Dengue viral fever has a myriad of presentations and complications. Bleeding is an acknowledged and notorious complication of dengue. Through complex pathophysiological mechanisms dengue fever can impact the risk and cause bleeding in many ways. Hypothesis have been put forward questioning the role of hematological disturbance through thrombocytopenia and platelet dysfunction, to low fibrinogen and factors involved in the coagulation cascade resulting in prolonged APTT. Hepatic dysfunction and coagulopathy worsened by disseminated intravascular coagulation and even vasculopathy are thought to possibly contribute towards bleeding, aided by the immunological disturbance seen in dengue viral fever [6,7,8]. When coupled together with use of either anti-platelet’s or anticoagulation the theoretical risk of bleeding is exponentially worse.
Warfarin is one of the most commonly used anticoagulants due to affordability, availability and proven efficacy. The factors that contribute towards bleeding are many and the risk differs on individual basis. But overall the risk of bleeding is greatest when initiating warfarin, or if the dose was supra-therapeutic, if there were drug interactions and when complicated with an ongoing illness. In fact a dose reduction is advised during inter-current illness. Advancing age is another confounding factor and there is still uncertainty whether it acts as an independent factor. Additionally when burdened with chronic diseases such as hypertension and renal insufficiency, the likelihood of bleeding is even greater when using warfarin [9, 10].
Bleeding can occur in any part of the body when using anticoagulation. Rectus sheath haematoma is a rare yet observed complication of anticoagulation [11]. Bilateral rectus sheath haematoma is an even rarer occurrence with few documented cases in literature [12,13,14]. Rectus sheath haematoma is commonly seen in women more than men and specially in their 6th to 7th decades of life [15]. The risk of developing rectus sheath haematoma is greater when having a background history of trauma, straining, coughing, pregnancy and abdominal surgery [16]. Rarely, rectus sheath haematomas have also been documented complicating dengue viral fever [14, 17]. Though conservative management is adequate in most circumstances with the cessation of anticoagulation, when complicated with haemodynamic instability supportive care coupled with blood transfusion may become necessary [11, 15]. Thus having awareness and maintaining a high index of suspicion in appropriate clinical circumstances is paramount for the early and accurate diagnosis of rectus sheath haematoma. This will result in the opportunity for quick institution of appropriate treatment measures, with improved outcome [18].
There are obligatory conditions where the use of anticoagulation is essential and needs to be continued as the benefit outweighs the potential risks. When bleeding occurs the choice of discontinuing or reducing oral anticoagulation depends on whether the episode was a major or minor event [19]. When compounded with an ongoing dengue viral infection the decision to continue anticoagulation challenges the physician to reassess its need. However a definitive clinical event such as an established bleed while having dengue viral fever may simplify the difficult clinical decision of stopping anticoagulation out of necessity.
In the absence of either obvious or occult bleeding, the clinician may choose to cease anticoagulation in the presence of dropping platelet counts to err on the side of caution. The point at which this has to be done should be decided on a case by case basis. The lowest threshold of absolute platelet count considered safe has varied, but usually lies between the range of 50 × 109/L (150–450) to 100 × 109/L (150–450) [5, 20]. The safe limit suggested to reinitiate anticoagulation is when platelet counts rise above 50 × 109/L (150–450) [5, 20].
The possible justifications to argue in favor of this course of action are twofold. Foremost in the presence of life threatening bleeds, anticoagulation should be discontinued even in obligatory circumstances. In such situations anticoagulation has been discontinued as long as by a week, and sub-therapeutic levels have been maintained even further successfully with minimal thromboembolic risk [5]. Additionally the annual risk of thrombosis with mechanical valves even without anticoagulation is only 20% [8] and thus may justify the decision. The second consideration being is the persistence of anticoagulation to a certain degree even following cessation. In average it takes 2–3 days for the INR to drop below 2, and nearly 4–6 days for it to normalize [21]. The single most important factor that determines this is the initial baseline INR level [22]. Based on this, even a higher level platelet count could be justified when stopping warfarin if the INR is inappropriately elevated at the outset. Thus a level of anticoagulation being present even following cessation may offer some degree of protection and theoretically grants a few days of bargaining time. That being said, the drop in platelet counts in dengue fever is also quite variable, and hard to predict as significant drop occurs in 3rd to 4th day of fever and the counts keep decreasing to an average of 7 days [23].
Despite all of this there is still disagreement as to if bleeding is associated with thrombocytopenia, even when very severe [7, 23]. The problem is further compounded by the fact that bleeding in dengue viral fever is probably multifactorial as mentioned above, and choosing only absolute platelet counts, whatever the count value as a sole criterion to stop and restart anticoagulation may in fact be an arbitrary decision, as it happens to be the easiest one to monitor.
The patient along with their primary need of anticoagulation and their associated comorbidities should be taken into consideration when making the clinical decision to cease anticoagulation. To achieve this, patients can be risk stratified. A higher risk is present when the need is following mechanical valve replacement, and more so if the replacement involves multiple valves. A prior history of thromboembolic episodes and having added comorbidities increases one risk (e.g. diabetes, hypertension or prior stroke), and places an individual into a high risk category as well. In such situations withholding warfarin and substituting heparin when INR becomes sub-therapeutic and omitting all forms of anticoagulation when platelets drop below 50 × 109/L (150–450) or even earlier in advanced forms of presentation of dengue spectrum with events of either bleeding or shock have been suggested. Alternatively when having low risk factors e.g. chronic atrial fibrillation with minimal risk factors, consider omitting warfarin to err on the side of caution by as much as one week without having stringent criteria is preferred [8, 24].
Our patient had all the classic and added risk factors needed to develop this rare yet potentially lethal complication, including cough secondary to bronchial asthma, prior abdominal surgery and distorted anatomy and developing dengue viral fever while being on warfarin. The fact that we preemptively stopped anticoagulation (both warfarin and unfractionated heparin) due to her high risk status, and her coagulation parameters being normal at the point in time of her haemorrhage points towards another cause, other than the anticoagulation as the cause for her to have bled. Thrombocytopenia though attributable to dengue viral fever could also have rarely resulted from heparin, in the form of heparin induced thrombocytopenia (HIT), type 1. However, HIT is predominantly pro-thrombotic and thus the propensity to bleed in the presence of thrombocytopenia favors dengue more than that of HIT. Though her other risk factors may have played a role in contributing towards the resultant bleed, one should strongly consider the role dengue viral fever had to play. Considering the event in question occurred during convalescence as commonly observed in other case reports of similar nature with significant bleeding [14], we can possibly assume that dengue viral fever through its complex mechanism may have been the primary cause for her to have bled.
The decision to continue or stop anticoagulation may never be an easy choice to make in dengue viral infection unless complicated with a bleeding event. In the absence of which a patient based risk stratification should be done considering all relevant information including the need for anticoagulation and any associated comorbidities that may inadvertently facilitate the risk of bleeding. Making the correct decision to stop anticoagulation in a timely manner may potentially help prevent catastrophic bleeding events considering the highly unpredictable nature of dengue viral infection and its propensity to cause bleeding in different phases of illness through complex mechanisms.
The clinical management of patients with dengue viral fever on mandatory anticoagulation is difficult, as the decision to continue or cease warfarin compels the physician to weigh the risks intrinsic to dengue fever versus that of lack of anticoagulation. There is limited guidance, and even the available guidance is based on case reports and extrapolations from similar clinical scenarios. The unpredictable course of dengue viral fever and the lack of understanding of the underlying pathophysiological process that predisposes to bleeding in dengue viral fever makes even the well thought out decision to stop anticoagulation in retrospect to appear arbitrary. However based on risk factors, making the correct decision in a timely manner to withhold anticoagulation can potentially avert catastrophic clinical events. Thus it should be stressed, if a decision is taken to cease anticoagulation in dengue viral fever it should be based on a case by case basis considering all relevant risk factors and the evolving clinical picture. Though lacking, the presence of a clear protocol and guidance would greatly aid clinicians when faced with making such difficult decisions.
