Haemostasis in rheumatoid arthritis without vasculitis
PARVAIZ A KOUL, MD, FAYAZ A BHAT, MD, ABDUL WAHID, MD, MOHAMMAD SHABAN, M Sc*
Internal Medicine and Clinical Hematology*,
Institute of Medical Sciences, Srinaga, India.
Address for Correspondence
Department of Internal Medicine,
SheriKashmir Institute of Medical Sciences,
Soura, Post Bag 27,
Srinagar 190 011, Kashmir (India).
Tel: 0091-194-2423339, 2420993.
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
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)
- <10 0-2.4 >200 0 >14.1 0-20
- 10-30 2.5-4.4 50-200 1-7 13-14 21-45
- 31-120 4.5-6.4 21-49 8-17 10-12 46-80
- >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:
- IDA 1.0-1.4 MDAG I
- IDA 1.5-2.4 MDAG II
- IDA 2.5-3.4 MDAG III
- IDA 3.5-4.0 MDAG IV
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
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.
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).
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.
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|Grade I (N=2)||GradeII (N=8)||GradeIII (N=6)||Grade IV (N=10)|
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|
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.