Is it high time to cease prophylactic platelet transfusions in dengue fever?

Dengue is an arboviral disease transmitted by Aedes aegypti and Aedes albopictus mosquitoes. The clinical features are highly variable, ranging from mild disease to severe dengue, leading to capillary leak, hemorrhage, and impaired organ function. Low platelet counts are commonly observed in dengue fever; several reports reveal that 79–100% of patients develop significant thrombocytopenia (1,2). Platelet transfusions are regularly administered by clinicians, often as prophylaxis, using varying thresholds of platelet counts. In a survey of  306 physicians from 20 countries, 38% of respondents supported prophylactic platelet transfusions at cut-off levels ranging from less than 5,000 to 50,000/mm3(3). In a single-center retrospective study during the dengue epidemic of 2013 in Delhi, the authors concluded that up to 23.2% of platelet transfusions may have been unnecessary (4). 

Why does thrombocytopenia occur in dengue?

The platelet counts begin to drop during the febrile stage of dengue; defervescence heralds the onset of the toxic stage when the counts drop to a nadir. Bone marrow depression with impaired production of platelets is one of the key mechanisms of thrombocytopenia. Platelet destruction occurs, as evidenced by reduced platelet survival times (5). Dengue virus-infected platelets release cytokines and chemokines and adhere to activated vascular endothelium. Adherence to infected endothelial cells leads to the lysis of platelets (6). Platelets also aggregate with leukocytes, with the release of inflammatory mediators by neutrophils and monocytes. Furthermore, the dengue virus infects stromal cells and hematopoietic precursors, thereby inhibiting the generation of megakaryocytes, the precursors of platelets (7). 

Another possible mechanism for thrombocytopenia in dengue is through the release of von Willebrand factor (vWF) from the Weibel Palade bodies of endothelial cells. Platelets adhere to vWF to form plugs, as part of the normal hemostatic mechanism. The ultra-large vWf multimers are cleaved by ADAMTS 13, a metalloprotease enzyme, to keep the hemostatic mechanism in balance and prevent excessive platelet adhesion. However, deficiency of ADAMTS 13 has been shown to occur in acute infective processes, including dengue fever that result in thrombocytopenia (8). Failure to cleave vWF multimers leads to extensive platelet adhesion to vWf, leading to microthrombi formation and organ failure. Similar to hemolytic uremic syndrome and thrombotic thrombocytopenic purpura, this mechanism may play an important role in dengue-associated thrombocytopenia (9). Considering this putative mechanism of thrombocytopenia in dengue, prior transfusion with fresh frozen plasma to replenish the ADAMTS 13 levels before platelet administration may be beneficial (10). 

Possible harmful effects of prophylactic platelet transfusion

Injudicious transfusion of blood products can lead to potential harm. Prophylactic platelet transfusions in dengue may lead to fluid overload, especially in children (11), and transfusion-associated lung injury (TRALI) (12). Recovery of platelet count in dengue fever is stimulated by the generation of thrombopoietin, the physiological response to thrombocytopenia. However, transfusion of platelets may inhibit thrombopoietin generation, and delay the recovery of platelet counts (13,14). The efficacy of prophylactic platelet transfusion in reducing clinically significant bleeding in dengue fever is shrouded in controversy. 

Prophylactic platelet transfusions and outcomes in dengue

Apart from a transient increase in counts, do platelet transfusions in dengue improve platelet function and clot strength? Thromboelastography (TEG) is commonly used during major surgery involving significant hemorrhage and involves the assessment of the tensile force that develops during the process of clotting, arising from the interaction between glycoprotein IIb/IIIa receptors and fibrin. Sundar et al. evaluated dengue patients who developed bleeding complications and underwent transfusion with random or single donor platelets (15). In this study of 74 patients, platelet transfusion increased the mean platelet count by 10,210/mm3 at 24 hours compared to pre-transfusion levels. However, there was no significant increase in clot strength evident on TEG. Besides, platelet transfusion seemed to have no salutary impact on clinical bleeding either.  

Lee et al. conducted a single-center, retrospective observational study of 7,500 dengue patients over a 4-year period (16). Among these patients, 788 (10.5%) developed thrombocytopenia of <20,000/mm3. Four hundred and eighty-six (61.7%) of these patients received platelet transfusion, with a median volume of 240 ml (range: 100–618 ml). Clinically significant bleeding occurred in 18.2% of patients who received platelet transfusion compared to 23.5% among those who did not, the difference being non-significant (p = 0.08). Increase in platelet counts to 50,000/mmwas delayed by a median of 1 day in the transfused compared to the control group (3 vs. 2 days, p <0.0001). Platelet transfusion was also associated with a longer median duration of hospital stay (6 vs. 5 days, p <0.0001 days). The incidence of severe disease requiring intensive care was similar between the two groups of patients. On propensity-matched analysis adjusting for possible confounders, prophylactic platelet transfusion was not associated with a lower incidence of clinically significant bleeding. 

A single-center randomized controlled trial (RCT) from Pakistan studied patients with platelet counts of less than 30,000/mm3 with either no bleeding, or mild (WHO grade 1 or 2) bleeding (17). The treatment group (43 patients) were administered single-donor platelets; the control group (44 patients) received standard care alone. The mean increase in platelet count at 24 and 72 hours was significantly higher in the treatment group compared to the control group. There was no new incidence of bleeding in patients without bleeding at baseline in either group. Among patients with WHO grade 1 or 2 bleeding, progression to more severe, grade 3 bleeding was observed in one patient in the treatment group. The mean time to cessation of bleeding was also not different in patients with WHO grade 1 or 2 bleeding at baseline. Adverse events were noted in the treatment group; three patients (7%) developed severe anaphylaxis with hypotension. Two deaths occurred in the treatment group, one due to TRALI, while the cause of death in the other patient was multifactorial. This study revealed no potential benefit from prophylactic platelet transfusions, with a relatively higher likelihood of severe adverse events. 

The efficacy of prophylactic platelet transfusion in the prevention of bleeding was evaluated in a retrospective cohort study of dengue patients (18). The study included patients with a platelet count of less than 20,000/mm3 without clinical bleeding. Prophylactic platelet transfusions were administered at the discretion of the clinician. Outcomes were compared between 188 patients who received prophylactic platelet transfusion with 68 who did not. The incidence of clinical bleeding was low; one patient (0.5%) developed clinical bleeding in the group that received prophylactic transfusion compared to two patients (2.9%) who did not. The bleeding was mild in both cases and did not require any further intervention. The platelet count 24 hours after it dropped below 20,000/mmwas higher in those who were not transfused compared with those who received a transfusion. The median duration for the platelet count to reach 50,000/mmwas similar between the two groups of patients. The length of hospital stay was also similar between the two groups of patients. This study also demonstrated that prophylactic platelet transfusion was ineffective in preventing bleeding in dengue fever.   

Lye et al. performed an RCT in adult patients with dengue admitted to five hospitals in Singapore and Malaysia (19). Patients had confirmed or probable dengue and thrombocytopenia of <20,000/mm3; those with persistent mild bleeding or severe bleeding were excluded. Of the 372 patients enrolled, 188 patients were randomized to receive prophylactic platelet transfusion and 184 to supportive care alone. In the prophylactic transfusion arm, 4 units of pooled platelets were administered each day if the platelet count was less than 20,000/mm3. Patients in the transfusion arm received a mean of  4·71 ± 2·17 units of platelets. Clinical bleeding by day 7 or until hospital discharge, the primary outcome,  occurred in 40/188 (21%) patients in the transfusion arm compared to 48/181 (26%) patients in the control group; the difference was not statistically significant. Clinically important bleeding by day 21 was also not different between the two groups (transfused vs. control: 22% vs. 27%; p = 0·34). Severe bleeding was rare; three (2%) patients in the transfusion group and seven (4%) patients in the control group experienced severe bleeding by day 21. In subgroups of patients with platelet counts of <10,000/mm3 and <5,000/mm3, the incidence of clinical bleeding was not significantly different between patients who received prophylactic transfusion compared with controls. Plasma leakage, defined as an increase of at least 20% in serum hematocrit, was also similar between groups. Adverse events were significantly more common in the transfusion group and included anaphylaxis, TRALI, and transfusion-associated fluid overload. This RCT clearly demonstrated that prophylactic platelet transfusion for platelet counts <20,000/mm3 was not superior to supportive care alone in the prevention of clinical bleeding in dengue fever; besides, adverse effects are more likely to occur in patients who undergo transfusion.

Key points 

  • Thrombocytopenia is typically present in most patients with dengue fever and occurs due to reduced generation of platelets in the bone marrow and increased peripheral destruction
  • Conventionally, prophylactic platelet transfusions are administered based on arbitrary cut-off levels
  • Although platelet transfusions lead to a transient rise, they may lead to a delay in the recovery of platelet counts in the long term
  • Prophylactic platelet transfusions have not been shown to reduce the incidence of clinical bleeding; furthermore, adverse events may occur, including volume overload, TRALI, and anaphylaxis. Besides the likelihood of adverse events, injudicious transfusions lead to pressure on blood banks during epidemics and increase the cost of care
  • In dengue fever, the incidence of severe bleeding appears to be unrelated to the extent of decrease in platelet counts even to levels below 10,000/mm3
  • Robust evidence suggests that platelet transfusions be confined to patients who experience severe bleeding, thereby conserving a scarce blood product for those who really need it

References

1.         Chaudhary R, Khetan D, Sinha S, Sinha P, Sonker A, Pandey P, et al. Transfusion support to Dengue patients in a hospital based blood transfusion service in north India. Transfus Apher Sci. 2006 Dec;35(3):239–44. 

2.         Lee MS, Hwang KP, Chen TC, Lu PL, Chen TP. Clinical characteristics of dengue and dengue hemorrhagic fever in a medical center of southern Taiwan during the 2002 epidemic. J Microbiol Immunol Infect. 2006 Apr;39(2):121–9. 

3.         Whitehorn J, Roche RR, Guzman MG, Martinez E, Gomez WV, Nainggolan L, et al. Prophylactic Platelets in Dengue: Survey Responses Highlight Lack of an Evidence Base. PLOS Neglected Tropical Diseases. 2012 Jun 26;6(6):e1716. 

4.         Chaurasia R, Zaman S, Chatterjee K, Das B. Retrospective Review of Platelet Transfusion Practices during 2013 Dengue Epidemic of Delhi, India. Transfus Med Hemother. 2015 Jul;42(4):227–31. 

5.         Isarangkura P, Tuchinda S. The behavior of transfused platelets in dengue hemorrhagic fever. Southeast Asian J Trop Med Public Health. 1993;24 Suppl 1:222–4. 

6.         Funahara Y, Ogawa K, Fujita N, Okuno Y. Three possible triggers to induce thrombocytopenia in dengue virus infection. Southeast Asian J Trop Med Public Health. 1987 Sep;18(3):351–5. 

7.         Quirino-Teixeira AC, Andrade FB, Pinheiro MBM, Rozini SV, Hottz ED. Platelets in dengue infection: more than a numbers game. Platelets. 2022 Feb 17;33(2):176–83. 

8.         Sosothikul D, Seksarn P, Pongsewalak S, Thisyakorn U, Lusher J. Activation of endothelial cells, coagulation and fibrinolysis in children with Dengue virus infection. Thromb Haemost. 2007 Apr;97(4):627–34. 

9.         Djamiatun K, van der Ven AJAM, de Groot PG, Faradz SMH, Hapsari D, Dolmans WMV, et al. Severe dengue is associated with consumption of von Willebrand factor and its cleaving enzyme ADAMTS-13. PLoS Negl Trop Dis. 2012;6(5):e1628. 

10.       Sellahewa K, Samaraweera N, Thusita K, Fernando J. Is fresh frozen plasma effective for thrombocytopenia in adults with dengue fever? A prospective randomised double blind controlled study. Ceylon Med J. 2008 Dec 12;53(2):36. 

11.       Lum LCS, Abdel-Latif MEA, Goh AYT, Chan PWK, Lam SK. Preventive transfusion in Dengue shock syndrome-is it necessary? J Pediatr. 2003 Nov;143(5):682–4. 

12.       Karoli R, Bhat S, Fatima J, Verma P. Acute lung injury after platelet transfusion in a patient with dengue fever. Asian J Transfus Sci. 2014 Jul;8(2):131–4. 

13.       Cardier JE, Balogh V, Perez-Silva C, Romano E, Rivas B, Bosch N, et al. Relationship of thrombopoietin and interleukin-11 levels to thrombocytopenia associated with dengue disease. Cytokine. 2006 May;34(3–4):155–60. 

14.       Shinjo K, Takeshita A, Nakamura S, Naitoh K, Yanagi M, Tobita T, et al. Serum thrombopoietin levels in patients correlate inversely with platelet counts during chemotherapy-induced thrombocytopenia. Leukemia. 1998 Mar;12(3):295–300. 

15.       Sundar V, Bhaskar E. Effect of Platelet Transfusion on Clot Strength in Dengue Fever with Thrombocytopenia Related Bleeding: A Thromboelastography-Based Study. Transfus Med Hemother. 2019 Dec;46(6):457–60. 

16.       Lee TH, Wong JGX, Leo YS, Thein TL, Ng EL, Lee LK, et al. Potential Harm of Prophylactic Platelet Transfusion in Adult Dengue Patients. Murray KO, editor. PLoS Negl Trop Dis. 2016 Mar 25;10(3):e0004576. 

17.       Assir MZK, Kamran U, Ahmad HI, Bashir S, Mansoor H, Anees SB, et al. Effectiveness of Platelet Transfusion in Dengue Fever: A Randomized Controlled Trial. Transfus Med Hemother. 2013;40(5):362–8. 

18.       Lye DC, Lee VJ, Sun Y, Leo YS. Lack of efficacy of prophylactic platelet transfusion for severe thrombocytopenia in adults with acute uncomplicated dengue infection. Clin Infect Dis. 2009 May 1;48(9):1262–5. 

19.       Lye DC, Archuleta S, Syed-Omar SF, Low JG, Oh HM, Wei Y, et al. Prophylactic platelet transfusion plus supportive care versus supportive care alone in adults with dengue and thrombocytopenia: a multicentre, open-label, randomised, superiority trial. The Lancet. 2017 Apr;389(10079):1611–8. 

2 thoughts on “Is it high time to cease prophylactic platelet transfusions in dengue fever?”

  1. Sir, what would be cut of or indication to transfuse platelets if we are inserting a CVC/arterial line in Dengue patients?

    1. I would prefer not use insert invasive lines in dengue patients unless pushed to the wall.

      A recent Cochrane review concludes that “there is no evidence from RCTs to determine whether platelet transfusions are required prior to central line insertion in patients with thrombocytopenia, and, if a platelet transfusion is required, what is the correct platelet transfusion threshold.” (Estcourt LJ, Desborough MJ, Hopewell S, Doree C, Stanworth SJ. Comparison of different platelet transfusion thresholds prior to insertion of central lines in patients with thrombocytopenia. Cochrane Database Syst Rev. 2015 Dec 2;2015(12):CD011771).

      I would definitely not aim for a count as high as 50,000/ cu mm before central lines in any case as recommended in other clinical circumstances.

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