Hypofibrinogenemia in a patient with systemic lupus erythematosus: always a bad sign? Or not

Sir,

Some hypercoagulable conditions such as disseminated intravascular coagulation (DIC), thrombotic thrombocytopenic purpura (TTP), and catastrophic antiphospholipid syndrome (CAPS) are rarely seen in the course of systemic lupus erythematosus (SLE). The determination of fibrinogen level can be helpful in the differential diagnosis of these three disorders. We describe the case of a 34-year-old female patient with SLE who presented with hypofibrionogenemia without findings suggesting DIC or CAPS. We would like to briefly discuss the meaning of hypofibrinogenemia in SLE.

A 34- year-old female was admitted to our rheumatology unit due to fever and fatigue of 3 weeks and one year, respectively, in April 2009. She had been diagnosed as having anaemia and had been treated with drugs including iron and B12 vitamin in a local hospital. Fatigue was attributed to profound anaemia. On physical examination, she had malar rash, bilateral cervical lymphadenopathy and hepatosplenomegaly. Her initial laboratory investigations showed a white blood cell count of 3400/mm³ (lymphocyte 800/mm³), a haemoglobin level of 8.5 g/dL, a platelet count of 337,000/mm³. Erythrocyte sedimentation rate (ESR) was 91 mm/h and the C-reactive protein level was 0.729 mg/dL. Peripheral blood smear was normal. Coagulation tests showed no abnormality except for low levels of fibrinogen 71 mg/dl (N = 200–400). The levels of C3 and C4 were 64.4 mg/dl (79–152) and 24 mg/dl (16–38), respectively. Other laboratory tests are shown in Table 1. She had no proteinuria on urinalysis. Direct Coombs test was 3 (+) positive. Antinuclear antibody, anti-ds-DNA, anti-Ro antibodies were positive whereas anti-cardiolipin antibodies, lupus anticoagulant, anti-RNP antibody, anti-Sm antibody, anti-La antibody and rheumatoid factor were all negative. D-dimer level was 563 (N = 0–500 ng/ml). Abdominopelvic computed tomography showed hepatosplenomegaly and a liver haemangioma. Cervical lymph node biopsy was performed to exclude the various causes of lymphadenopathy; the biopsy revealed a reactional lymph node. Bone marrow biopsy material and lymph node were analyzed with flow-cytometry and found to be normal

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Table 1

Some laboratory findings of the patient during the follow-up period

	Admission	Week 1	Week 2	During the therapy (Month 1)
Hct (35–47%)	23.7	21.3	25.8	34.8
White blood count (3.5–11 103/ul)	3400	5000	6800	12,100
Lymphocyte (1.5–4 103/μl)	800	500	0	1700
PLT (150–440 103/μl)	337,000	201,000	443,000	275,000
ESR (0–20 mm/h)	91	88	29	16
CRP (0–0.8 mg/dl)	0.729	2.83	0.929	0.976
ALT (2–40 U/L)	5	50	26	20
LDH (240–480 U/L)	1681	2243	1174	ND
Coombs test	+3	ND	ND	ND
D-dimer (0–500 ug/dl)	563	1381	887	ND
Fibrinogen (200–400 mg/dl)	71	121	128	353

She was diagnosed as having SLE on the basis of the malar rash, lymphopenia, autoimmune haemolytic anaemia, and ANA and anti-ds-DNA positivity. She was treated with methylprednisolone (48 mg/day) and hydroxychloroquine (400 mg/day). One month later, her laboratory examinations showed a white blood cell count of 12,100/mm³ (lymphocyte 1700/mm³), a haemoglobin level of 11.4 g/dL and a platelet count of 275,000/mm³. ESR was 16 mm/h and C-reactive protein level was 0.9 mg/dL. The fibrinogen level was in normal ranges (353 mg/dl).

In this case, it is possible to account for the presence of hypofibrinogenemia in several ways. First, fibrinogen is synthesized in hepatocytes and is involved in the final steps of coagulation as a precursor of fibrin monomers required for the formation of the haemostatic plug. ¹ Disorders of fibrinogen are usually caused by genetic mutations that result in hypofibrinogenemia or an abnormal molecule (dysfibrinogenemia). ² The possibility of congenital hypofibrinojemia is very low in our case because fibrinogen levels improved after treatment with steroid.

Second, hypofibrinogenemia may also occur due to impaired hepatic synthesis secondary to hepatic failure or decompensated cirrhosis. However, the synthesis function of the liver was normal in our patient.

Third, it has been reported that massive blood transfusions or heparin therapy may give rise to hypofibrinogenemia or afibrinogenemia. ^3,4 Neither heparin nor blood transfusions were performed in our case. Therefore, hypofibrinogenemia was not related to therapy.

Can hypofibrinogenemia be directly or indirectly linked with SLE?

DIC, TTP, and CAPS are hypercoagulable states seen rarely in the course of SLE. The clinician may encounter difficulties in the differential diagnosis of these conditions. An increase in the levels of D-dimer and a decrease in the levels of fibrinogen along with prolonged PT and a-PTT are seen in the acute DIC, while these laboratory tests are usually normal in patients with TTP. In our case, a-PTT, PT, and D-dimer levels were nearly normal and hypofibrinogenemia resolved promptly after the initiation of methylprednisolone. We did not observe any bleeding in our case. Also, there was no sign of a hemophagocytic lymphohistiocytosis in the bone marrow examination.

It has been reported that antifibrinogen antibodies can be seen in SLE patients. Ozaki et al. ⁵ showed antifibrinogen antibodies in a patient with SLE in the course of DIC. However, it would be reasonable to suggest that hypofibrinogenemia in this case may be due to DIC rather than antibodies to fibrinogen. Dear et al. ² reported a case with SLE who had prolonged thrombin time caused by anti-fibrinogen autoantibodies. Unfortunately, we did not determine thrombin time in our case. It might have been very valuable to perform a test for thrombin time in order to show the presence of anti-fibrinogen autoantibodies.

Another possibility may be related to the relationship between inflammation and the clotting system. Sergent et al. ⁶ has shown a relationship between SLE activity and consumption of fibrinogen. These authors suggested that clinical activation associated with anti-DNA positivity in SLE patients may accelerate fibrinogen consumption. ⁶ In our case, this may be a possibility because fibrinogen levels returned to normal after treatment with methylprednisolone. This can be explained by the upregulating of the genes responsible for the hepatic synthesis of fibrinogen by glucocorticoids. ⁷

In a study by Ames et al. ⁸ it has been shown that plasma fibrinogen levels in patients with SLE increase throughout follow-up regardless of disease activity. Fibrinogen levels can be modified by glucocorticoid use because the gene responsible for hepatic synthesis of fibrinogen is unregulated by glucocorticoid. ⁷ Considering the fact that increased fibrinogen levels can be a predictive factor for the development of cardiovascular events, ⁹ cerebrovascular diseases ¹⁰ , and osteonecrosis of femoral head in patients with SLE, ¹¹ it is tempting to speculate that normal fibrinogen levels in the course of SLE may be protective against the complications mentioned above. Therapeutic benefit of glucocorticoids in SLE is not only counteracted by an unfavourable lipid profile, but also by higher than average fibrinogen levels, both conditions being associated with heightened atherothrombotic events. ³ Therefore, fibrinogen should be considered as a follow-up tool for cardio-cerebrovascular complications rather than an acute phase reactant in SLE patients.

In conclusion, hypofibrinogenemia can be seen in some patients with SLE independent from DIC and CAPS.