Haemostasis in rheumatoid arthritis without vasculitis

PARVAIZ A KOUL, MD, FAYAZ A BHAT, MD, ABDUL WAHID, MD, MOHAMMAD SHABAN, M Sc*


Departments of Internal Medicine and Clinical Hematology*,
Institute of Medical Sciences, Srinaga, India.
Address for Correspondence

Parvaiz Ahmad Koul, MD
Department of Internal Medicine,
SheriKashmir Institute of Medical Sciences,
Soura, Post Bag 27,
Srinagar 190 011, Kashmir (India).
Tel: 0091-194-2423339, 2420993.
Fax: 0091-194-2403470
Email: parvaizk@rediffmail.com


INTRODUCTION

Rheumatoid arthritis is a chronic disease of unknown etiology that affects multiple systems of the human body. Among other manifestations abnormalities in coagulation parameters have been reported and have variously revealed accelerated metabolism of fibrinogen (1,2), increased levels of fibrin split products in blood (3) and in synovial fluid (3-5), and increased blood fibrinolytic activity (6). Conn et al found evidence of mild overcompensated intravascular coagulation and fibrinolysis in patients with RA (7), which they believed may play a role in the initiation and perpetuation of the inflammatory process. In addition, spontaneous inhibitors to coagulation factors have been reported to appear, the most frequent being those directed against factors VIII, V and Xa phospholipid complex- the lupus anticoagulant (8-10).
Rheumatoid arthritis is a major scourge in our part of the globe but no data is available on coagulation parameters in such cases and the present study was designed to address this issue and deduce its possible association with disease activity.

MATERIALS AND METHODS

Twenty six randomly selected patients with rheumatoid arthritis (ARA criteria) and 20 healthy controls were enrolled for the study. A detailed clinical history and examination was recorded on a predefined proforma, with particular emphasis on disease symptoms, duration of morning stiffness, any abnormal bleeding, examination of various joints, presence of pallor, subcutaneous nodules and peripheral neuropathy. Rithchie articular index (RAI), pain score and grip strength (mean of six readings) were recorded in all cases. Disease severity was ascertained according to the following:
Score Morning stiffness Pain scale Grip strength RAI Hb ESR
(duration) (cm) (mm Hg) (g/dl)

  1. <10 0-2.4 >200 0 >14.1 0-20
  2. 10-30 2.5-4.4 50-200 1-7 13-14 21-45
  3. 31-120 4.5-6.4 21-49 8-17 10-12 46-80
  4. >120 6.5-10 <20 >18 <9.9 >81

The parameters were added and mean index of disease activity (IDA) obtained and on the basis of these values mean grades of disease activity (MDAG) were calculated as follows:

On the basis of the scoring 2 patients had grade I RA, 8 had grade II RA, 6 had grade III RA and 10 patients had grade IV RA. The general pararmeters of the patients are depicted in table 1.
All he patients underwent routine investigations, hemograms were performed on a Coulter cell counter, and serum biochemical parameters on a multichannel autoanalyzer (Hitachi 704, Japan). For coagulation studies venous blood samples drawn without undue stasis and frothing into plastic syringes having 19 to 21 SWG. Samples were collected in coded glass tubes containing sodium citrate in 1:10 dilution as the anticoagulant and sent to the laboratory for analysis. Various parameters studied included prothrombin time (kits from Sigma Diagnostics, USA), APTT, fibrinogen, fibrin split products, D-dimers (kits from Diagnostic Stago, France) and euglobin lysis time (ELISA). Quantitative estimation of protein C and S was performed using E.LISA method (kits from Diagnostic Stago, France). Antithrombin III levels were assayed using chromogenic assay (kits from Diagnostic Stago, Franace). Factors VIII, IX, XI and XII levels were estimated employing factor deficient plasma supplied by Sigma Diagnostics, USA. Skin biopsies were obtained from all cases from the volar aspect of the forearm. Sural nerve biopsies were performed in a cases.
Informed consent was obtained from all the participants of the study and the study was approved by the Institute academic and ethics committee. Student's t-test was employed for statistical analysis for continuous variables. Preanalysis log transformation was done for skewed data. Mutivariate analysis of variance was employed to determine the association of different variables on coagulation parameters. Values have been expressed as mean+SEM and a p-value of <0.05 was considered significant.

RESULTS

The 26 patients consisted of 17 females and 9 males with ages ranging from 13 to 60 years (mean age 38.81+2.5 years), whereas the controls consisted of 8 females, mean age 35.3+2.72 years. None of the patients had any evidence of bleeding, thromboembolic phenomena, presence of active neuropathy or any clinical or histopathological (skin/nerve biopsies) features of vasculitis. As expected, Ritchie articular index , Morning stiffness and grip strength demonstrated significant change with the increasing severity of the disease (p values 0.00007, 0.003, 0.002 respectively). The various hematological and coagulation parameters have been depicted in table 1. None of the patients had DIC and only isolated abnormailities of coagulation were observed. A significant difference was observed in platelets, ESR, AT III, factors VIII, IX and protein S levels between cases and controls. Hemoglobin levels showed a decreasing trend with increasing severity of the disease (p 0.01) whereas an increasing trend was observed in the platelets (p=0.01) and ESR (p=0.0007).

DISCUSSION

Although isolated coagulation abnormalities were observed, our patients did not demonstrate abnormalities consistent with DIC or an overcompensated DIC as observed by earlier studies in patients with RA with or without vasculitis. Conn et al (7), found elevated levels of fibrinogen, FDP's and platelets in patients of rheumatoid arthritis with associated vasculitis. Fewer patients on steroids had abnormal coagulograms and none had decompensated DIC. None of our cases had evidence of vasculitis on the basis of sural nerve/skin biopsies. A subgroup of 12 controls was fed with NSAIDS/steroids for 4 days and coagulation parameters tested. No coagulation abnormalities were demonstrated in these cases. Activation of the hemostatic system was recently found to be associated with disease activity in a recent study in children with juvenile rheumatoid arthritis (11), when the researchers found elevated levels of d-dimers, fibrinogen and prothrombin fragments. In another study in children with juvenile rheumatoid arthritis prothrombin fragments 1+2, thrombin-antithrombin complex, D-dimers and fibrinogen were significantly elevated and correlated with disease activity. A subclinical activation of the hemostatic system in JRA might be caused by the action of the immunomediators on cells (monocytes, endothelial cells) playing a role in the regulation of blood coagulation system (12)
In contrast to the earlier studies (13-15), thrombocytosis was not observed in the present study. Absence of thrombocytosis in our cases lends weight to the earlier hypothesis of thrombocytosis occuring as a compensatory response to active DIC (15). Thrombocytois was found to be associated with decreased platelet survival and increased fibrinogen turnover in an earlier study suggesting that it was a compensatory response to DIC (15). However, a small sample size would not allow deduction of any conclusions.
Protein C were abnormally low in one case with grade II RA. The patient had no evidence of hepatic dysfunction and PT/APTT were elevated with positive d-dimers.
The presence of normal or near normal PT/APTT suggests that no change in factors VIII or V. Decreased factor VIII levels in 5 cases (with associated increase in APTT/PT in 1 case and hypofibrinogenemia in 1 case) could be explained on the basis of development of factor VIII inhibitors and acquired hemophilia in RA that has been at times severe enough to result in life threatening bleeding and q3 absence of factor VIII from the serum. Factor IX levels were normalin all the cases and a decrease in protein S in one case was the only abnormality in the case. A congenital deficiency of protein S was considered in the patient but could not substantiated as the patient was lost to follow-up.
Platelet counts and ELT were normal in all cases strongly advocating against a severe DIC.
Our results demonstrate that apart from mild and isolated abnormalities of coagulation, DIC of any severity is not seen in patients with RA without vasculitis and as such is very unlikely to contribute to the pathogenesis of the disorder.

 

REFERENCES

 

1. Takeda Y. Studies of metabolism and distribution of fibrinogen in patients with rheumatoid arthritis. J Lab Clin Med 1967;69:624-633.
2. Anderson RB, Frilis TH. Metabolism of fibrinogen in patients with rheumatoid arthritis and in a control group. Acta Rheumatol Scan 1971;17:94-104.
3. Bennet RM, Eddie-Quartey AC, Holt PJL. Fibrin degredation products in rheumatoid arthritis. Ann Rheum Dis 1972;31:388-392.
4. Gornsen J, Andersen RB, Feddersen C. Fibrinogen, fibrin breakdown products in pathologic synovial fluids: an immunologic study. Arthris Rheum 1971;14:503-511.
5. Burnhart MI, Riddie JM, Bluhm GB, et al. Fibrin promotion and lysis in arthritic joints. Ann Rheum Dis 1967;26:206-218.
6. Andersen RB, Winther O. Blood fibrinolysis and activity of rheumatoid arhritis. Acat Rheumatol Scand 1969;15:178-184.
7. Conn DT, McDuffie DC, Kazmier FJ, Scroeter AL, Sun CJ. Coagulation abnormalities in rheumatoid disease. Arthritis Rheum 1976;19:1237-43.
8. Feinstein DI, Rappaport SI. Acquired inhibitors of blood coagulation. Pro Hemost Throm 1972;1:75.
9. Shapiro SS, Huntin M. Acquired inhibitors of blood coagulation factors. Semin Throm Haemost 1975;1:336.
10. Lechner K. Acquired inhibitors in non hemophiliac patients. haemostasis 1974;3:65.
11. Gallisti S, Mangge H, Neuwirth G, Muntean W. Activation of the hemostatic system in children with juvenile rheumatoid arthritis correlates with disease activity. Thromb Res 1998;92:267-72.
12. Gallistl H, Mangge H, Neurwith G, Muntean W. Activation of the haemostatic system in children with juvenile rheumatoid arthritis correlates with disease activity. Thromb Res 1998;92:267-72.
13. Hernandez LA, Rowan RM, Kennedy AC, Buchanan WM. Thrombocytosis in rheumatoid arthritis- A clinical study of 200 patients. Arthritis Rheum 1976:6:635-8.
14. Hutchinson RM, Davis P, Jayson MIV. Thrombocytosis in rheumatoid arthritis. Ann Rhem Dis 1976;35:138-40.
15. Ehrenfeld M, Penchas S, Eliakim M. Thrombocytosis in rheumatoid disease. Ann Rhem Dis 1977;36:579-82.

  Grade I (N=2) GradeII (N=8) GradeIII (N=6) Grade IV (N=10)
Age (yrs) 34.0+8.48 41.62+13.97 42.50+8.89 35.30+15.48
RAI 1.0+0.0 1.25+0.70 2.0+0.63 2.90+0.31
Mor. Stiffness 75.0+63.64 51.25+4.25 90.0+46.47 123.0+9.48
Grip strength 100.0+0.0 56.62+19.02 45.33+21.36 38.90+28.22

 


Table 1. Showing the general parameters in various grades of Rheumatoid arthritis.
RAI= Ritchie articular Index, Mor. Stiffness= Morning stiffness. Values are expressed as mean+SEM.

 

  Variable Cases (n=26) Controls (n=20) p-value
1 Age (yrs.) 28.81+ 2.57 35.30+2.72 0.36
2 PT (s) 14.35+0.37 13.55+0.24 0.09
3 PTTK (s) 36.92+1.39 35.90+3.26 0.55
4 PTI (%) 85.38+2.03 89.52+1.8 0.55
5 Hb (g/dl) 11.68+0.39 12.91+0.48 0.055
6 TLC (X109/l) 7.50+0.52 7.57+0.39 0.91
7 Platelets (X109/l) 256.69+15.70 214.3+13.90 0.049
8 ESR (mm) 35.11+2.12 13.0+1.48 <0.0001
9 Protein C 117.19+10.63 118.20+4.38 0.052
10 Protein S 90.15+3.79 104.20+4.83 0.006
11 AT III 107.65+1.86 118.20+4.83 0.052
12 ELT 184.15+5.66 185+30+20.59 0.88
13 Fibrinogen 2.25+0.13 2.62+0.11 0.045
14 FDP 0.27+0.38 0.10+0.26 0.49
15 Factor VIII 70.31+4.36 84.60+1.73 0.004
16 Factor IX 84.19+3.06 93.70+1.20 0.007

 

Table 2. showing comparison of parameters between cases and controls. Hb=Hemoglobin, ATIII= Antithrombin III, ELT= Euglobin lysis time, FDP= Fibrin degradation products. Values are expressed as mean+SEM.

 

First published September 2003

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