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Thromb Haemost 2007; 98(02): 392-396
DOI: 10.1160/Th06-12-0718
Platelets and Blood Cells
Schattauer GmbH

Reduction of painful vaso-occlusive crisis of sickle cell anaemia by tinzaparin in a double-blind randomized trial

Mohamad Hasan Qari
1   College of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
,
Soad Khalil Aljaouni
1   College of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
,
Mohamad Salleh Alardawi
1   College of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
,
Huda Fatani
1   College of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
,
Fatin Mohamad Alsayes
1   College of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
,
Panagiotis Zografos
2   Leo Pharmaceutical Products, Athens, Greece
,
Mohamad Alsaigh
1   College of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
,
Adnan Alalfi
1   College of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
,
Mohamad Alamin
1   College of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
,
Abdulilah Gadi
1   College of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
,
Shaker A. Mousa
3   The Pharmaceutical Research Institute at Albany, Albany, New York, USA
› Author Affiliations
Further Information

Publication History

Received 15 December 2006

Accepted after resubmission 30 May 2007

Publication Date:
28 November 2017 (online)

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Summary

A randomized double-blind clinical trial was performed to test the safety and efficacy of a low-molecular-weight heparin, tinzaparin (Innohep®), for the management of acute painful vasoocclusive crisis characteristic of sickle cell anemia (SCA). We studied 253 patients with acute painful crisis but with no other complications of SCA, randomized to treatment or control groups. In the treatment group, 127 patients received tinzaparin at 175 IU/kg, subcutaneous once daily, along with supportive care including morphine analgesia; in the control group, 126 patients received placebo and the same supportive care.The maxi- mal experimental treatment period was seven days. Analysis revealed a statistically significant reduction in number of days with the severest pain score, overall duration of painful crisis, and duration of hospitalization (p <0.05 for each comparison of tinzaparin vs. placebo).The decline in pain intensity was sharper for tinzaparin-treated patients, and complications consisted of two minor bleeding events that were reported and treated by cessation of tinzaparin.This investigation demonstrated that tinzaparin, administered at its approved treatment regimen, reduced the severity and duration of acute crisis of SCA.

Keywords

Sickle cell anemia - tinzaparin - heparin - pain - genetic disease
 

  • References

  • 1 Steinberg MH. Pathophysiologically based drug treatment of sickle cell disease. Trends Pharmacol Sci 2006; 27: 204-210.
    CrossrefPubMedGoogle Scholar
  • 2 Embury SH. Sickle cell disease. In: Hoffman R, Benz Jr EJ, Shattil SJ, Furie B, Cohen HJ, Silberstein LE. eds. Hematology, Principles and Practice. 2nd ed. New York: Churchill Livingston; 1995: 611-648.
    Google Scholar
  • 3 Mousa SA, Johansen K. Pharmacodynamic effects of low molecular weight heparin tinzaparin in obese subjects following subcutaneous administration of 75 IU/kg on plasma tissue factor pathway inhibitor and nitric oxide. Int Angiol 2005; 24: 40-42.
    PubMedGoogle Scholar
  • 4 Mousa SA. Elevation of plasma von Willebrand factor and tumor necrosis factor-a in obese subjects and their reduction by the low molecular weight heparin tinzaparin. Int Angiol 2005; 24: 278-281.
    PubMedGoogle Scholar
  • 5 Mousa SA. Low-molecular-weight heparins in thrombosis and cancer: emerging links. Cardiovasc Drug Rev 2004; 22: 121-134.
    CrossrefPubMedGoogle Scholar
  • 6 Stevenson JL, Choi SH, Varki A. Differential metastasis inhibition by clinically relevant levels of heparins--correlation with select in inhibition, not anti-thrombotic activity. Clin Cancer Res 2005; 11: 7003-7011.
    CrossrefPubMedGoogle Scholar
  • 7 Wu O, Robertson L, Langhorne P. et al. Oral contraceptives, hormone replacement therapy, thrombophilias and risk of venous thromboembolism: a systematic review. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) Study. Thromb Haemost 2005; 94: 17-25.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 8 Jaywant S, Pai A. A comparative study of pain measurement scales in acute burn patients. Ind J Occup Ther 2003; 35: 13.
    PubMedGoogle Scholar
  • 9 Browne PV, Mosher DF, Steinberg MH. et al. Disturbance of plasma and platelet thrombospond in levels in sickle cell disease. Am J Hematol 1996; 51: 296-301.
    CrossrefPubMedGoogle Scholar
  • 10 Devine DV, Kinney TR, Thomas PF. et al. Fragment D-dimer levels: an objective marker of vaso-occlusive crisis and other complications of sickle cell disease. Blood 1986; 68: 317-319.
    PubMedGoogle Scholar
  • 11 Hagger D, Wolff S, Owen J. et al. Changes in coagulation and fibrinolysis in patients with sickle cell disease compared with healthy black controls. Blood Coagul Fibrinol 1995; 6: 93-99.
    CrossrefPubMedGoogle Scholar
  • 12 Key NS, Slungaard A, Dandelet L. et al. Whole blood tissue factor procoagulant activityis elevated in patients with sickle cell disease. Blood 1998; 91: 4216-4223.
    PubMedGoogle Scholar
  • 13 Kurantsin-Mills J, Ofosu FA, Safa TK. et al. Plasma factor VII and thrombin-anti-thrombin III levels indicate increased tissue factor activity in sickle cell patients. Br J Haematol 1992; 81: 539-544.
    CrossrefPubMedGoogle Scholar
  • 14 Kurantsin-Mills J, Ibe BO, Natta CL. et al. Elevated urinary levels of thromboxane and prostacyclin metabolites in sickle cell disease reflect activated plate lets in the circulation. Br J Haematol 1994; 87: 580-585.
    CrossrefPubMedGoogle Scholar
  • 15 Nsiri B, Gritli N, Bayoudh F. et al. Abnormalities of coagulation and fibrinolysis in homozygous sickle cell disease. Hematol Cell Ther 1996; 38: 279-284.
    CrossrefPubMedGoogle Scholar
  • 16 Peters M, Plaat BEC, ten Cate H. et al. Enhanced thrombin generation in children withsickle cell disease. Thromb Haemost 1994; 71: 169-172.
    PubMedGoogle Scholar
  • 17 Solovey A, Gui L, Key NS. et al. Tissue factor expression by end othelial cells in sickle cell anemia. J Clin Invest 1998; 101: 1899-1904.
    CrossrefPubMedGoogle Scholar
  • 18 Triadou P, Fonty E, Ambrosio AS. et al. Platelet functions in sickle cell disease during steady state. Nouv Rev Fr Hematol 1990; 32: 137-142.
    PubMedGoogle Scholar
  • 19 Francis RB. Large-vessel occlusion in sicklecell disease: pathogenesis, clinical consequences, and therapeutic implications. Med Hypotheses 1991; 35: 88-95.
    CrossrefPubMedGoogle Scholar
  • 20 Kirkpatrick MB, Haynes J. Sickle cell disease and thepulmonary circulation. Semin Resp Crit Care Med 1994; 15: 473.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 21 Murphy RC, Shapiro S. Pathology of sicklecell disease. Ann Intern Med 1945; 23: 376.
    CrossrefPubMedGoogle Scholar
  • 22 Pavlakis SG, Bello J, Prohovnik I. et al. Brain infarction in sickle cell anemia: magnetic resonance imaging correlates. Ann Neurol 1988; 23: 125-130.
    CrossrefPubMedGoogle Scholar
  • 23 Chiu D, Lubin B. Roel of sen B, et al. Sickled erythrocytes accelerate clotting in vitro: an effect of abnormal membrane lipid asymmetry. Blood 1981; 58: 398-401.
    PubMedGoogle Scholar
  • 24 Hebbel RP, Boogaerts MA, Eaton JW. et al. Erythrocyte adherence to endothelium in sickle-cell anemia: a possible determinant of disease severity. N Engl J Med 1980; 302: 992-995.
    CrossrefPubMedGoogle Scholar
  • 25 Lubin B, Chiu D, Bastacky J. et al. Abnormalitiesin membrane phospholipidsorganization in sickled erythrocytes. J Clin Invest 1981; 67: 1643-1649.
    CrossrefPubMedGoogle Scholar
  • 26 Adams R, McKie V, Nichols F. et al. The use of transcranial ultrasonography to predict stroke on sickle cell disease. N Engl J Med 1992; 326: 605-610.
    CrossrefPubMedGoogle Scholar
  • 27 Chiang EY, Frenette PS. Sickle cell vaso-occlusion. Hematol Oncol Clin North Am 2005; 19: 771-784.
    CrossrefPubMedGoogle Scholar
  • 28 Semple MJ, Al-Hasani SF, Kioy P. et al. A double blind trial of ticlopidine in sickle cell disease. Thromb Haemost 1984; 51: 303-306.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 29 Zago MA, Costa FF, Ismael SJ. et al. Treatment of sickle cell diseases with aspirin. Acta Haematol 1984; 72: 61-64.
    CrossrefPubMedGoogle Scholar
  • 30 Chaplin Jr H, Monroe MC, Malecek AC, Morgan LK, Michael J, Murphy WA. Preliminary trial of minidose heparin prophylaxis for painful sickle cell crises. East Afr Med J 1989; 66: 574-584.
    PubMedGoogle Scholar
  • 31 Evans EA, Mohandas N. Membrane-associated sickle hemoglobin: a major determinant of sickle erythrocyte rigidity. Blood 1987; 70: 1443-1449.
    PubMedGoogle Scholar
  • 32 Setty BN, Chen D, Stuart MJ. Sickle cell vaso-occlusive crisis is associated with abnormalities in the ratio of vasoconstrictor to vasodilator prostanoids. Pediatr Res 1995; 38: 95-102.
    CrossrefPubMedGoogle Scholar
  • 33 Claster S, Vichinsky EP. Managing sicklecell disease. Br Med J 2003; 327: 1151-1155.
    CrossrefPubMedGoogle Scholar
  • 34 Styles LA, Lubin B, Vichinsky E. et al. Decrease of very late activation antigen-4 and CD36 on reticulocytes in sickle cell patients treated with hydroxyurea. Blood 1997; 89: 2554-2559.
    PubMedGoogle Scholar
  • 35 Kumar A, Eckman JR, Wick TM. Inhibition of plasma-mediated adherence of sickle erythrocytes to microvascular endothelium by conformationally constrained RGD-containing peptides. Am J Hematol 1996; 53: 92-98.
    CrossrefPubMedGoogle Scholar
  • 36 Kaul DK, Tsai HM, Liu XD. et al. Monoclonal antibodies to alphaVbeta3 (7E3 and LM609)inhibit sickle red blood cell-endothelium interactions induced by platelet-activating factor. Blood 2000; 95: 365-367.
    PubMedGoogle Scholar
  • 37 Space SL, Lane PA, Pickett CK. et al. Nitricoxide attenuates normal and sickle red blood cell adherence to pulmonary endothelium. Am J Hematol 2000; 63: 200-204.
    CrossrefPubMedGoogle Scholar
  • 38 Morris CR, Morris Jr SM, Hagar W. et al. Arginine therapy: a new treatment for pulmonary hypertension in sickle cell disease?. Am J Respir Crit Care Med 2003; 168: 63-69.
    CrossrefPubMedGoogle Scholar
  • 39 Head CA, Brugnara C, Martinez-Ruiz R. et al. Low concentrations of nitric oxide increase oxygen affinity of sickle erythrocytes in vitro and in vivo [see comments]. J Clin Invest 1997; 100: 1193-1198.
    CrossrefPubMedGoogle Scholar
  • 40 Drexler H, Zeiher AM, Meinzer K. et al. Correction of endothelial dysfunction in coronary microcirculation of hypercholesterollaemic patients by L-arginine. Lancet 1991; 338: 1546-1550.
    CrossrefPubMedGoogle Scholar
  • 41 Creager MA, Gallagher SJ, Girerd XJ. et al. L-arginine improves endothelium-dependent vasodilatation in hypercholesterolemic humans. J Clin Invest 1992; 90: 1248-1253.
    CrossrefPubMedGoogle Scholar
  • 42 Kharitonov SA, Lubec G, Lubec B. et al. L-arginine increases exhaled nitric oxideinnormal human subjects. Clin Sci (Lond) 1995; 88: 135-139.
    CrossrefPubMedGoogle Scholar
  • 43 Tsao PS, McEvoy LM, Drexler H. et al. Enhanced endothelial adhesiveness in hypercholesterolemia is attenuated by L-arginine. Circulation 1994; 89: 2176-2182.
    CrossrefPubMedGoogle Scholar
  • 44 Mousa SA. Pharmacodynamic properties of the low molecular weight heparin, tinzaparin: effect of molecular weight distribution on plasmat issue factor pathway inhibitor in healthy human subjects. J Clin Pharmacol 2003; 43: 727-734.
    CrossrefPubMedGoogle Scholar
  • 45 Stevenson JL, Choi SH, Varki A. Differential metastasis inhibition by clinically relevant levels of heparins-correlation with selectin inhibition, not antithrombotic activity. Clin Cancer Res 2005; 11: 7003-7011.
    CrossrefPubMedGoogle Scholar
  • 46 Matsui NM, Varki A, Embury SH. Heparin inhibits the flow adhesion of sickle red blood cells to P-selectin. Blood 2002; 100: 3790-3796.
    CrossrefPubMedGoogle Scholar