Vascular occlusion in sickle cell disease: current concepts and unanswered questions

Francis, Robert B.; Johnson, Cage S.

doi:10.1182/blood.v77.7.1405.bloodjournal7771405

Cited by 101 publications

(95 citation statements)

References 106 publications

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“…1972;Rothman et al, 1986;Koshy et ul. 1988;Francis & Johnson, 1991). It should also be noted, however, that HCII levels have been found to be below 60% in 4/3 79 apparently healthy individuals (Anderson et al, 1986) and it has been suggested that factors in addition to low HCII levels may be necessary to increase the risk of thrombosis appreciably (Bertina et al, 1987).…”

Section: Discussionmentioning

confidence: 99%

“…While there is little evidence that thrombosis plays a primary role in the pathogenesis of most vaso-occlusive complications of sickle cell syndromes, there is considerable evidence to show an increased thrombotic risk in these patients. Pulmonary thrombosis/embolism has been documented histologically as the cause of death in 8% of subjects who died after the age of 10 and in another autopsy study, pulmonary embolism was found in 2 5% of 72 subjects compared with 15% of 72 age matched controls (Francis & Johnson, 1991). Thrombosis has also been recognized to be increased in maternal placentas and pulmonary embolism is a relatively frequent complication in untransfused sickle cell patients in pregnancy (Koshy et al, 1988).…”

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confidence: 99%

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Sickle cell disorders and chronic intravascular haemolysis are associated with low plasma heparin cofactor II

Porter¹,

Young²,

Mackie³

et al. 1993

Br J Haematol

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Thrombotic events are known to be increased in patients with sickle cell syndromes and a variety of abnormalities of coagulation or endothelial function have been described, although the relevance of these findings either to the pathogenesis of vaso-occlusive phenomena or the risk of thrombosis are unclear. Heparin cofactor II (HCII) and antithrombin III are circulating inhibitors of thrombin and low plasma levels have been associated with an increased risk of thrombosis in otherwise healthy individuals. We describe for the first time abnormally low plasma levels of HCII in patients with sickle cell syndromes. 45 adult patients with sickle cell syndromes (31 SS, 10 SC, 4 S beta Thal) were compared with 61 age matched control patients for HCII in plasma. There was a highly significant reduction in HCII in SS patients irrespective of crisis or transfusion state 0.68 +/- 0.15 U/ml (mean +/- SD) compared with controls 1.00 +/- 0.19 U/ml (P < 0.001). HCII antigen was also significantly reduced (0.53 +/- 0.19 U/ml) compared with controls (1.02 +/- 0.23 U/ml, P < 0.0001). By contrast there was no reduction in antithrombin III in this group. HCII (0.63 +/- 0.13 U/ml, P < 0.001) and HCII antigen (0.54 +/- 0.08 U/ml, P < 0.001) are also significantly reduced in SC patients HCII levels increased towards control values during sickle cell crises, in patients taking the contraceptive pill, or with regular blood transfusion; however, plasma HCII concentrations were not increased acutely by exchange transfusion. HCII was also decreased in thalassaemia intermedia and pyruvate kinase deficiency, suggesting that intravascular haemolysis may be the cause of reduced HCII levels.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Sickle cell disorders and chronic intravascular haemolysis are associated with low plasma heparin cofactor II

Porter¹,

Young²,

Mackie³

et al. 1993

Br J Haematol

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“…This understanding of the relationship of the protein network to properties of the whole cell has been advanced by the study of pathological states such as inherited disorders of red blood cells including sickle cell disease, the thalassaemias and hereditary spherocytoses and ovalocytosis (Mohandas and Chasis, 1993;Mohandas and Evans, 1994). In these conditions, changes in haemoglobin structure, such as those in haemoglobin S for example, have led to altered cellular properties including changes in cell deformability and increased adhesiveness (Barabino etaL, 1987;Francis, 1991;Francis and Johnson, 1991;Morris etal., 1993).…”

Section: Abbreviationsmentioning

confidence: 99%

The malaria-infected red blood cell: Structural and functional changes

Cooke

Mohandas

Coppel

2001

Advances in Parasitology

187

149

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The asexual stage of malaria parasites of the genus Plasmodium invade red blood cells of various species including humans. After parasite invasion, red blood cells progressively acquire a new set of properties and are converted into more typical, although still simpler, eukaryotic cells by the appearance of new structures in the red blood cell cytoplasm, and new proteins at the red blood cell membrane skeleton. The red blood cell undergoes striking morphological alterations and its rheological properties are considerably altered, manifesting as red blood cells with increased membrane rigidity, reduced deformability and increased adhesiveness for a number of other cells including the vascular endothelium. Elucidation of the structural changes in the red blood cell induced by parasite invasion and maturation and an understanding of the accompanying functional alterations have the ability to considerably extend our knowledge of structure-function relationships in the normal red blood cell. Furthermore, interference with these interactions may lead to previously unsuspected means of reducing parasite virulence and may lead to the development of novel antimalarial therapeutics.

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“…Microvascular occlusion in SS disease is a multifactorial process (Francis & Johnson, 1991). Coagulation activation in the steady state has been reported (Peters et al, 1994;Kurantsin Mills et al, 1992;Hagger et al, 1995) and disordered coagulation may play a role in the pathogenesis of vascular occlusion in sickling disorders (Francis, 1992).…”

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confidence: 99%

Protein C and protein S in homozygous sickle cell disease: does hepatic dysfunction contribute to low levels?

et al. 1997

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Summary. The aim of this study was to confirm reports of low protein C (PC) and S (PS) concentrations in steady-state patients with homozygous sickle cell (SS) disease when compared to a racially matched normal haemoglobin (AA) control group and to examine the mechanisms of this reduction with respect to hepatic function, coagulation activation and haematological indices.In 36 SS patients and 35 AA race-matched controls PC (functional and immunoreactive), PS (free and total) were measured. C4B binding protein (C4B) was assessed by immunoelectrophoresis and D-dimer by ELISA. Hepatic function was assessed by prothrombin (PT) time (49 SS, 64 AA), factor V (34 SS, 36 AA) and factor VII concentrations (28 SS, 29 AA). Proteins induced in vitamin K absence or antagonism (PIVKA) were sought in 12 SS's. The relationship between PC, PS and total bilirubin, haemoglobin (Hb) F and reticulocyte count was also assessed.PC, PS and C4B were lower in SS disease. SS patients had longer PT times, and lower factor V and VII concentrations in comparison to AA controls. PC (functional and immunoreactive) and free PS correlated with PT. Within SS genotype PT correlated negatively with factor V and factor VII. Factor V and VII were positively correlated. PIVKAs were not detected. There was no correlation between PC, PS and Ddimer, haemolytic rate or Hb F concentration.Prolongation of PT time, low factor V and VII suggest that hepatic dysfunction, rather than coagulation activation or haemolytic rate, accounts for the reduced concentrations of PC and PS in steady-state SS disease. The absence of PIVKAs suggests a hepatocellular problem.

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Vascular occlusion in sickle cell disease: current concepts and unanswered questions

Cited by 101 publications

References 106 publications

Sickle cell disorders and chronic intravascular haemolysis are associated with low plasma heparin cofactor II

Sickle cell disorders and chronic intravascular haemolysis are associated with low plasma heparin cofactor II

The malaria-infected red blood cell: Structural and functional changes

Protein C and protein S in homozygous sickle cell disease: does hepatic dysfunction contribute to low levels?

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