Spontaneous Hemoperitoneum Secondary To Warfarin Toxicity: Learning The Balancing Act

Author Information

Bhosle S*, Mhaskar P**, Honavar P***, Samant PY****.

(*Second Year Resident, **Senior Registrar, ***Assistant Professor, ***Additional Professor, Department of Obstetrics and Gynecology, Seth G.S. Medical College and K.E.M. Hospital, Mumbai, India).

Abstract

Spontaneous hemoperitoneum is presence of intra-abdominal hemorrhage from non-traumatic cause. Warfarin is a known entity to cause hemoperitoneum which can be life threatening. Warfarin, a coumarin derivative, is a commonly used and safe drug in the prevention of thromboembolic events; its toxicity is dose dependent. Management of unexpected bleeding poses a difficulty in controlling International Normalized Ratio (INR) while avoiding thrombosis. This is a case report of spontaneous hemoperitoneum secondary to warfarin toxicity in a case of rheumatic heart disease with choked valve.

Introduction

Warfarin is used in conditions like mechanical heart valves, atrial fibrillation, embolic events, cerebral ischemic events and venous thromboembolism. Each condition though requires a different level of anticoagulation. It is life saving in cases of choked heart valve. With warfarin toxicity, spontaneous hemoperitoneum can occur or there can be bleeding in the retroperitoneal space.[1] INR level above therapeutic range is the most important risk factor for warfarin- induced major bleeding, independent of the indication for therapy, with the risk increasing with INR > 3.[2] Here we present a case of intraperitoneal hemorrhage due to warfarin toxicity with choked valve adding to difficulties in the management.

Case Report

24 year old patient with history of two spontaneous abortions presented to us with vomiting and acute abdominal pain. She had undergone mitral valve replacement for severe mitral stenosis 2 years ago and was on warfarin 5 mg once a day since then.

In her recent pregnancy, she had been admitted in cardiac ICU for thrombosed mitral valve in first trimester. Her INR then was 1.42. She was started on unfractionated heparin and inj. streptokinase. In the course of this admission, she aborted spontaneously. She remained admitted for nearly 45 days. Her INR was maintained around 3. Echocardiogram showed adequate movement of the affected valve leaflets. The patient was discharged on tab warfarin 5 mg when she was stable. 

Patient presented to us on the day after discharge with acute pain in abdomen and pelvis. There was no vaginal bleeding, vomiting, foul discharge. She was afebrile, had tachycardia, her blood pressure was 100/60 mm Hg. Marked pallor was noted. Abdominal examination revealed guarding and tenderness with slight abdominal distension. Ultrasonography (USG) showed ill-defined non homogenous adnexal mass of about 5 cm diameter. Computerised axial tomography scan (CT scan) of abdomen and pelvis revealed ill-defined collection in pelvis suggestive of hemoperitoneum. Her investigations are listed in the table below. After admission, cardiologists omitted warfarin and started Inj. heparin 25,000 units in 500 ml of normal saline, 1000 units/ hour at the rate of 20 ml/ hour.

DAY	1	2	3	5	7
Hemoglobin  (Hb)	8.4	6	8.1	3.8	8.5
Prothrombin time (PT)	41.2	62	37.4	63.9	29.6
International normalized ratio (INR)	3.61	5.54	3.23	6.45	2.47
PCV transfusion	1 unit	2 unit	1 unit	4 units	1 unit
Blood products		4 FFP 4 cryoprecipitate		8 FFP 4 cryoprecipitate 4 platelets

When her INR increased to 6.45 and abdominal girth increased significantly, cardiology reference was urgently re-sought and they advised correction of the same with transfusion of fresh frozen plasma (FFPs) and blood. She was kept nil by mouth, was transfused with 4 units packed cell volume and FFPs, electrolyte imbalance was corrected over 4 - 5 days. Her hemoglobin increased to 8.5, INR reduced to 2.47, abdominal girth reduced. Patient was started on tab warfarin 2 mg daily after 7 days of admission with inj heparin 25000 unit / day. Heparin was omitted completely when her INR reached therapeutic range. On the day of discharge her hemoglobin was 10.8 and INR 2.06. She was symptomatically better and the hemoperitoneum had resolved.

Discussion

Pregnancy itself is a hypercoagulable state. It is an adaptive mechanism for preventing postpartum bleeding.[3] The risk of thrombosis or embolism increases when combined with additional underlying hypercoagulable states. Pregnancy changes the plasma levels of many clotting factors, such as fibrinogen. Thrombin levels increase. Protein S, an anticoagulant, decreases.[4] However, protein C and antithrombin III, , the other major anticoagulants, remain constant. Increased levels of  plasminogen activator inhibitor-1 (PAI-1) and plasminogen activator inhibitor-2 (PAI-2), synthesized from the placenta can cause impaired fibrinolysis.[5] Mechanical valves carry the risk of valve thrombosis which is increased during pregnancy. In a large review, this risk was 3.9 % with oral anticoagulants (OACs) throughout pregnancy, 9.2% when heparin was used in the first trimester and OACs in the second and third trimester, and 33% with heparin use throughout pregnancy.[6] The type and location of the prosthetic valve and other factors like history of prior thromboembolic event, atrial fibrillation, prosthesis in mitral position, and multiple prosthetic valves, determine the risk of valve thrombosis and thromboembolic events. Spontaneous abortion is the most frequent fetal complication associated with pregnancy in women with mechanical heart valves (28%).[7] Warfarin and heparin both carry this risk. 

Warfarin is a coumarin oral anticoagulant used for prophylaxis as well as treatment of thromboembolism. Warfarin treatment depends upon interaction between physiological, environmental and genetic factors.[8] Cyp2C9 liver enzyme is involved in warfarin metabolism. Two common allelic variants associated with reduced enzyme activity are CYP2C9*2 and CYP2C9*3.  Persons who inherit one or two copies of CYP2C9*2 or CYP2C9*3 are more sensitive to warfarin as compared to others and they would require lower doses of warfarin and are at a greater risk of hemorrhage with warfarin initiation.[9] Vitamin K epoxide reductase complex subunit-1 (VKORC 1) is the site of action of warfarin. It is the major allele in Asian populations, and may be a contributing factor for lower warfarin dosing requirements often observed in Indian patients. Inherited differences in VKORC 1 affect warfarin efficacy. Warfarin also inhibits synthesis of natural anticoagulants proteins C and S thus results in high rates of bleeding. Warfarin has a narrow therapeutic index, hence physicians prescribing this drug have to adjust the dose in such a way that it achieves effective thrombus prevention for whatever indication it is prescribed but also avoids fatal dose related toxicity.

In our case, spontaneous intraperitoneal hemorrhage caused intestinal irritation and thus vomiting and abdominal pain. To diagnose hemoperitoneum, USG and CT scan can be done. CT scan plays an important role as it is a sensitive method defining both site and extent of hemorrhage. In our case of anticoagulant induced hemorrhage, nasogastric decompression, bowel rest, correction of electrolyte disturbances, blood transfusion for anemia correction and correction of coagulopathy with FFP, was our treatment strategy. This patient being a case of heart disease (with mechanical valve replacement) had the critical need of ongoing anticoagulation hence heparin was given as a temporary measure, and to be safe oral anticoagulation was continued after resolution of hematoma with regular monitoring of INR. To prevent similar catastrophic events, regular systemic examination and monitoring of INR is required and should be kept in the range of 2.0 - 3.5 for optimum outcome and lesser morbidity.[10]

Conclusion

Warfarin related toxicity can be treated by withholding the drug and transfusion of FFP and PCV and readjustment of dose. The only way to prevent such an incident is careful monitoring of INR to prevent over-dosage, drug interactions and regular follow up of patient with INR report. It is desirable to do genetic mutation study of above two genes before starting warfarin to avoid toxicity. The science of balancing the patient symptomatology and maintaining INR within the target range, continuing anticoagulation for the indication by switching over to heparin followed by resuming warfarin once favorable, is a challenging job and was a lesson learned.

References

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Citation

Bhosle S, Mhaskar P, Honavar P, Samant PY. Spontaneous Hemoperitoneum Secondary To Warfarin Toxicity: Learning The Balancing Act. JPGO 2017. Volume 4 No. 1. Available from: http://www.jpgo.org/2017/01/spontaneous-hemoperitoneum-secondary-to.html