* 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.
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.
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.
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
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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: email@example.com).
Copyright College of American Pathologists Nov 2002
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