Boy With Lupus Anticoagulant Hypoprothrombinemia Syndrome Case Report Biology Essay

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Lupus anticoagulant is commonly detected in patients with systemic lupus erythematosus. It is associated with thromboembolism. If hemorrhage occurs, it is due to associated thrombocytopenia or coagulopathy. Lupus anticoagulant hypoprothrombinemia syndrome is a rare disease in which patient presents with significant bleeding due to prothrombin deficiency despite the presence of lupus anticoagulant. It is most commonly described in patients with systemic lupus erythematosus. Corticosteroid is the treatment of choice in the correction of coagulopathy and control of bleeding. We reported a 9-year old boy who presented with recent onset bleeding tendency. He developed significant intramuscular bleeding after bone marrow examination. Clotting profile showed prolonged prothrombin time and activated partial thromboplastin time. Lupus anticoagulant was detected and factor II level was decreased. He was diagnosed to have lupus anticoagulant hypoprothrombinemia syndrome secondary to systemic lupus erythematosus. He was successfully treated with corticosteroid with bleeding stopped and factor II level normalized. He experienced no complication of hemorrhage or thromboembolism in the subsequent course of illness over 4 years.

Introduction

Systemic lupus erythematosus is an autoimmune disease with multiorgan involvement characterized by the presence of autoantibodies. Lupus anticoagulant is one of the antiphospholipid antibodies, it is common in patients with systemic lupus erythematosus with prevalence up to 62% (1). It manifested in vitro with prolongation of activated partial thromboplastin time but paradoxically associated with thrombotic tendency in clinical settings. Bleeding complication is rare; however, hemorrhage may occur when there is thrombocytopenia, factors deficiencies or acquired inhibitors to coagulation factors. In rare cases, it presents with hypoprothrombinemia in a condition named lupus anticoagulant hypoprothrombinemia syndrome (LA HPS), which can cause significant clinical bleeding. Rapport et al reported the first case of LA HPS associated with systemic lupus erythematosus in 1960 presenting with serious bleeding due to profound acquired hypoprothrombinemia (2). As a rare entity, less than 40 cases had been reported in the literature so far in patients with systemic lupus erythematosus. We reported here a boy with lupus anticoagulant hypoprothrombinemia syndrome presented with bleeding tendency. A review on the literature and discussion on the management of this condition will be performed.

Case report

A 9-year-old, previously healthy, Chinese boy was admitted to our hospital for 1-week history of fever and joint pain over proximal interphalangeal joints of the right middle and ring finger. He also had recurrent epistaxis, gingival bleeding and easy bruising over the lower limbs for 1 month. He did not have a family history or personal history of bleeding tendency in the past. He was treated in private sector with azithromycin. There was no other drug history. His father suffered from systemic lupus erythematosus (SLE) with nephritis which was presented during childhood.

On physical examination, there was hepatomegaly and generalized lymphadenopathy over cervical, axillary and groin region. Multiple ecchymoses were noted over bilateral lower limbs. There was mild tenderness over the proximal interphalangeal joints of the right middle and ring finger with decreased range of motion but no obvious swelling or erythema. He developed swinging fever after admission but clinically he was not septic with normal vitals signs.

Investigations showed thrombocytopenia with platelet count of 27 x 109/L, mild normochromic normocytic anaemia with hemoglobin 11g/dL and normal leukocyte count of 5.6 x 109/L with lymphopenia 0.56 x 109/L. Blood film was normal. Reticulocyte count was <1%. Clotting profile was deranged with markedly prolonged prothrombin time (PT) to 23.5 seconds and activated partial thromboplastin time (APTT) to 114.7 seconds. Erythrocyte sedimentation rate was raised to 54mm/hr. C-reactive protein was normal. Liver and renal function tests were normal. Urine microscopy showed microscopic hematuria but no dysmorphic red blood cells. Microbiological workup was unrevealing. Bone marrow examination was performed to rule out malignancy and bone marrow failure. It showed normal trilineage hematopoiesis.

He was given intravenous vitamin K but the clotting profile did not improved (Table 1). Fibrinogen was normal and D-dimer was mildly increased. Thrombin time was normal. Mixing study with normal plasma partially corrected the PT but failed to correct the APTT. Lupus anticoagulant was detected with diluted Russell viper venom test (dRVVT). Screening test with dRVVT (LA screen) showed prolonged clotting time of 142 seconds, addition of phospholipid in confirmatory test (LA confirm) corrected the clotting time to 65.1 seconds. The LA screen/LA confirm ratio was 2.18, which is greater than 1.2 and was suggestive of the presence of lupus anticoagulant. No reliable results could be obtained for the factor inhibitor assay due to interference by the presence of lupus anticoagulant.

He complained of pain over the left buttock after the bone marrow examination. Physical examination showed a large ecchymosis and intramuscular hematoma over the left buttock. He also had on and off epistaxis. Hemoglobin dropped from 11.2 to 7.7g/dL over 2 days. Fresh frozen plasma and further dose of vitamin K were given with no significant improvement in clotting profile.

He was suspected to have autoimmune disease in view of thrombocytopenia, presence of lupus anticoagulant and family history of systemic lupus erythematosus. Prednisolone 40mg/day (1.5mg/kg) was then started. There was no further epistaxis the next day and pain over the buttock hematoma decreased. Autoimmune workup later came back to show low complements level with C3 0.38g/L (normal range 0.93-2.03g/L) and C4 <0.1g/L (normal range 0.13-0.52g/L), and raised rheumatoid factor to 60IU/mL (normal range <20IU/mL). Direct antiglobulin test was positive for IgG and C3d. Antinuclear antibody (ANA) was positive 1:2560 with raised anti-double-stranded DNA antibody (Anti-dsDNA) up to 199IU/mL. Anti-Ro was positive. Anti-cardiolipin IgG was raised to 51 GPL/mL (normal range <15 GPL/mL).

In view of clinical features of arthritis, hematological involvement with thrombocytopenia and lymphopenia, positive ANA, raised anti-dsDNA and presence of lupus anticoagulant, we made the diagnosis of systemic lupus erythematosus as patient fulfilled 4 out of the 11 criteria according to American College of Rheumatology classification (3;4). He showed good clinical response with resolution of fever, joint pain, hepatomegaly and lymphadenopathy. Platelet count normalized on day 5 of prednisolone treatment and clotting profile showed gradual improvement. No further clinical bleeding was noted. Extrinsic and common pathway factor levels were checked in view of the prolonged prothrombin time. Since fresh frozen plasma had been given, the factor levels were checked one week later. Prothrombin (Factor II) level was found to be low at 0.25IU/mL (normal range 0.5-1.5IU/mL). Levels of factor V (1.0IU/mL), VII (1.39IU/mL) and X (1.18IU/mL) were normal. The presence of lupus anticoagulant associated with the low factor II level suggested the rare diagnosis of lupus anticoagulant hypoprothrombinemia syndrome.

Prothrombin time normalized 2 weeks after prednisolone and APTT showed significant improvement. Systemic lupus erythematosus was under control with prednisolone and there was no other new manifestation. Factor II level repeated 4 months after treatment was normal. Lupus anticoagulant remained positive at 5 months as evidenced by the prolonged dRVVT and elevated LA screen/LA confirm ratio. Hydroxychloroquine was added later for the control of SLE. As he was asymptomatic, prednisolone was tapered slowly despite C3 was slightly low and anti-dsDNA was elevated. He was currently on prednisolone 5mg alternate day and hydroxychloroquine 200mg daily. He remained stable with normal prothrombin time and did not experience any episode of bleeding or thrombosis on weaning of steroid up to 4 years after presentation. He was noted to have bilateral mild posterior subcapsular cataract as a result of long-term use of steroid. Hence, we plan to taper off steroid later according to clinical progress.

Discussion

Lupus anticoagulant is commonly detected in patients with systemic lupus erythematosus. It is associated with thromboembolism while bleeding complication is rare except in cases with thrombocytopenia or acquired coagulation inhibitors. We have reported a 9-year old boy diagnosed with systemic lupus erythematosus, presenting with significant hemorrhage in the presence of lupus anticoagulant. He presented to us with bleeding tendency and was found to have thrombocytopenia and coagulopathy with marked prolongation of PT and APTT. Normal liver function ruled out liver diseases as the cause of clotting derangement. Fibrinogen was normal so the clinical picture was not compatible with disseminated intravascular coagulation. Mixing study with normal plasma failed to correct the APTT which indicated the presence of inhibitors. Lupus anticoagulant was then detected with the diluted Russell viper venom test. Lupus anticoagulant is usually associated with thrombotic tendency but our patient developed significant intramuscular bleeding. Though the presence of thrombocytopenia may contribute to the bleeding tendency, this level of platelet count usually would not result in significant intramuscular bleeding. Since the prothrombin time was also prolonged and mixing study partially corrected the PT, the presence of factor deficiency was suggested. We then proceeded to investigate the extrinsic and common pathway coagulation factors. As fresh frozen plasma had been given to treat the hemorrhage, we postponed the test on factors level to minimize its interference. Steroid was started as the treatment of SLE and gradual improvement in prothrombin time was also noted. Factor II level checked 1 week after starting steroid was still decreased to 0.25IU/mL. The level may be even lower on presentation that accounted for the intramuscular bleeding. The low factor II level and the presence of lupus anticoagulant confirmed the diagnosis of lupus anticoagulant hypoprothrombinemia syndrome in our patient associated with systemic lupus erythematosus.

Lupus anticoagulant hypoprothrombinemia syndrome is a documented but rare disorder with less than 40 cases reported in the literature in patients with systemic lupus erythematosus. It is characterized by the presence of lupus anticoagulant with bleeding tendency due to associated prothrombin deficiency. This syndrome is most commonly seen in patients with systemic lupus erythematosus. It can also occur transiently in children with viral infection (5-8), associated with antiphospholipid syndrome (9), lymphoma (10), as drug reaction or in healthy adults (11). Summary of previous case reports on LA HPS associated with systemic lupus erythematosus was shown in table 2. Clinical manifestations vary from minor bleeding with skin bruises, epistaxis, gum bleeding, menorrhagia or hematuria to life-threatening hemorrhage with diffuse muscular bleeding, gastrointestinal bleeding or intracranial hemorrhage. Laboratory findings include prolonged PT and APTT. Prolonged PT is related to low factor II level. Prolonged APTT does not improve with mixing study due to the presence of lupus anticoagulant. Most patients had factor II level <20% on diagnosis but severe hemorrhage such as intracranial or gastrointestinal bleeding may also occur with higher factor II level at 20-30%. Diagnosis requires alertness to this rare entity. In patients with lupus anticoagulant presenting with bleeding tendency and prolonged prothrombin time, factor II level should be checked to look for associated hypoprothrombinemia in LA HPS. Antiprothrombin antibody has been identified in previous case report. It is different from other acquired coagulation factors inhibitors. It does not bind to the active site of prothrombin and hence would not neutralize the coagulant activity. Instead, it binds to prothrombin to form antigen-antibody complex and results in rapid clearance of prothrombin-antiprothrombin antibody complexes from circulation causing hypoprothrombinemia and bleeding tendency (12).

Corticosteroid is the treatment of choice for LA HPS associated with systemic lupus erythematosus. Most patients showed rapid response to steroid with bleeding stopped, usually within 1 to 6 days, and gradual normalization of prothrombin level within few weeks to months after steroid treatment. Use of intravenous methylprednisolone was required in some cases for rapid control of severe hemorrhage followed by longer course of oral prednisolone (13-15). However, it is common to have recurrence of hypoprothrombinemia with bleeding tendency on weaning of steroid and use of immunosuppressive agents had been tried as steroid-sparing agent. Taddio et al reported 2 cases with LA HPS showing rapid response to intravenous methylprednisolone but recurrence of hypoprothrombinemia on weaning prednisolone. Cyclophosphamide was added with steady improvement in prothrombin level (15). Use of azathioprine had also been reported together with steroid or as steroid-sparing agent but the response was variable (12;13;16). Intravenous immunoglobulin had been shown to be useful in a patient with incomplete response to steroid (17). Fresh frozen plasma and vitamin K had been given in many patients as initial treatment but they were not effective in correction of clotting derangement or cessation of hemorrhage. Our patient demonstrated good response to steroid with bleeding stopped within 1 day and normalization of prothrombin time within 2 weeks. Prothrombin level was normalized 4 months later. Though the C3 was still slightly low and anti-dsDNA remained elevated during follow-up, our patient did not have clinical symptoms of SLE. Hence, steroid was tapered slowly over the years and he did not experience recurrence of bleeding tendency on weaning steroid.

It was postulated that the low factor II level might counterbalance the thrombotic effect of lupus anticoagulant in LA HPS. This was evidenced by a woman with history of recurrent abortions and positive lupus anticoagulant who successfully gave birth to a baby only after the development of hypoprothrombinemia (18). On the contrary, thromboembolism complication may occur in association with successful treatment of hypoprothrombinemia. There were three such cases reported in the literature. The first case is a 10-year old girl with systemic lupus erythematosus presenting with hematuria, successfully treated with prednisolone, subsequently complicated by deep vein thrombosis after normalization of factor II level (13). Peacock et al reported a case with LA HPS presenting with catastrophic hemorrhage including recurrent gastrointestinal bleeding and intracranial hemorrhage. Bleeding was controlled with normalization of PT after steroid treatment. However, patient subsequently died of ischemic acute myocardial infarction (19). Vinet et al reported another patient with LA HPS presenting with cerebellar subdural hematoma. She was treated with corticosteroids, plasma exchange and intravenous immunoglobulins with normalization of prothrombin level. She then presented with ischemic stroke secondary to an embolism originating from Libmann-Sacks endocarditis (20). Treatment with steroid resulted in improvement in APTT but cannot reverse the risk of thrombosis associated with lupus anticoagulant. Correction of hypoprothrombinemia might thus exacerbate the hypercoagulable state. Aspirin had been used in some cases to prevent thrombosis associated with lupus anticoagulant when normal prothrombin level was achieved (15) or during pregnancy (21). However, the benefit of aspirin as primary thrombosis prophylaxis in asymptomatic individuals with positive antiphospholipid antibodies was not confirmed in a previous study (22). Currently, there is no consensus on the management of LA HPS. Corticosteroid is the treatment of choice for the control of bleeding. Some patients had recurrence of hypoprothrombinemia on weaning steroid. In this situation, conservative treatment will suffice if patient is asymptomatic with mild hypoprothrombinemia. Addition of other immunosuppressants may be indicated if there was clinical bleeding. There is no evidence to support the use of routine thrombosis prophylaxis after hypoprothrombinemia has resolved. Close follow-up is essential with treatment aiming at balancing the risk of bleeding tendency associated with hypoprothrombinemia and the risk of thromboembolism associated with lupus anticoagulant. Our patient did not suffer from any clinical bleeding while weaning steroid. Lupus anticoagulant remained positive and we would look out for possible complication of thrombosis.

Conclusion

In patients with lupus anticoagulant presented with clinical bleeding, we need to consider the rare entity of lupus anticoagulant hypoprothrombinemia syndrome with coagulation test on prothrombin level. Corticosteroid therapy is effective in control of clinical bleeding. Close follow-up is required to adjust treatment to avoid complication with hemorrhage or thromboembolism.

Table 1. Laboratory values during the disease course and treatment

1stday

2ndday

5thday

9thday

12thday

16thday

3 weeks

4 months

5 months

Reference range units

Treatment

Vit K

Vit K

Fresh frozen plasma

Prednisolone 40mg/day --------------------------------à

15mg/day

13mg/day

Hydroxychloroquine 200mg/day

Hemoglobin

11

11.3

7.7

7.9

8.9

9.7

10.7

13.3

13.1

11.5-14.5 g/dL

Platelet

27

31

27

259

312

283

247

220

223

150-400 109/L

PT

23.5

22.8

21.4

16.6

14.9

10.7

9.1

9.1

9.2

8.0-12.0 seconds

PT 1:1 mix

16

9.1

APTT

114.7

>120

104.3

60.2

59.3

44.8

35.8

48.7

51.1

24.0-38.0 seconds

APTT 1:1 mix

115.2

49

Fibrinogen

3.5

3.4

2.0-4.0 g/L

dRVVT

142

64.8

23-43 seconds

LA ratio*

2.18

2.22

<1.2

Factor II

0.25

0.88

0.5-1.5 IU/mL

*LA ratio: Lupus anticoagulant screen/lupus anticoagulant confirm

Table 2: Summary of literature on LA HPS associated with systemic lupus erythematosus

Author

Age/Sex

Bleeding manifestation

Factor II

PT (Sec)

APTT (Sec)

Treatment

Bleeding stop (time interval)

Time to normal factor II

Rapaport, 1960 (2)

11/F

Epistaxis, gum bleeding, hematuria

8%

Prolonged

Prolonged

Steroid

Yes (1 day)

2 weeks

Biggs, 1964 (23)

11/F

45/M

Bleeding after dental extraction, hematuria

Hematuria, epistaxis, skin bruise, cerebral hemorrhage

14%

2.5%

22

31

NR

NR

NR

NR

NR

NR

NR

NR

Gonyea, 1968 (24)

12/F

Severe bleeding

31%

43

250

Steriod, azathioprine

Yes (6 days)

3 months

Corrigan, 1970 (25)

12/F

Skin bruises, hematuria

<1%

26.4

73

Steroid

Yes (2 days)

4 weeks

Shaulian, 1981 (26)

37/F

Menorrhagia

Low

Prolonged

120

Steroid

NR

NR

Bajaj, 1983 (12)

12/F

Epistaxis and gum bleeding

6%

19

79

Steroid. azathioprine

Yes (NR)

NR

Schwartz, 1984 (27)

13/M

Prolonged bleeding after dental extraction

23%

16

50

Steroid, azathioprine

NR

NR

Small, 1988 (28)

22/M

Epistaxis, gum bleeding

4%

23

118

Steroid

Yes (3 days)

1 week

Hift, 1991 (29)

24/M

Epistaxis, muscular bleeding

2%

16

121

Steroid

Yes (NR)

NR

Eberhard, 1994 (13)

15/F

10/F

11/F

Menorrhagia, epistaxis

Gross hematuria

Epistaxis, subconjunctival hemorrhage

5%

12%

4%

21.5

21.4

19

114.1

61.5

60

Steroid, Azathioprine

Steroid

Steroid

Yes (NR)

Yes (NR)

Yes (NR)

8 days

10 days

NR

Grau, 1997 (30)

12/F

Prolonged bleeding from skin biopsy

Epistaxis, skin bruise

30%

23

47

Steroid

Yes (NR)

1 month

Vivaldi, 1997 (31)

17/F

Epistaxis, menorrhagia

5%

Prolonged

Prolonged

Steroid, IVIg

Yes (NR)

NR

Erkan, 1999 (14)

19/F

47/F

Menorrhagia, retinal hemorrhage

hematuria, occult blood in stool

11%

21%

17.8

22.1

62.8

71.9

Steroid, hydroxychloroquine

Steroid, CPM

Yes (3 days)

Yes (NR)

NR

NR

Ayoub, 1999 (32)

26/F

Epistaxis, menorrhagia, gastrointestinal bleeding

20%

40.3

117

Steroid

Yes (Rapid)

Factor II partially improved with no bleeding

Yacoborich, 2001 (33)

12/F

Diffuse muscular hemorrhage

5%

68

NR

Steroid, hydroxychloroquine

Yes (NR)

3 months

Baca, 2002 (34)

13/F

11/M

Epistaxis, hematuria, menorrhagia

Epistaxis

1%

1%

25.6

28

88.3

76.2

Steroid

Steroid, hydroxychloroquine

Yes (Rapid)

Yes (Rapid)

2 months

Factor II did not improve but no bleeding

Vinet, 2006 (20)

50/F

Subdural hematoma

25%

Prolonged

>100

Steroid, plasma exchange, IVIg,

CPM

Yes (NR)

NR

Taddio, 2007 (15)

13/M

12/F

Hematuria, skin bruise

Epistaxis, menorrhagia, skin bruise

12%

32%

16.5

15.6

42

61

Steroid, cyclophosphamide

Steorid, azathioprine, CPM

Yes (NR)

Yes (NR)

NR

NR

Nair, 2009 (35)

14/M

13/F

Skin bruise, epistaxis, gum bleeding

Gum bleeding

<1%

4.3%

52

33

128

90.1

NR

NR

NR

NR

NR

NR

PT: prothrombin time, APTT: activated partial thromboplastin time, NR: not reported, IVIg: intravenous immunoglobulin, CPM: cyclophosphamide

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