Online ISSN : 1687-8329

    




Quick Search 
 
Author  
Year    
Title  
Vol:  

 
 
January2005 Vol.42 Issue:      1 Table of Contents
Full Text
PDF


Cerebral Hemodynamics in Asymptomatic Patients with Sickle Cell Disease and Thalassemia: Correlation with Hemostatic State

Hala El-Khawas1, Shaza . El Wahab2, Nahed Salah1, Hossam El Dosoukey Nassr2, Maryse Soliman2
Departments of Neurology1, Internal Medicine2, Ain Shams University

ABSTRACT

Background: Sickle cell disease (SCD) and β thalassaemia are common in Africa and Mediterranean area. Stroke, especially cerebral infarction, is a major cause of morbidity and mortality in these patients. Hypercoagulable state was found in these cases and seems to be multifactorial. Primary prevention of stroke by transfusion therapy may be feasible if there is a way to identify patients at greater risk. Subjects and Methods: Neurologically asymptomatic 26 patients (6 with SCD and 20 with β thalassaemia) were tested by transcranial Doppler ultrasound (TCD)  for their cerebral haemodynamics to detect early changes suggestive of ongoing occlusive vasculopathy. Plasma protein C (PC), protein S (PS) and antithrombin III (AT III) were estimated. The results  TCD, PC, PS and AT III were compared to that of 10 healthy controls. CT brain was done for patients with abnormal TCD results. Results: PC, PS and AT III were highly significantly lower in patients compared to the controls. TCD disclosed abnormality in 10 patients (38.46%).  Patients with positive TCD findings were found to have significantly lower plasma levels of PC and PS compared to the patients with normal TCD findings. Conclusion: Identification of thalassaemia and SCD patients at high risk for stroke is important, because this is the major criterion for initiating chronic blood transfusion, antithrombotic agents or even bone marrow transplantation. Because these lines of treatment carry significant risks, a high predictability of future stroke is necessary to justify their selection. Screening with TCD and assay of natural anticoagulants disclose patients at risk for stroke.

(Egypt J. Neurol. Psychiat. Neurosurg., 2005, 42(1): 223-233).

 




INTRODUCTION

 

Sickle cell disease (SCD) and thalassaemia major (TM) are among the most common   haemoglobinopathies, and are prevalent in    Africa and the   Mediterranean belt  respectively.  Patients with  SCD and β TM are known to have an increased thrombotic  risk1,2. Characteristics of a chronic hypercoagulable state are present in both TM and SCD patients. Both have shortened platelets life span with impaired its function3, increased vascular endothelial adhesion molecules and lowered coagulation inhibitor proteins4.

One of the most devastating complications is an occlusive vasculopathy involving large cerebral vessels which occur in 7-11%of patients and a further 14% have asymptomatic cerebrovascular stroke on imaging3,5,6.

It’s now possible to identify those at risk prior to a first stroke using transcranial doppler ultrasound (TCD).This technique can detect high velocities in the large cerebral vessels in asymptomatic patients .It can predict and identify those at highest risk of stroke7,8.

A numbers of studies tried o identify haemostatic abnormalities that may contribute to the vaso-occlusive process. Bayazit and Kilinc9 found decreased levels of protein C and antithrombin III in patients with SCD. Eldor et al.2 found an elevated  levels of thrombin- antithrombin III complexes, decreased  factor II, protein C and   protein S in TM patients compared to the control healthy individuals.

So the aim of the work is to evaluate the pro-thrombotic state in asymptomatic patients with sickle cell disease and β-thalassaemia by assessment of the levels of protein C,S and antithrombin III in relation to cerebral blood flow using TCD to identify patients at a risk for stroke.

 

PATIENTS AND METHODS

 

The   patients included in this study  were 26 patients who were recruited at haematology clinic in Ain Shams university hospital with a diagnosis of either β- thalassaemia or  sickle cell disease. All the patients were neurologically asymptomatic and non had experienced clinical neurological signs or symptoms of cerebral thrombotic events. Patients were excluded from the study if they have  history of stroke, transient ischaemic attacks or seizures.     

 

All patients were subjected to the following:

1.            Detailed history taking especially past history of previous cerebrovascular strokes, transient ischemic attacks, seizures, deep venous thrombosis recurrent pulmonary embolisms, mycocardial infarctions etc. ….

2.            Thorough clinical examination:

a)   For presence of pallor, jaundice, hepatosplenomegaly, leg ulcers.

b)   Full neurological examination: patients were excluded from the study if they have evidence of neurological deficits, seizures or history of TIA.

3.            Routine biochemical tests: (liver functions tests and renal function tests).

4.            ECG, abdominal ultrasonography and echocardiography.

5.            Hematological assessment:

a)   Complete blood picture including blood indices, blood film and ESR.

b)   HB electrophoresis to prove the diagnosis of sickle cell diseasse and β-thalassaemia.

c)   Total iron profile: serum ferritin level, serum iron level, TIBC.

d)   Protein C, S and antithrombin III level assay.

 

Sample collection:

4.5 ml whole venous blood were collected under complete aseptic conditions and added to 0.5 ml of 0.109 M (3.2%) trisodium citrate anticoagulant solution. Samples were immediately centrifuged at 2500 g for 15 minutes and plasma was collected and stored at -70°C till assay time.

 

Antithrombin III assay:

The antithrmbin III was assayed using the 2 point method utilizing the STA-stochrom AT III kit supplied by diagnostica stago, France. The results were obtained using an ST4 instrument also supplied by diagnostica stago, France.

A calibration curve was constructed for each test run using physiological saline to prepare 1: 30 and 1: 60 dilutions of the unicalibrator and alone to represent the zero point. A control was also included in each test run with a dilution of 1: 30 using saline.

Patients plasma was diluted by saline 1: 30. 200 µl of the diluted plasma was incubated at 37°C for 2-4 minutes before the 60 sec. incubation with the 12 NIH units of bovine thrombin (reconstituted reagent 1) and mixing 200 µl chromogenic substrate (reag 2) was then added to the mixture of incubated for 60 sec at 37°C. 200 µl of 50% acetic acid were added and mixed before the absorbance of the obtained color was read at 405 nm against a blant. The blant was obtained by mixing 200 µl 50% acetic acid, 200µl test sample, 200µl reagent 1 and 200µl reagent 2. A linear-linear graph paper was used to plat the AT-III calibrator value (%) on the X-axis and the corresponding absorbance value on the Y-axis. The absorbance values of the controls and the patients plasma on this calibration line to determine their AT III levels (%). Assay linearity was between 0-125%.

 

Protein S assay:

Protein S assay was performed using STA-staclot® protein S and an ST4 instrument supplied by diagnostica stago, France.

Patients plasmas and quality control were diluted 1: 10 with an owren-koller buffer. 100 µl of test samples, standard or controls were incubated with 100µl of the reconstituted lypholysed human plasma (reagent 1) free of plasma S and 100µl of reconstituted human activated protein C (reagent 2) and 100µl of reconstituted bovine factor Va (reagent 3). 100µl of 0.025 M Ca Cl2 were added tend the dotting was noted. A calibration curve was constructed for each test run using the Owren-Koller buffer to prepare 1: 10, 1: 20 and 1: 40 dilutions.

Results were obtained using a linear graph paper the % of protein S activity was plotted for each calibration point on the X-axis and the corresponding clotting time (in seconds) on the Y-axis. The level of protein S for patients was deduced from the calibration line. The assay linearity was between 10-150%.

 

Protein C assay:

Protein C was assayed using STA-stoclot® protein C and an ST4 instrument supplied by diagnostica stago, France. The controls to patients plasma S were diluted 1: 10 with an owren-koller buffer. 100 µl of diluted plasma or control were incubated with 100µl of reconstituted lypholyzed human plasma free of protein C and 100µl of reconstituted highly purified extract of Agkistroden C controtrix venom for 180 sec at 37°C. 100µl of pre-warmed 0.025 M Ca Cl2 was added with the clotting time noted.

A calibration curve was constructed for each test run using a unicalibrator diluted by the Owren-koller buffer as 1: 10, 1: 20 and 1: 40 dilutions. Then the linear graph paper was used to plot the % of protein C activity for each calibration point on the X-axis and the corresponding clotting time (seconds) on the Y-axis then patients protein C was deduced from the calibration line. The assay linearity was between 10 and 120%.

6.             Transcranial Doppler (TCD):

TCD was performed Using a pulsed Doppler device (DWL Electronische Systeme GmbH, Germany) operating at 2 MHz. the highest peak systolic and mean blood flow velocities in 2mm increments in the middle, anterior and posterior cerebral arteries, internal carotid artery, vertebral and basilar arteries were recorded for each patient. Final evaluation of the ultrasonographic findings followed Seibert et al.(10), criteria predictive for cerebrovascular complications in patients with sickle cell disease. Patients  were considered to have positive TCD findings if they have maximum flow velocity greater than 200 cm/S, maximum velocity in the posterior cerebral, vertebral or basilar arteries greater than the maximum velocity in the middle cerebral artery, mean blood flow velocity of more than 120 cm/sec and turbulence, decreased flow velocity in the segment distal to the stenotic lesion,    spectral broadening and arterial wall covibration10,11,12.

Patients with positive TCD findings were subjected to computed tomography of the brain to asses for the presence of ischemic cerebral lesions.

The patients were compared to  control group  of ten healthy individuals who match patient group for  age and sex. The control group   were subjected to the same protocol except for CT brain.

 

Statistical Methods:

SPSS software package version 9.2 (1992) was used for data analysis, utilizing student T-test to compare between 2 meanings of parametric data and Wilcoxon Rank sum test for comparison between 2 groups of non parametric data.  The probability of error  at 0.05  considered significant, while at 0.01 and 0.001 considered  highly significant.

 

RESULTS

 

The study was conducted on 26 patients, 20 patients (76.9%) with a diagnosis of β-thalassaemia  and 6 (23.1%) with sickle cell disease,  compared  to 10 healthy controls.

The studied group comprises 15 females (53%) and 11 males (47%). Their age ranges between 18 and 40 years (mean 25.19 ±SD 6.68).

Serum iron level was significantly high (<0.05) in the patients group compared to the control and serum ferritin level was highly significantly elevated (P<0.01) in this group  (Table 1).

As regards  protein C, protein S and antithrombin III patients had  highly significantly lower protein C and  protein S levels (P<0.001) and significantly lowered antithrombin III level (P<0.05) compared to the control group (Table 1 and Fig. A).

Regarding TCD, there is highly significantly increased mean blood flow velocities in   patients’ group (112.84±40.11 cm/s) compared to the control (57.59±5.93 cm/s) (P<0.001)  (Table 2). Ten patients (38.46%) were found to have abnormal TCD findings and 16 (61.54%) with normal study (Fig. B).

Patients with abnormal TCD results showed non significant difference as regards age, Hb, haematocrit, serum iron and ferretin compared to the patients with  normal TCD (P>0.05). Yet they show highly significantly lowered PC level and significant lowered PS level compared to patients with normal TCD study (P<0.001  and  P<0.05  respectively). However antithrombin III level showed non significant difference between the two groups (P>0.05)  (Table 3 and Fig. C).  

Among patients with abnormal TCD studies, CT brain showed ischemic lesion in the form of silent lacunar infarcts, deep white matter and periventricular infarcts in 5 patients (19.2%). Those patients with ischemic lesions showed highly significant lower protein C level (P<0.01) and significantly lower protein s level (P<0.05) in comparison to patient with normal CT studies. Antithrombin III level showed non significant difference between the 2 groups (P>0.05) (Table 6).

Patients with positive TCD findings and positive CT studies showed highly significantly lower protein C levels (P<0.001), significantly lowered PS (P<0.05) and significantly higher serum iron (P<0.05) in comparison to patients with negative TCD findings and negative CT studies (Table 7). 


 

 

Table 1. Comparison between haemostatic data of the  patients and control group.

 

Parameter

All patients

Mean±SD

Control group

Mean±SD

P value

Sig.

Ferr

461±333

158±127

<0.01

HS

Iron

165±62.6

115±40.3

<0.05

S

PC

68.3±21.4

89.9±19.3

<0.001

HS

PS

72.1±12.8

91.6±18.7

<0.001

HS

ATIII

88.0±17.5

100±12.8

<0.05

S

Ferr= ferritin                            PS= protein S                            S= significant

PC=protein C                           ATIII= antithrombin III           HS= highly significant

 

 

 

Fig. (A): Statistical comparison between controls and patients regarding mean values PC and PS.

 

Table 2. Comparison between patients  group and control group as regarding TCD  findings (mean flow velocity).

 

 

Variable

(mean flow velocity)

Control group

Patients group

P value

Sig.

MCA

57.59±5.93

112.84±40.11

<0.001

HS

ICA

46.50±7.2

86.61±17.5

<0.001

HS

ACA

55.56±6.16

84.53±25.77

<0.001

HS

BA

55.17±9.7

64.15±16.51

>0.05

NS

 

 

MCA = Middle cerebral artery.          ICA = Internal carotid artery.                             ACA = Anterior cerebral artery.       

BA  = Basilar artery.                                            HS    = Highly significant.                   NS  = Non significant.

 

Table 3. Comparison between patients  with  positive TCD findings and negative TCD findings.

 

Parameter

Negative TCD

(No.=16)

Mean±SD

Positive TCD

(No.=10)

Mean±SD

P value

Sig.

Age

24.4±7.12

26.4±6.1

>0.05

NS

Hct

26.4±4.48

26.0±3.48

>0.05

NS

HB

8.44±1.2

8.50±0.95

>0.05

NS

Ferr

433±274

505±423

>0.05

NS

Iron

164±44.1

166±87

>0.05

NS

PC

79.3±18.9

50.6±10.3

<0.001

HS

PS

76.2±14.5

56.6±5.10

<0.05

S

ATIII

87.6±21.9

88.6±7.15

>0.05

NS

HS = Highly significant.      NS  = Non significant.

Hct = Hematocrit Hb = Hemoglobin                 Ferr = Ferritin

 

Fig. (B): Frequency of positive findings among patients.

 

 

 

 

Fig. (C): Statistical comparison between negative and positive TCD changes

regarding mean values PC and PS.

Table 4. Comparison between patients with positive TCD and control group.

 

Parameter

Positive TCD

Mean±SD

Control

Mean±SD

P value

Sig.

Ferr

505±423

158±127

<0.05

S

Iron

166±87

115±40.3

>0.05

NS

PC

50.6±10.3

89.9±19.3

<0.001

HS

PS

56.6±5.10

91.6±18.7

<0.001

HS

ATIII

88.6±7.15

100±12.8

<0.001

HS

HS = Highly significant.         NS = Non significant.             S = Significant.                        PC = Protein C      

PS  = Protein S        ATIII = Antithrombin III       Ferr= ferritin

 

Table 5. Comparison between  patients with negative TCD and control group.

 

Parameter

Negative TCD

Mean±SD

Control

Mean±SD

P value

Sig.

Ferr

433±274

158±127

<0.01

HS

Iron

164±44.1

115±40.3

<0.01

HS

PC

79.3±18.9

89.9±19.3

>0.05

NS

PS

76.2±14.5

91.6±18.7

<0.05

S

ATIII

87.6±21.9

100±12.8

>0.05

NS

HS = Highly significant.         NS = Non significant.             S = Significant.       

PC = Protein C       PS  = Protein S        ATIII = Antithrombin III

 

Table 6. Comparison between group (1) patients with negative CT findings and group (2) with positive CT findings as regards PC, PS and ATIII.

 

Variable

Patients with negative CT findings

Patients with positive CT findings

P value

Sig.

PC

73.90±19.24

44.60±11.63

<0.01

HS

PS

74.38±13.15

62.60±4.21

<0.05

S

AT III

87.42±19.17

90.40±8.73

>0.05

NS

 

PC = Protein C       PS = Protein S         ATIII = Antithrombin III

HS = Highly significant.         S   = Significant       NS  = Non significant.

 

Table 7. Comparison between group (1) patients with negative TCD and negative CT findings and group (2) patients with positive TCD and  positive CT findings.

 

 

Variable

Patients with negative CT findings

Patients with positive CT findings

P value

Sig.

PC

73.90±19.24

44.60±11.63

<0.01

HS

PS

74.38±13.15

62.60±4.21

<0.05

S

AT III

87.42±19.17

90.40±8.73

>0.05

NS

 

PC = Protein C       PS = Protein S         ATIII = Antithrombin III                       Hct = Hematocrit   

Hb = Hemoglobin   Ferr = Ferritin                         HS = Highly significant.         S   = Significant       NS  = Non significant.

 


DISCUSSION

 

Haemoglobinopathies, including Thalass-aemia and sickle cell  disease are associated with higher than normal incidence of thromboembolic events including recurrent strokes and transient ischemic cerebral attacks, as well as peripheral arterial and venous thrombosis13,14.

                Several mechanisms predispose patients to an increased risk of ischaemic stroke, these include rigidity of the abnormal circulating  red blood cells, adherende of the red  blood cells to the vessel wall, intravascular sluding and certain haemostatic anomalies, all suggest a chronic hypercoagulable state and predispose to thrombotic  infarction15,16.

                Protein C, activated by thrombin and in the presence of PS, inhibits the clotting abilities of factor V and VIII. Antithrombin III is  a plasma  inhibitor  protein that blocks the enzymatic activity of some serine protease coagulation factors. Both PC and ATIII  are synthesized only by the liver9,17.  

Almost all the thalassaemia patients had levels below the normal range of protein C (antigen and activity) and free protein S. The low levels of these inhibitors lead to a chronic hypercoagulable state and  later to thrombotic events2.

Patients with SCD run a risk of having decreased levels of natural coagulation inhibitors due to possible hemostatic abnormalities. The thrombotic events caused by deficiency of natural coagulation inhibitors play a role in chronic leg ulcers and pulmonary and cerebral infarcts frequently found in patients with sickle cell anemia. The mortality and morbidity rates are high in patients with sickle cell anemia due to   complications created by thrombotic events18.   

The occlusive vasculopathy involoving large cerebral large cerebral vessels may progress for months or years before symptoms develop, allowing the opportunity to detect them before a clinical stroke occurs7,8,19.

                Stenotic lesion can be identified using  transcranial Doppler  which is cheap and non invasive method of evaluating cerebral haemodynamics. TCD can detect high velocities in the large cerebral arteries in asymptomatic patients thus can predict and identify  those at highest risk  of stroke20 identification of whom is of significant prognostic and therapeutic implication.

The present study confirmed the significant decrease in protein C, protein S, antithrombin III plasma level in  asymptomatic  thalassaemic and SCD patients. Also the serum iron  and  serum ferritin levels were found to be significantly elevated in those patients.  The same results were obtained in other studies9,21.                          

Several mechanisms contribute towards the low levels of coagulation inhibitors proteins and enhanced prothrombotic  state in  thalassaemia and SCD. First, the deoxygenated and deformable RBCs membrane have  abnormally exteriorized procoagulant anionic phospholipids which are capable of accelerating prothrombin activation22,23. Second, impaired liver function may contribute to reduced protein synthesis. Some degree of hepatic dysfunction may be found in SCD and TM patients. Hepatic dysfunction could be due to acute or chronic viral associated hepatitis, iron overload, hepatic crisis related to severe intrahepatic cholestasisand ischemic necrosis in these patients9,24,25. In this study, the mean values of liver function tests in patients and controls  were non significantly different. However, the serum iron and serum ferritin levels were found to be significantly elevated in the patients compared to the control, which may suggest iron overload that may lead to hepatic dysfunction and impaired protein synthesis.

Wright and coworkers21 have reported similar findings in  patients with homozygous sickle cell disease and suggested that hepatic dysfunction may contribute to low protein C and protein S levels.

                In our study, TCD  detected high flow velocities in 38.46% of asymptomatic thalassaemic and SCD patients. The study also revealed significant low plasma levels of PC, PS, and ATIII in patients with positive TCD findings compared to the control. However, only PS and C  that were significantly lowered in those patients compared to the patients with normal TCD study. The high flow velocity is an indicator of stenosis in large vessels, its presence might be expected to identify silent infarcts as well26. In our study, CT brain was performed in the patients with abnormal TCD results only. Lesions due to occlusive vasculopathy were detected in 5 patients (50% of those with abnormal TCD findings). Patients with positive CT findings showed a more significantly lowered plasma level of PC and PS than those with negative CT findings.                                                                                                  

Data from previous studies27,28 suggest that TCD is more sensitive than MR angiography in enabling the identification of patients with SCD who are at risk for stroke. Abboud et al.(28)  noted that patients with normal MR angiograms were more likely to have resolved abnormal TCD findings at follow –up than were the patients with stenosis or occlusion, yet 3 out of 9 patients with abnormal TCD results and subsequent stroke had initially normal MR angiogram. Therefore for further quantification, the risk of stroke in those patients could be achieved by varyfing  a hypercoagulable state in addition to the repeated abnormal on TCD, even if the results on MR angiogram were normal29.

Ischemic and thrombotic events are more prevalent in TM and SCD patients who are not receiving regular transfusion. Blood transfusion or exchange transfusion  has been shown to greatly reduce the risk of first stroke  in the patients who have abnormal results on  TCD3,19,30. It has been observed that thalassemic patients respond to treatment with platelet inhibitor drugs (asprin and dipyridamole) with a rise in their  arterial oxygen content as does patients with SCD2.

The decision to initiate antithrombotic or transfusion therapy  on the basis  of TCD should be made after careful  consideration  of the lowered natural anticoagulant proteins, as well as MRI and MRA. The complications and costs of transfusion are considerable, but they are predictable  and manageable. These issues must be weighed against the risk of irreversible brain damage due to stroke, the severity of which can’t be predicted. The strategy that we tested offers a way  of lessening the burden of this important complication of two common haemoglobinopathies.

In conclusion; Transcranial Doppler is a safe, effective and well tolerated imaging method for early identification of asymptomatic adults with cerebral vasculopathy.

Thalassaemic patients and those with sickle cell disease are at a risk of thrombotic events especially cerebral thrombosis as documented by the presence of low plasma levels of protein C,S and antithrombin III correlated with the demonstration of high mean flow velocities recorded by TCD. These findings will be the rationale for keeping the risky patients on prophylactic long-term anticoagulation, transfusion therapy whenever indicated and even bone marrow transplantion for refractory cases.

It is highly recommended that:

1.         TCD should be performed annually for patients with thalassaemia and sickle cell disease and every 6 months for patients who have pathological sonographic findings.

2.         Complementary structural examinations using MRI and MRA and assessment of plasma levels of protein C,  S and antithrombin III are advisable for patients with abnormal Doppler findings.

 

REFERENCES

 

1.      Liesner R, Mackie I, Cookson J, McDonald S, Chitolie A and Machin S (1998): Prothrombotic changes in children with sickle cell disease: relationships to cerebrovascular disease and transfusion. Br J Haematol; 103: 1037-1044.

2.      Eldor A, Drust R, Hy AM; Goldfarb, Gillis S, Rachmilewitz EA, Abramov A, Maclouf J and Guillin MC (1999): A chronic hypercoagulable state in patients with β-thalassaemia major is already present in childhood. Br J Haematol; 107: 739-746.

3.      Eldor A and Rachmilewitz EA (2002): The hypercoagulable state in thalassemia. Blood; 99: 36-43.

4.      Tomer A, Harker LA, Kasey S and Echman JR (2001): Thrombogenesis in sickle cell disease. J Lab Clin Med; 137: 398-407.

5.      Bhene-Frempon K, Weiner SJ and Sleeper LA (1998): Cerebrovascular accidents in sickle cell disease: rates and risk factors. Blood; 91: 288-294.

6.      Crowley JJ and Samile S (1999): Imaging of sickle cell disease. Pediatr Radiol; 29: 646-661.

7.      Adams RJ, McKie VC, Nichols F, Carl E, Zhang L and Hess D (1992): The use of transcranial Doppler ultrasonography to predict stroke in sickle cell disease. N Engl J Med; 326: 605-610.

8.      Adams RJ, McKie VC, Carl EM, Nicols FT and Brambilla D (1997): Long term stroke risk in children with sickle cell disease screened with Transcranial Doppler. Annals of Neurology; 42: 699-704.

9.      Bayazit AK and Kilinc Y (2001): Natural coagulation inhibitors (protein C, protein S, antithrombin) in patients with sickle cell anemia in a steady state. Pediatric International; 43: 592-596.

10.    Seibert JJ, Glasier CM, Kirby RS, Allison DL, James CA, Becton DL, Kinder DL, Cox KS, Lairry F, Jackson JF and Graves RA (1998): Transcranial Doppler,  MRA and MRI as a screening examination for cerebrovascular disease in patients with sickle cell anemia an 8-year study. Pediatr Radiol; 28: 138-142.

11.    Sloan M A, Alexandrov AV, Tegeler CH, Spencer MP, Caplan LR, Feldmann E, Wechsler LR, Newell DW, Gomez CR,  Babikian LR, lefkowitz D, Goldman RS  and  Armon C (2004):  Assesment: Transcranial Doppler ultrasonography. Report of the  therapeutics and technology  Assesment  subcommittee of the American  academy of neurology.  Neurol; 62: 1468-1481.

12.    Babilkian V (1999): Transcranial Doppler evaluation of patients with ischemic cerebrovascular disease. In: Babikian V and Wechsler LR, eds. Transcranial Doppler ultrasonography. 2nd ed.,  Mosby, Missouri, St. Louis, p. 87-104.

13.    Michaeli J, Mittelman M, Grisaru D and Rachmilewitz (1992): Thrombemobolic complications in β-thalassaemia major. Acta haematologica; 87: 71-74.

14.    Platt OS, and Doser GJ (1993): Sickle cell disease. In: Nathan DG, Oski FA, ed. Hematology of infancy and childhood. Philadelphia, WB Saunders, p. 732-87.

15.    Malouf AJ, Hamrick- Turner JE, Doherty MC, Dhillon GS, Lyer RV, and Smith MG (2001): Implementation of the STOP protocol for the stroke prevention in sickle cell anemia by using Duplex Power Doppler Imaging. Radiology; 219: 359-365.

16.    Francis RB  and Johnson CS (1991): Vascular occlusion in sickle cell disease: current concepts and unanswered questions. Blood; 77: 1405-1414.

17.    El Hazmi MA, Warsy AS and Bahakim H (1993): Blood protein C and S  in sickle cell disease. Acta Hematologica; 90: 114-117.

18.    Khaunduri U, Gravell D, Christie BS, Zachariah M and Cherian E (1998): A contributory factor for stroke in sickle cell disease. Thromb Haemost; 79: 879-880.

19.    Adams RJ, McKei VC and Brambilla DJ (1998): Stroke prevention trial in sickle cell anemia (STOP): study design. Control Clin Trials; 19: 110-129.

20.    Winrow N, and Melhem EM (2003): Sickle cell disease and stroke in pediatric population, evidence-based diagnostic evaluation. Neuroimaging Clin N Am; 13: 185-96.

21.    Wright JG, Malia RG, Cooper P, Thomas P, Preston EE and Serziant GR (1997): Protein C and protein S in homozygous sickle cell disease: does hepatic dysfunction contribute to low levels? Br J haematol; 98: 627-630.

22.    Lane PA, O'Cannell JL and Marler RA (1994): Erythrocyte membrane vesicles and irreversibly sickled cells bind protein S. Am J Heamtol; 47: 295-300.

23.    Helly D, Elder A, Griot R, Ducrocq R, Guillin MC and Bezeaud A (1996): Increased procoagulant activity of red blood cells from patients with homozygous sickle cell disease and beta-thalassaemia. Thromb Haemost; 76: 322-7.

24.    Balistreri WF (1996): Liver disease associated with systemic disorders. In:Behrman RE, Kliegman RM, Arvin AM (eds). Nelson Textbook of Pediatrics. W.B. Saunders, Philadelphia. 1142-3.

25.    D'Angelo A, Vigano-D'Angelo S, Esmon CT, and Comp PC (1988): Acquired deficiencies of protein S. Protein S activity during oral anticoagulation in liver disease and disseminated intravascular coagulation. J Clin Invest; 81: 1445-54.

26.    Charles H, Winfred W, Suzanne G, Lewis HM and Adams J (2001): Silent infarcts in children with sickle cell anemia and abnormal cerebral artery velocity. Arch Neurol; 58: 2017-2018.

27.    Adams RJ, Nickols FT and Figueroa R (1992): TCD correlation with cerebral angiography in sickle cell disease. Stroke; 23: 1073-1077.

28.    Abboud MR, Cure J and Gallagher D (1999): Magnetic resonance angiography in children with abnormal TCD in the STOP study (Abstract): From the 23rd annual meeting of the National sickle cell disease program, p. 49.

29.    Steen RG, Emudianughe T and Hankins GM (2003): Brain imaging findings in pediatric patients with SCD. Radiology; 228: 216-25.

30.    Adams RJ, Mc Kei VC and Hsu L (1998): Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on Transcranial Doppler ultrasonography. N Engl J Med; 339: 5-11.


 

 

الملخص العربى

 

دراسة ديناميكية الأوعية الدموية المخية والعوامل المانعة للتجلط عند مرضى أنيميا الخلايا المنجلية

وأنيميا البحر المتوسط البالغين والغير مصابين.

 

شملت الدراسة 26 مريضا من مرضى أنيميا الخلايا المنجلية (وعددهم 6) ومرضى أنيميا البحر المتوسط (وعددهم20) وهؤلاء لا يعانون من أي أعراض جلطات مخية وقد تم عمل الآتي لهم: أخذ التاريخ المرضي وفحصهم بدقة وعمل صورة دم كاملة وسرعة ترسيب ووظائف كبد وكلى وفصل كهربائي للهيموجلوبين للتأكد من التشخيص. عمل موجات فوق الصوتية عبر الدماغ لدراسة ديناميكية الأوعية الدموية المخية وأيضا أشعة مقطعية على المخ للمرضى الذين لديهم تغيرات في الموجات فوق الصوتية. قياس مستوى البروتينات المانعة للتجلط في البلازما(سي واس ومضاد الثرومبين-3) في هؤلاء المرضى. وقد تم مقارنة هؤلاء المرضى بعشرة أشخاص أصحاء تم لهم أيضا موجات فوق صوتية عبر الدماغ وقياس البروتينات المانعة للتجلط. وقد أوضحت الدراسة وجود تغيرات في الأوعية الدموية المخية ظهرت في الموجات الفوق صوتية عبر الدماغ في 10 من المرضى  كما أوضحت أيضا انخفاض مستوى البروتينات المانعة للتجلط في بلازما المرضى مقارنة بالأصحاء. من هذا يتضح أن عمل مسح لمرضى أنيميا الخلايا المنجلية وأنيميا البحر المتوسط باستخدام الموجات فوق الصوتية عبر الدماغ وكذلك قياس مستوى العوامل المانعة للتجلط في البلازما يكشف المرضى المعرضين لخطر الإصابة بالجلطة المخية وبالتالي يمكن وقاية هؤلاء المرضى عن طريق العقاقير المانعة للتجلط ونقل دم طازج لهم وزرع نخاع العظام للحالات الغير مستجيبة لوسائل العلاج المعروفة.



2008 � Copyright The Egyptian Journal of Neurology,
Psychiatry and Neurosurgery. All rights reserved.

Powered By DOT IT