Elevated plasma levels of fibrinopeptide a during sickle cell anemia pain crisis–evidence for intravascular coagulation

Leichtman, David A.; Brewer, George J.

doi:10.1002/ajh.2830050303

Cited by 36 publications

(10 citation statements)

References 14 publications

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“…Such spicules, which have been found in the plasma of patients with sickle cell disease [20,21], dramatically increase the rate of thrombin formation [ 191. Several investigators have reported indirect evidence of intravascular thrombin formation in subjects with sickle cell disease, generally in the form of elevated levels of fibrinopeptide A [22], signs of platelet activation [23], and consumption of protein C [24].…”

Section: Discussionmentioning

confidence: 99%

Is sickle cell crisis a thrombotic event?

Green

Scott

1986

American J Hematol

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Although large vessel thrombi are occasionally reported in patients with homozygous sickle cell disease, the role of intravascular coagulation in typical pain crises is controversial. Therefore, we studied 24 sickle cell patients during and between episodes of pain crisis, using several sensitive tests of hemostasis. Fibrinogen was measured by a clotting assay, beta-thromboglobulin (beta-TG) and fibrinopeptide A (FPA) were quantitated by radioimmunoassay, and protein C was determined by absorbing the zymogen from test plasma, activating it with thrombin-thrombomodulin complex, and measuring activity with a selective synthetic substrate. Fibrinogen was elevated in asymptomatic patients (355 +/- 145 mg/dl) but was no different from the value in these same patients during crisis (333 +/- 180 mg/dl, p greater than 0.1). Similarly, beta-TG 136 +/- 52 ng/ml vs 118 +/- 56; FPA 3.7 +/- 4.8 ng/ml vs 5.2 +/- 4.5, and protein C 71 +/- 20% vs 66 +/- 19 showed no important changes during crisis. However, all these values were significantly different from those in age- and sex-matched healthy controls. beta-TG, fibrinogen, and FPA were elevated (p less than 0.001, 0.005, and 0.05, respectively), and protein C was decreased (p less than 0.003). We conclude that while chronic intravascular coagulation is common in patients with sickle cell disease, there is no evidence that the pain crisis per se is a thrombotic event.

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Section: Discussionmentioning

confidence: 99%

Is sickle cell crisis a thrombotic event?

Green

Scott

1986

American J Hematol

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“…those observed by Whitaker et al [7] in sub jects with established macrovascular throm bosis (deep-vein thrombosis, pulmonary em bolism, and arterial thromboembolism) [7], The levels observed in most steady-state pa tients are lower, suggesting that activation of coagulation in the steady state is less pro nounced. The normal fpa levels previously reported in the steady state [6] may reflect a lower sensitivity of plasma fpa levels to lowgrade activation of coagulation, perhaps due to the very short half-life (approximately 3 min) of this peptide fragment in vivo [5]. Studies comparing the levels of fpa and D-dimer in steady-state sickle cell subjects are needed.…”

Section: Discussionmentioning

confidence: 99%

“…Fibrinopeptide A (fpa) is pro duced by the action of thrombin on the alpha chain of fibrinogen, and is the first fragment produced in the transformation of fibrino gen to fibrin [5], fpa has been reported to be elevated during painful crisis, but to be nor mal in uncomplicated sickle cell disease dur ing the steady state [6]. fpa levels in plasma are very sensitive to artifact due to in vitro thrombin activity, so that flawless venipunc ture technique, special anticoagulants, and prompt processing of plasma to remove cross-reacting fibrinogen are necessary to ob tain valid results.…”

Section: Introductionmentioning

confidence: 99%

Elevated Fibrin <i>D</i>-Dimer Fragment in Sickle Cell Anemia: Evidence for Activation of Coagulation during the Steady State as well as in Painful Crisis

Francis¹

1989

Pathophysiol Haemos Thromb

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The fibrin D-dimer degradation fragment is produced by plasmin degradation of cross-linked fibrin. Elevated plasma D-dimer levels indicate increased plasmin degradation of cross-linked fibrin, and are therefore an indirect indication of increased plasmin degradation of cross-linked fibrin, and are therefore an indirect indication of increased thrombin activity and fibrin formation. With an ELISA assay sensitive to plasma D-dimer levels of less than 50 ng/ml, elevated levels of D-dimer were found in 23 of 25 subjects with sickle cell disease tested during the steady state, and in all 21 subjects tested serially while hospitalized for painful crisis (total of 40 samples). Mean D-dimer was 79 ± (SD) 25 ng/ml in 35 normal subjects, 566 ± 739 ng/ml in sickle cell disease subjects in the steady state, and 1,038 ± 1,010 ng/ml in sickle cell subjects during painful crisis; these differences were highly significant (p < 0.001). No correlation was observed between levels of D-dimer in the steady state and the time since the last painful crisis; D-dimer was elevated in all 7 patients tested more than 6 months after their last painful crisis. Most steady-state patients did not have other microvascular occlusive manifestations, such as active leg ulcers or aseptic necrosis of bone, which could explain the increased D-dimer levels observed. It is concluded that incerased thrombin activity and fibrin formation are features of steady-state sickle cell disease, and that they further increase during painful crisis. Possible causes and implications of increased thrombin activity and fibrin formation in subjects with sickle cell disease are discussed.

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“…Multiple physiologic events are thought to contribute to vaso-occlusion, including hemoglobin S polymerization with consequent RBC deformation [1], cell dehydration leading to increased hemoglobin polymerization [2,3], RBC adhesion to endothelial cells and extracellular matrix (ECM) proteins [4], and activation of coagulation [5][6][7]. Red blood cells containing predominantly hemoglobin S (SS RBC) adhere most avidly to laminin among ECM proteins [8].…”

Section: Introductionmentioning

confidence: 99%

B‐CAM/LU expression and the role of B‐CAM/LU activation in binding of low‐ and high‐density red cells to laminin in sickle cell disease

et al. 2004

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Red blood cells from patients with sickle cell disease (SS RBC) adhere to laminin and over-express the high-affinity laminin receptor basal cell adhesion molecule/Lutheran protein (B-CAM/LU). This receptor has recently been shown to undergo activation in vitro through a protein kinase A-dependent mechanism. Low-density SS RBC express twothirds more B-CAM/LU than high-density SS RBC. However, high-density SS RBC have been identified as most adherent to laminin under flow conditions. We investigated the ability of low-and high-density SS RBC to interact with laminin under various conditions and explored factors that might be responsible for the differences in B-CAM/LU-laminin interaction between high-and low-density SS RBC. We confirmed that high-density SS RBC adhere to laminin more strongly than low-density SS RBC under flow conditions. However, low-density SS RBC bind soluble laminin most strongly and are the most adherent to laminin under static conditions. Soluble recombinant Lutheran extracellular domain protein completely blocked SS RBC adhesion to laminin under both static and flow conditions. The protein kinase A inhibitor 14-22 amide inhibited adhesion to laminin during flow by high-density SS RBC from patients with strongly adherent cells but had no effect on adhesion observed after a static phase. Deletion of the cytoplasmic domain of B-CAM as well as mutation of the juxtamembranous tyrosine residue failed to reduce B-CAM-mediated adhesion to laminin by transfected MEL cells. These studies confirm that B-CAM/LU is the most critical receptor mediating adhesion to laminin under both static and flow conditions. Dense SS RBC are most adherent to laminin despite bearing fewer laminin receptors, apparently due to a reversible protein kinase A-dependent process that is unlikely to involve direct phosphorylation of B-CAM/LU. Our results also suggest that the nature of the interaction of B-CAM/LU with laminin may be different under static and flow conditions. Am.

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Elevated plasma levels of fibrinopeptide a during sickle cell anemia pain crisis–evidence for intravascular coagulation

Cited by 36 publications

References 14 publications

Is sickle cell crisis a thrombotic event?

Is sickle cell crisis a thrombotic event?

Elevated Fibrin <i>D</i>-Dimer Fragment in Sickle Cell Anemia: Evidence for Activation of Coagulation during the Steady State as well as in Painful Crisis

B‐CAM/LU expression and the role of B‐CAM/LU activation in binding of low‐ and high‐density red cells to laminin in sickle cell disease

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