Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002895 (sickle cell disease)
 11,747 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although the mechanisms involved in the persistent clinical complications of sickle cell disease have not yet been fully delineated, previous studies suggest that sickle cell (HbSS) patients have a disposition to generate more thrombin and plasma in vivo than normal subjects. The reasons for the impaired regulation of haemostasis in HbSS patients is poorly understood. We report studies evaluating the extent to which in vivo coagulation and fibrinolysis are altered in HbSS patients in steady state. The concentrations of total factor VII (F(VII)t), factor VII zymogen (F(VII)z), thrombin-antithrombin III (TAT), fibrinopeptide A(FPA), and fibrin D-dimer in plasmas of 50 normal controls (HbAA) and 45 HbSS steady state patients, were measured using sensitive and specific enzyme-linked immunoassays. The average plasma concentration of F(VII)t, in sickle cell plasma was significantly lower than that of the control subjects (0.70 +/- 0.19 U/ml versus 1.16 +/- 0.41 U/ml), whereas F(VII)z in the patients and controls were 0.47 +/- 0.15 U/ml and 1.15 +/- 0.33 U/ml respectively, P < 0.001. Both measures of factor VII suggest a higher factor VII turnover in sickle cell disease. The mean concentration of TAT in the plasma of HbSS patients were significantly higher than those of HbAA controls (371 +/- 44 pM versus 42 +/- 2 pM) (P < 0.001), a difference that is strongly indicative of higher rates of in vivo thrombin generation by HbSS patients. Plasmas of HbSS patients had significantly higher concentrations of FPA compared to those of the control subjects (12.85 +/- 1.96 ng/ml versus 4.22 +/- 0.37 ng/ml) (P < 0.001). The D-dimer levels were also higher in the HbSS than control plasmas (1029.6 +/- 58.6 ng/ml versus 224.3 +/- 27.6 g/ml) (P < 0.001), with the patients' values being indicative of enhanced fibrinolysis. These results strongly suggest accelerated in vivo coagulation and fibrinolysis in HbSS patients even during steady state. They are consistent with the hypothesis that haemostasis is less tightly regulated in the HbSS patients than in HbAA controls. The altered regulation of haemostasis may contribute to the initiation of vaso-occlusive processes associated with sickle cell painful episodes.
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PMID:Plasma factor VII and thrombin-antithrombin III levels indicate increased tissue factor activity in sickle cell patients. 139 Feb 42

Changes in platelet function have been observed for sickle cell disease (SCD). Levels of the arachidonic acid metabolites, thromboxane A2 (released by stimulated platelets) and prostacyclin (released from vascular endothelium), which stimulate and inhibit platelets, respectively, have been implicated in overall regulation of platelet function. Circulating basal levels of thromboxane and prostacyclin were determined in 1) a group of SCD volunteers (n = 21; at half-yearly steady state intervals and also at 24 hr, 72 hr, and 7 days after start of pain crisis) and 2) an age-, sex-, and race-matched control group (n = 18; single determinations). Circulating levels of beta-thromboglobulin (beta-TG), as well as thrombin (clotting)-stimulated platelet release of thromboxane, were also determined. Statistically significant decreases were found for prostacyclin, basal thromboxane, and thrombin-induced (maximal) thromboxane (alone or per platelet), for steady state SCD vs. normal controls. In addition, significant increases in maximal thromboxane were identified in crises (24, 72 hr) compared with steady state. Crisis beta-TG (24 hr) was significantly elevated compared with controls or steady state SCD. The ratio of basal thromboxane to prostacyclin was increased in crisis, but not significantly. Crisis frequency may correlate in part with changes in platelet function: steady state maximal thromboxane and released thromboxane per platelet were significantly lower in SCD volunteers who had crises during the study vs. those who did not (equivalent study time). The data support altered platelet function in SCD, possibly refractoriness (desensitization), manifest as decreased thromboxane release, to thrombin and/or other stimuli: alternate explanations are discussed.
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PMID:Platelet regulatory prostanoids and platelet release products in sickle cell disease. 153 87

Recent evidence suggests that sickle cell disease (SCD) can be considered a hypercoagulable state, in which both platelet activation and thrombin generation are abnormally increased. Although thrombosis is now known to play an important role in at least one of the vasocclusive complications of SCD, namely stroke, the significance of hypercoagulability in the pathogenesis of vascular occlusion in SCD remains unclear. This review summarizes current evidence regarding platelet, coagulation, and fibrinolytic abnormalities in SCD and their possible role in vascular occlusion. Potential implications for therapy are also discussed.
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PMID:Platelets, coagulation, and fibrinolysis in sickle cell disease: their possible role in vascular occlusion. 189 65

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 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 less than 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 increased 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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PMID:Elevated fibrin D-dimer fragment in sickle cell anemia: evidence for activation of coagulation during the steady state as well as in painful crisis. 273 76

Platelet activation at sites of enmeshed sickled red cells in the microcirculation may contribute to platelet plug formation and microinfarction in sickle cell anemia. To test this hypothesis platelets from 116 sickle cell anemia patients free of crisis, 32 patients with crisis, 16 convalescents within 1 week of crisis, and 180 normal controls were studied. Platelets store 90% of their ADP in dense secretory granules. During activation ADP is secreted and permanently lost from the cell. This leads to a decrease in cellular ADP concentration and a sharp rise in the ATP/ADP ratio. ATP and ADP were ethanol-extracted from platelet-rich plasma, measured in the luciferase-luciferin assay and expressed in nmoles per 10(8) cells. No adenine nucleotide differences were found in platelets from patients free of crisis compared with normal controls. The ADP concentration of platelets from patients in crisis was significantly lowered, indicating that in vivo platelet secretion of ADP had occurred. Total and released ADP was decreased from 2.69 to 1.66, and from 1.90 to 1.21 respectively, and the total ATP/ADP ratio was increased from 1.85 to 2.84 (P less than 0.001). ADP stores in platelets from convalescents were significantly different from sickle controls (P less than 0.001) but were less abnormal than ADP stores in platelets from crisis patients (P less than 0.01), indicating recovery. Total and released ADP was decreased to 1.97 and 1.31 respectively, and the ATP/ADP ratio was increased to 2.38. Platelets from patients in crisis were able to release their remaining granular ADP in response to thrombin as effectively as normal platelets. Thus significant platelet activation with ADP release occurs during acute sickle pain crisis. This might contribute to platelet plug formation and microvascular obstruction.
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PMID:Platelet activation during pain crisis in sickle cell anemia patients. 274 22

Measurements of the coagulation system were carried out in children with sickle cell disease (SCD) in both steady state and on the 1st day of painful crisis and were compared to age- and sex-matched healthy controls. No significant differences were found in prothrombin time, partial thromboplastin time, thrombin time, reptilase time, plasma fibrinogen, antithrombin III, factor VIII:C, ristocetin-cofactor (Ri-Cof) and platelet aggregation responses to ADP, collagen and adrenaline. Abnormal aggregation responses to ristocetin were noted in all patients with SCD when compared to controls. Daily measurements during the first 4 days of painful crisis showed significant elevation of fibrinogen and Ri-Cof and enhancement of aggregation to ADP and adrenaline by the 3rd day of crisis. It was concluded that the changes noted, rather than being primarily responsible for the onset of crisis, can only be secondary changes arising from the aetiological factors of crisis, i.e. stasis and acute-phase proteins.
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PMID:Coagulation changes in sickle cell disease in early childhood. 311 56

Ticlopidine is an inhibitor of platelet action that has been used in the treatment of a variety of disease states in which platelets play a prominent role. Studies in animals and man have demonstrated that ticlopidine is a potent inhibitor of platelet aggregation induced by adenosine diphosphate (ADP), and variably inhibits aggregation due to collagen, adrenaline (epinephrine), arachidonic acid, thrombin, and platelet activating factor. Inhibition of platelet aggregation is both dose- and time-related, with its onset of activity being 24 to 48 hours, its maximal activity occurring after 3 to 5 days, and its activity still being present 72 hours after a final dose. Ticlopidine also inhibits the release reaction of platelets, prolongs bleeding time, reduces plasma levels of platelet factor 4 and beta-thromboglobulin in patients in whom these proteins are elevated, and may also inhibit platelet adhesion, increase red cell filtrability and decrease whole blood viscosity. In a large number of animal models, ticlopidine markedly inhibits thrombus formation or graft occlusion. Ticlopidine is well absorbed after oral administration. It is extensively metabolised and at least one of its metabolites is pharmacologically active. Therapeutic trials in patients with chronic arterial occlusion due to thrombangitis obliterans or arteriosclerosis obliterans, post-myocardial infarction, cerebrovascular thromboembolic disease, subarachnoid haemorrhage, vascular shunts or fistulas for haemodialysis, and sickle cell disease have shown promise for the use of ticlopidine. However, trials of patients with intermittent claudication, angina pectoris, diabetes mellitus with microvascular disease, aortocoronary bypass grafts, and vascular prostheses have had conflicting results or have shown an unfavourable side effect profile. Further studies are clearly required to establish the role of ticlopidine in many of these areas, some of which are already in progress. Overall, side effects occur in 10 to 15% of patients receiving ticlopidine. The most common side effects are gastrointestinal disturbances and skin rashes. Neither of these necessarily require discontinuation of therapy in most patients. Agranulocytosis, thrombocytopenia, and cholestatic jaundice have also been reported. Bleeding is infrequent except possibly in patients receiving ticlopidine prior to some surgical procedures.
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PMID:Ticlopidine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in platelet-dependent disease states. 330 67

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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PMID:Is sickle cell crisis a thrombotic event? 378 60

Seventeen parameters of coagulation and fibrinolysis were measured in 33 patients with sickle cell disease; 30 were tested in steady state (SS) and 19 in crisis (Cr). There were 16 patients in both groups. The same parameters were measured in 16 controls of similar ethnic origin (Black controls; BC) and 20 Caucasian controls (CC), all with HbA only. Highly significant differences (P < 0.001) between Black and Caucasian control groups were noted for: fibrinogen, fibrinopeptide-A (FPA), beta-thromboglobulin (beta TG) and D-dimer. Significant differences (P < 0.03) in plasminogen activator inhibitor (PAI) and functional antithrombin III levels were also noted. Results of the sickle cell patients were therefore compared with those of the Black controls. Sickle cell patients in SS had raised v Wf compared with BC, which increased further during Cr (P = 0.001), but showed no significant increase in fibrinogen. Functional protein C was reduced in SS (P = 0.004) but with no further fall in Cr, while free protein S was normal in SS but reduced in Cr (P = 0.02). Total protein S and ATIII were normal in SS and Cr. FPA and beta TG were not significantly raised in SS or Cr compared with BC. There were, however, highly significant increases in D-dimer and thrombin-antithrombin complexes (TAT) in both SS and Cr compared with BC (P < 0.001 for SS and Cr vs BC). Thus significant activation of coagulation with consequent increase in fibrinolysis occurs during both the sickle cell crisis and in the steady state.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Changes in coagulation and fibrinolysis in patients with sickle cell disease compared with healthy black controls. 760 84

There is evidence for increased factor VII turnover and the associated increased thrombin generation and fibrinolytic activities in sickle cell disease (SCD) that may affect in vivo platelet and endothelial cell reactivity. We studied the release of specific eicosanoids that are indicative of in vivo platelet activation and endothelial cell injury. The circulating and urinary levels of 2,3-dinor thromboxane B2(2,3-dinor-TxB2),TxB2,PGI2 [as 6-keto-PGF1 alpha], and PGE2 were measured in 15HbSS patients, eight HbAA non-haemolytic anaemic individuals and 12 healthy HbAA controls using specific RIAs. The mean urinary 2,3-dinor-TxB2 in the HbSS patients was significantly higher than in both the healthy HbAA and the anaemic controls. 6-keto-PGF1 alpha was undetected in the urines of the healthy HbAA controls, but was measured insignificant amounts in the HbSS and the HbAA anaemic patients. The urinary concentrations of PGE2 and TxB2 in HbSS patients' samples were also significantly higher than those of both control groups (P < 0.05). PGE2 and TxB2 levels were below the detection limit in the plasmas of the HbAA subjects, but were measurable in the HbSS and HbAA anaemic plasmas. The plasma level of 6-keto-PGF1 alpha in the HbSS patients was also significantly higher than in the control groups. The data indicates a persistent inflammatory process in the HbSS patients, and is consistent with the hypothesis that there is platelet and endothelial cell activation in SCD.
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PMID:Elevated urinary levels of thromboxane and prostacyclin metabolities in sickle cell disease reflects activated platelets in the circulation. 799


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