Alterations of haemostatic and fibrinolytic markers in adult patients with growth hormone deficiency and with acromegaly

Summary:

Alterations of coagulation and fibrinolytic systems might contribute to the increased cardiovascular and cerebrovascular mortality observed in patients with both chronic growth hormone (GH) excess (acromegaly) and deficiency (GHD). However, contrasting results have been so far reported. To assess the importance of GH in modulating haemostatic system, several haemostatic variables in patients with GHD and acromegaly were measured. Twenty-four adult patients with GHD (8 childhood- and 16 adult-onset; age: 41 ± 12 years, insulin like growth factor-I, IGF-I: 6.7 ± 4 nmol/L), 10 non-diabetic acromegalic patients (age: 39 ± 15 years; IGF-I: 109 ± 37 nmol/L) and 64 healthy volunteers age- and sex-matched with cases were studied. The plasma levels of tissue-type plasminogen activator antigen (t-PA), prothrombin fragment 1 + 2 (F1 + 2) and thrombin-antithrombin complex (TAT) were measured by ELISA. Plasminogen activator inhibitor type 1 (PAI-1) was measured by an immunoactivity assay and fibrinogen by von Clauss method. GH levels were measured by IFMA and IGF-I by RIA. GHD patients had higher PAI-1 (12.7 ± 16.7 vs 4.8 ± 5.3 U/ml, p < 0.01), fibrinogen (363 ± 104 vs 291 ± 71 mg/dL, p < 0.05) and TAT levels (6.8 ± 9 vs 3.6 ± 2.8 ng/ml, p < 0.05) than controls. Taking the 95th pecentile of the normal distribution in the control group as the cut-off point for normal plasma levels of the haemostatic variables, high PAI levels were found in 25% of patients with GHD (P < 0.01), while high fibrinogen and TAT levels were observed in 21% (P < 0.05). The alterations were mostly present in patients with adult-onset GHD, with the exception of hyperfibrinogenaemia which was equally present in adult- and childhood-onset patients. Acromegalic patients had higher mean fibrinogen levels than controls (398 ± 111 vs 291 ± 71 mg/dL, p < 0.05), 40% having hyperfibrinogenaemia (P < 0.01, vs controls). They also had t-PA levels lower than controls and GHD. No correlations between hormonal and haemostatic variables were found. Body mass index and waist to hip ratio correlated positively with PAI-1 levels in GHD patients only. In conclusion, this study shows that several abnormalities of coagulation variables (increased PAI-1, fibrinogen and TAT levels) are present in patients with GHD, while only hyperfibrinogenaemia is found in patients with acromegaly. These changes do not appear to be directly related to IGF-I levels or to the degree of GH deficiency/excess. However, these abnormalities may be an additional trigger for the development of coronary heart disease and thromboembolic complications mostly in patients with GHD.

Acromegaly - growth hormone deficiency - fibrinogen - plasminogen activator inhibitor 1 and coagulation variables

References

• 1 Alessi M C, Peiretti F, Morange P, Henry M, Nalbone G, Juhan-Vague I. Production of plasminogen activator inhibitor 1 by human adipose tissue. Possible link between visceral fat accumulation and vascular disease.  Diabetes. 46 860-867 1997; 
• 2 Attanasio A F, Lamberts S WJ, Matranga A MC, Birkett M A, Bates P C, Valk N K, Hilsted J, Bengtsson B Å, Strasburger C J. the Adult Growh Hormone Deficiency Study Group . Adult growth hormone (GH)-deficient patients demonstrate heterogeniety between childhood onset and adult onset before and during human GH treatment.  J Clin Endocrinol Metab. 82 82-88 1997; 
• 3 Beshyah S A, Johnston D G. Cardiovascular disease and risk factors in adults with hypopituitarism.  Clin Endocrinol. 50 1-15 1999; 
• 4 Beshyah S A, Markussis V, Harbourne T, Nicolaides A N, Johnston D G. Haemostatic mechanisms are normal despite increased vascular mortality in hypopituitary adults.  Horm Metab Res. 25 449-450 1993; 
• 5 Bülow B, Hagmar L, Mikoczy Z, Nordström C-H, Erfurth E M. Increased cerebrovascular mortality in patients with hypopituitarism.  Clin Endocrinol. 46 75-81 1994; 
• 6 Cortellaro M, Cofrancesco E, Boschetti C, Mussoni L, Donati M B, Cardillo M, Catalano M, Gabrielli L, Lombardi B, Specchia G, Tavazzi L, Tremoli E, Pozzoli E, Turri M. for the PLAT Group . Increased fibrin turnover and high PAI-1 activity as predictors of ischemic events in atherosclerotic patients: a case-control study.  Arterioscler Thromb. 13 1412-1417 1993; 
• 7 Eriksson P, Reynisdottir S, Lonnqvist F, Stemme V, Hamsten A, Arner P. Adipose tissue secretion and plasminogen activator inhibitor-1 in non obese and obese individuals.  Diabetologia. 41 65-71 1998; 
• 8 Hamsten A, De Faire U, Walldius G, Dahlen G, Szamosi A, Landou C, Blombäck M, Wiman B. Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction.  Lancet. 2 3-9 1987; 
• 9 Johansson J O, Landin K, Johansson G, Tengborn L, Bengtsson B Å. Serum treatment with growth hormone decreases plasminogen activator inhibitor-1 and tissue plasminogen activator in growth hormone-deficient adults.  Thromb Haemostasis. 76 422-428 1996; 
• 10 Johansson J O, Landin K, Tengborn L, Rosén T, Bengtsson B Å. High fibrinogen and plasminogen activator inhibitor activity in growth hormone-deficient adults.  Arterioscler Thromb. 14 434-437 1994; 
• 11 Jørgensen J OL, Pederson S A, Ingerslev J, Møller J, Skakkebaek N E, Christiansen J S. Growth hormone (GH) therapy in GH-deficient patients, the plasma factor VIII-von Willebrand factor complex and capillary fragility. A double-blind, placebo-controlled cross over study.  ScandJ Clin Lab Inv. 50 417-420 1996; 
• 12 Juhan-Vague I, Alessi M C. PAI-1, obesity, insulin resistance and risk of cardiovascular events.  Thromb Haemostasis. 78 656-660 1997; 
• 13 Kannel W B, D'Agostino R B, Belanger A J. Fibrinogen, cigarette smoking and risk of cardiovascular disease: Onsights from the Framingham Study.  Am Heart J. 113 1006-1010 1987; 
• 14 Landin K, Stigendal L, Eriksson E, Krotkiewski M, Risberg B, Tengborn L, Smith U.. Abdominal obesity is associated with an impaired fibrinolytic activity and elevated plasminogen activator inhibitor-1.  Metabolism. 39 1044-1048 1990; 
• 15 Landin-Wilhelmsen K, Tengborn L, Wilhelmsen L, Bengtsson B-Å. Elevated fibrinogen levels decrease following treatment of acromegaly.  Clin Endocrinol. 46 69-74 1997; 
• 16 Markussis V, Beshyah S A, Fisher C, Sharp P, Nicolaides A N, Johnston D G. Detection of premature atherosclerosis by high-resolution ultrasonography in symptom-free hypopituitary adults.  Lancet. 340 1188-1192 1992; 
• 17 Marques-Vidal P, Sie P, Cambou J-P, Hugues C, Perret B. Relationships of plasminogen activator inhibitor activity and lipoprotein (a) with insulin, testosterone, 17-beta-estradiol, and testosterone binding globulin in myocardial infarction patients and healthy controls.  J Clin Endocrinol Metab. 80 1794-1798 1995; 
• 18 Meade T W, Mellows S, Brozovic M, Miller G J, Chakrabarti R R, North W R, Haines A P, Stirling Y, Imeson J D, Yhompson S G. Haemostatic function and ischaemic heart disease: principal results of the Northwick Park heart Study.  Lancet. 2 533-537 1986; 
• 19 Miller G J, Bauer K A, Cooper J A, Rosenberg R D. Activation of the coagulant pathway in cigarette smokers.  Thromb Haemostasis. 79 549-553 1998; 
• 20 O'Sullivan A J, Kelly J J, Hoffman D M, Freund J, Ho K KY. Body composition and energy expenditure in acromegaly.  J Clin Endocrinol Metab. 78 381-386 1994; 
• 21 Rajasoorya C, Holdaway I M, Wrightson P, Scott D J, Ibbertson H K. Determinants of clinical outcome and survival in acromegaly.  Clin Endocrinol. 41 95-102 1994; 
• 22 Rosén T, Bengtsson B A. Premature mortality due to cardiovascular disease in hypopituitarism.  Lancet. 336 285-288 1990; 
• 23 Rosén T, Edén S, Larson G, Wilhelmsen L, Bengtsson B Å. Cardiovascular risk factors in adult patients with growth hormone deficiency.  Acta Endocrinol (Copenh). 129 195-200 1993; 
• 24 Sacca' L, Cittadini A, Fazio S. Growth hormone and the heart.  Endocr Rev. 15 555-573 1994; 
• 25 Sartorio A, Cattaneo M, Bottasso B, Mannucci P M, Faglia G. High plasma levels of plasminogen activator inhibitor in adults with childhood-onset growth hormone deficiency. Letter to the editor.  Endocrinol Metab. 2 165-166 1995; 
• 27 Scelles V, Raccah D, Alessi M C, Vialle J , Juhan-Vague I, Vague P. Plasminogen activator inhibitor 1 and insulin levels in various insulin resistance states.  Diabetes Metab. 18 38-42 1992; 
• 28 Smith F B, Lee A J, Fowkes F G, Price J F, Rumley A, Lowe G D. Haemostatic factors as predictors of ischemic heart disease and stroke in the Edinburgh Artery Study.  Arterioscl Throm Vas. 17 3321-3325 1997; 
• 29 Thompson S G, Kienast J, Pyke S DM, Haverkate F, van del Loo J CW. for the ECAT . Angina Pectoris Study Group: Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris.  N Engl J Med. 332 635-641 1995; 
• 30 VonClauss A. Gerinnerungsphysiologische Schnellmethode zur Bestimmung des Fibrinogens.  Acta Haematol. 17 37-246 1957; 
• 31 Wildbrett J, Hanefeld M, Fucker K, Pinzer T, Bergmann S, Siegert G, Breidert M. Anomalies of lipoprotein pattern and fibrinolysis in acromegalic patients: relation to growth hormone levels and insulin-like growth factor I.  Exp Clin Endocr Diab. 105 331-335 1997; 
• 32 Wilhelmsen L, Svärdsudd K, Korsan-Bengtsen K, Larsson B, Welin L, Tibblin G. Fibrinogen as a risk for stroke and myocardial infarction.  N Engl J Med. 311 501-505 1984; 
• 33 Wright A D, Hill D M, Lowy C, Fraser T R. Mortality in acromegaly:.  Quart J Med. 39 1-16 1970;