuma H, Matsumoto T. Molecular mechanism of type I congenital heparin cofactor (HC) II deficiency caused by a missense mutation at reactive P2 site: HC II Tokushima. Thromb Haemost. 2001;85:101-107.

61. Kondo S, Tokunaga F, Kario K, Matsuo T, Koide T. Molecular and cellular basis for type I heparin cofactor II deficiency (heparin cofactor 11 Awaji). Blood. 1996;87:1006-1012.

62. Corral J, Aznar J, Gonzalez-Conejero R, et al. Molecular characterization of the first homozygous heparin cofactor II deficiency: involvement in conformational disease [abstract]. Thromb Haemost. 2001;July suppl:OC987.

63. Blinder MA, Andersson TR, Abildgaard U, Tollefsen DM. Heparin cofactor IIOslo: mutation of Arg-189 to His decreases the affinity for dermatan sulfate. J Biol Chem. 1989;264:128-5133.

64. Maim J, Laurell M, Nilsson IM, Dahlback B. Thromboembolic disease: critical evaluation of laboratory investigation. Thromb Haemost. 1992;68:7-13. 65. Bick RL, Ucar K. Hypercoagulability and thrombosis. Hematol Oncol Clin North Am. 1992;6:1421-1431.

66. Awidi AS, Abu-Khalaf M, Herzallah U, et al. Hereditary thrombophilia among 217 consecutive patients with thromboembolic disease in Jordan. Am J Hematol. 1993;44:95-100.

67. Bandello F, Vigano D'Angelo S, Parlavecchia M, et al. Hypercoagulability and high lipoprotein(a) levels in patients with central retinal vein occlusion. Thromb Haemost. 1994;72:39-43.

68. Lopaciuk S, Bykowska K, Kopec M. Prevalence of heparin cofactor II deficiency in patients with a history of venous thrombosis. Pol] Pharmacol. 1996; 48:109-111.

69. Mateo J, Oliver A, Borrell M, Sala N, Fontcuberta J. Laboratory evaluation and clinical characteristics of 2,132 consecutive unselected patients with venous thromboembolism: results of the Spanish Multicentric Study on Thrombophilia (EMET-Study). Thromb Haemost. 1997;77:444-451.

70. Vielhaber H, Ehrenforth S, Koch HG, Scharrer I, van der Werf N, Nowak-- Gottl U. Cerebral venous sinus thrombosis in infancy and childhood: role of genetic and acquired risk factors of thrombophilia. Eur) Pediatr. 1998;157:555560.

71. Ehrenforth S, Junker R, Koch HG, et al. Multicentre evaluation of combined prothrombotic defects associated with thrombophilia in childhood. Childhood Thrombophilia Study Group. Eur J Pediatr. 1999;158:597-51 04.

72. Ho CH, Chau WK, Hsu HC, Gau JP, Yu TJ. Causes of venous thrombosis in fifty Chinese patients. Am I Hematol. 2000;63:74-78.

73. Andersson TR, Bell H. Plasma heparin cofactor II in alcoholic liver disease. Hepatol. 1988;7:79-84.

74. Langley PG, Williams R. Physiological inhibitors of coagulation in fulminant hepatic failure. Blood Coagul Fibrinolysis. 1992;3:243-247.

75. Toulon P, Ledjev 1, Ozier Y, Garnier iF, Houssin D. Lack of correction of acquired heparin cofactor II deficiency in patients with liver failure after successful orthotopic liver transplantation. Thromb Haemost. 1992;68:230-231.

76. Velasco F, Villalba R, Fernandez M, et al. Diminished anticoagulant and fibrinolytic activity following liver transplantation. Transplantation. 1992;53: 1256 1261.

77. Andersson TR, Sie P, Pelzer H, Aamodt LM, Nustad K, Abildgaard U. Elevated levels of thrombin-heparin cofactor II complex in plasma from patients with disseminated intravascular coagulation. Thromb Res. 1992;66:591-598.

78. Kario K, Matsuo T, Kodama K, Katayama S, Kobayashi H. Preferential consumption of heparin cofactor It in disseminated intravascular coagulation associated with acute promyelocytic leukemia. Thromb Res. 1992;66:435-444.

79. Toulon P, Jacquot C, Capron L, Frydman MO, Vignon D, Aiach M. Antithrombin III and heparin cofactor II in patients with chronic renal failure undergoing regular hemodialysis. Thromb Haemost. 1987;57:263-268.

80. Toulon P, Moulonguet-Doleris L, Costa JM, Aiach M. Heparin cofactor 11 deficiency in renal allograft recipients: no correlation with the development of thrombosis. Thromb Haemost. 1991;65:20-24.

81. Ceriello A, Quatraro A, Dello Russo P, Marchi E, Milani MR, Giugliano D. Evidence for a reduced heparin cofactor II biological activity in diabetes. Haemostasis. 1990;20:357-361.

82. Duboscq C, Quintana I, Barros J, Kordich L. Heparin cofactor II in diabetic patients. Blood Coagul Fibrinolysis. 1994;5:201-204.

83. Ceriello A, Marchi E, Barbanti M, et al. Non-enzymatic glycation reduces heparin cofactor II anti-thrombin activity. Diabetologia. 1990;33:205-207.

84. Mascia F, Paoletti P, Mameli G, Mamusa AM, Cirillo R, Marongiu F. Der

matan sulphate, heparin cofactor If, and Fl +2 peptide in non-insulin-dependent diabetes mellitus. Thromb Res. 2000;97:263-265.

85. Meier P, Marbet GA, Berger W, Ducked F, Friedli W. Patterns of contact phase proteins indicating neuropathy in diabetic patients. Blur 1990;61:222-225. 86. Gram J, Jespersen J. Increased concentrations of heparin cofactor 11 in di

abetic patients, and possible effects on thrombin inhibition assay of antithrombin Ill. Clin Chem. 1989;35:52-55.

87. Porter JB, Young L, Mackie IJ, Marshall L, Machin SJ. Sickle cell disorders and chronic intravascular haemolysis are associated with low plasma heparin cofactor II. Brj Haematol. 1993;83:459-465.

88. O'Driscoll A, Mackie I), Porter JB, Machin Sj. Low plasma heparin cofactor II levels in thalassaemia syndromes are corrected by chronic blood transfusion. Br J Haematol. 1995;90:65-70.

89. Liesner R, Mackie I, Cookson ), et al. Prothrombotic changes in children with sickle cell disease: relationships to cerebrovascular disease and transfusion. Br J Haematol. 1998;103:1037-1044.

90. Toulon P, Chadeuf G, Bouillot IL, et al. Involvement of heparin cofactor II in chymotrypsin neutralization and in the pancreatic proteinase-antiproteinase interaction during acute pancreatitis in man. Eur] Clin Invest. 1991;21:303-309.

91. Boshkov LK, Warkentin TE, Hayward CP, Andrew M, Kelton IG. Heparininduced thrombocytopenia and thrombosis: clinical and laboratory studies. Br] Haematol. 1993;84:322-328.

92. Street AM. Hunter's syndrome with an endogenous anticoagulant. Am Hematol. 1996;53:277.

93. Andersen BS, Rahr HB, Sorensen JV. Determination of coagulation inhib

itor levels and resistance to activated protein C in patients undergoing gastric surgery for benign and malignant disorders. Haemostasis. 1997;27:157-162.

94. Lindahl AK, Odegaard OR, Sandset PM, Harbitz TB. Coagulation inhibition and activation in pancreatic cancer: changes during progress of disease. Cancer. 1992;70:2067-2072.

95. Andersson TR, Berner NS, Larsen ML, Odegaard OR, Abildgaard U. Plasma heparin cofactor II, protein C and antithrombin in elective surgery. Acta Chir Scand. 1987;153:291-296.

96. Sandset PM, Hogevold HE, Lyberg T, Andersson TR, Abildgaard U. Extrinsic pathway inhibitor in elective surgery: a comparison with other coagulation inhibitors. Thromb Haemost 1989;62:856-860.

97. Turner-Gomes SO, Mitchell L, Williams WG, Andrew M. Thrombin regulation in congenital heart disease after cardiopulmonary bypass operations.] Thorac Cardiovasc Surg. 1994;107:562-568.

98. Cardigan RA, Hamilton-Davies C, McDonald S, et al. Haemostatic changes in the pulmonary blood during cardiopulmonary bypass. Blood Coagul Fibrinolysis. 1996;7:567-577.

99, Chan AK, Leaker M, Burrows FA, et al. Coagulation and fibrinolytic profile of paediatric patients undergoing cardiopulmonary bypass. Thromb Haemost. 1997;77:270-277.

100. Toulon P, Lame M, Ledjev I, et al. Heparin cofactor II deficiency in patients infected with the human immunodeficiency virus. Thromb Haemost. 1993;70:730-735.

101. Olson ID. College of American Pathologists Consensus Conference XXXVI: Diagnostic Issues in Thrombophilia: introduction and general considerations. Arch Pathol Lab Med. 2002;126:1277-1280.

Douglas M. Tollefsen, MD, PhD

Accepted for publication April 22, 2002.

From the Hematology Division, Department of Medicine, Washington University School of Medicine, St Louis, Mo.

Presented at the College of American Pathologists Consensus Conference XXXVI: Diagnostic Issues in Thrombophilia, Atlanta, Ga, November 9-11, 2001.

Reprints: Douglas M. Tollefsen, MD, PhD, Hematology Division, Campus Box 8125, Washington University School of Medicine, 660 South Euclid Ave, St Louis, MO 63110 (e-mail: tollefsen@im.wustl.edu).

Copyright College of American Pathologists Nov 2002
Provided by ProQuest Information and Learning Company. All rights Reserved