Dengue fever has emerged as a major public health problem in tropical and subtropical regions across the world. With an increase in the global burden of this arboviral infection, health care services are continuously striving to improve patient management and searching for innovative approaches to control vector transmission. Various grades of bleeding manifestations have been defined by World Health Organization (WHO); but, there are few guidelines as to the transfusion management of patients with dengue.
Prophylactic platelet transfusions are given in dengue fever with thrombocytopenia to prevent hemorrhagic complications. Although the use of prophylactic platelet transfusions is increasing in countries where dengue is endemic, it is associated with risks and has financial implications. The decision to transfuse platelets is based on several factors including estimation of platelet count and function, cause of thrombocytopenia, the status of coagulation system, the presence or likelihood of bleeding and the risks of transfusion. Other transfusion strategies include blood transfusion for severe bleeding manifestations, fresh frozen plasma (FFP) and cryoprecipitate for patients with deranged coagulation profile.
The review was carried out after searching the literature in PubMed, Science Direct and Google scholar using keywords combinations: Dengue fever, platelets, transfusion, prophylactic transfusions, and thrombocytopenia.
World Health Organization has classified dengue as the most important mosquito borne viral disease in the world in its 2012 report. Dengue is now endemic in >125 countries. Almost 75% of the world's population exposed to dengue lives in the Asia Pacific region of the world. The incidence of dengue has increased 30-fold between 1960 and 2010. Dramatic expansion of dengue in the recent past has been attributed to urbanization, population explosion, ineffective vector control measures, weather changes, and increase in travel. Emerging strains of virus with higher virulence are causing more severe epidemics.
Global estimates of dengue show dengue infections to the tune of 50 million to 200 million annually with over 20,000 dengue related deaths each year. However, due to poor disease surveillance, inadequate reporting, difficulties in diagnosis, and lack of consistent analysis, the true global burden of disease and associated impact is not known.
Like most arboviruses, dengue virus is maintained in nature in cycles that involve preferred blood-sucking vectors and vertebrate hosts. The virus is transmitted to humans by Aedes aegypti and in some cases by Aedes albopictus. The expansion of villages, towns, and cities in endemic areas, and the increased mobility of people have increased the number of epidemics. Dengue fever, which was once confined to Southeast Asia, has now spread its tentacles to Southern China, countries in the Pacific Ocean and America.
The dengue virus is an RNA virus of the flaviviridae family with four major serotypes. Various genotypes within each serotype have varying epidemic potential. Once inside the skin, dengue virus binds to Langerhans cells and enters through binding between viral proteins and membrane proteins on the Langerhans cell. The dendritic cell moves to the nearest lymph node. Meanwhile, the virus genome is translated in membrane-bound vesicles on the cell's endoplasmic reticulum, where new viral proteins are produced that replicate the viral RNA and begin to form viral particles. Immature virus particles are transported to the Golgi apparatus and the mature new viruses bud on the surface of the infected cell and are released by exocytosis. They are then able to enter other white blood cells, such as monocytes and macrophages.
Various antibodies are generated; some bind closely to the viral proteins and target them for phagocytosis, but some bind the virus less well and deliver the virus into a part of the phagocytes where it is not destroyed but is able to replicate further. The pathogenesis of dengue is a complex interplay of host immunity and genetic predisposition combined with certain viral virulence factors. The dengue virus genome encodes three structural proteins mainly capsid (C), precursor membrane (prM) and envelope protein (E). The seven nonstructural proteins include NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5. Recent evidence suggests that antibody binds to an epitope based on the affinity and accessibility of that epitope in the intact virion. Demonstration of neutralizing antibodies and their target epitopes on the dengue virion has implications for vaccine design.
Dengue hemorrhagic fever is associated with an abnormal immune response with production of cytokines or chemokines, activation of T-lymphocytes and disturbance of hemostatic system. Release of cytokines causes systemic effects of plasma leakage and circulatory insufficiency. Moreover, there is increase in apoptosis and endothelial cell dysfunction.
Halstead described the antibody dependent enhancement theory. Upon second infection with a heterotypic dengue virus, antibody dependent enhancement occurs, which increases risk of developing dengue hemorrhagic fever in individuals recovered from a primary dengue infection. There is enhanced T-cell activation in secondary infection. This phenomenon is known as original antigenic sin. Severe dengue is associated with predominance of high cytokine producing cells with excessive release of inflammatory cytokines. This causes vascular leak and tissue damage.
The bleeding manifestations in dengue are caused by vasculopathy, thrombocytopenia, platelet dysfunction and coagulopathy. Thrombocytopenia in dengue is multifactorial. In the early stage, bone marrow hypo-cellularity followed later by immune mediated destruction of platelets are proposed as the mechanisms for thrombocytopenia. Platelet dysfunction (the absence of adenosine diphosphate release) was initially demonstrated in patients with dengue hemorrhagic fever during convalescence. The platelet dysfunction could be due to exhaustion from platelet activation triggered by immune complexes.
During the acute febrile stage, mild prolongation of the prothrombin time and partial thromboplastin time, as well as reduced ﬁbrinogen levels, have been demonstrated by various authors. However, the coagulation abnormality is well-compensated for in the majority of patients.
Viral virulence factors have been identified with specific viral mutations linked to disease severity. Host factors such as extremes of age, female sex, ethnicity, and comorbidities such as diabetes and hypertension are associated with severe disease. Human genetic susceptibility to severe dengue has been better defined with certain human leukocyte antigen polymorphisms in genome wide association studies.
Thrombocytopenia is a common cause of concern in dengue to both patients and attending clinicians. There are no clear guidelines for management of thrombocytopenia and platelets are ordered as a routine in most hospitals. Prophylactic platelet transfusions are deﬁned as platelet transfusions given in the absence of clinical bleeding, in contrast to therapeutic platelet transfusions given to patients with clinical bleeding. There is controversy as to the efficacy of prophylactic platelet transfusions and the exact trigger for platelet transfusion in dengue. Although some recommend a trigger of <20,000/μl in the absence of bleeding, lowering the transfusion trigger to <10,000/μl as has been shown in a study on patients with acute myeloid leukemia does not increase the risk of bleeding. However, it reduces the number of patients who receive platelet transfusions. The British Committee for standardization in hematology guidelines on platelet transfusion recommend a trigger of 10,000/μl for stable thrombocytopenic patients without additional risk factors for bleeding. Similar guidelines have been issued by the Directorate of national vector borne diseases control program, Government of India [Table 1]. Besides recommending a trigger of 10,000/μl, these guidelines also state that prophylactic platelet transfusions are not required in stable patients with platelet count below 20,000/μl.
Studies in pediatric patients of dengue shock syndrome have shown no benefits of prophylactic platelets and FFP transfusion. Instead, such transfusions are the cause of fluid overload and prolonged hospital stay. In a study on adults with acute dengue, the authors found prophylactic platelet transfusions to be ineffective in preventing bleeding. Lack of efficacy of prophylactic platelet transfusions has been reported in literature by various authors. In a comparative study between patients with dengue shock syndrome who received platelet transfusions and those who did not receive transfusions, the authors observed significant difference in the development of pulmonary edema and the length of hospitalization but no difference was observed in the incidence of bleeding manifestations. Preventive transfusions also did not produce improvement in coagulation status. The Trial of Platelet Prohylaxis study of United Kingdom examined the safety of a therapeutic only platelet transfusion strategy with no prophylactic platelet transfusions in thrombocytopenic patients. In dengue shock syndrome patients who received prophylactic platelet transfusion, it was observed that the increment in platelet count was transient and returned to pre transfusion values within 5 h of transfusion.
In patients with dengue hemorrhagic fever or dengue shock syndrome, duration of shock is the main risk factor for severe bleeding. Hence, early recognition and prevention of shock is the key to treatment. Serial monitoring of hematocrit along with judicious intravenous therapy reduces the use of blood products and shortens hospital stay.
In a study on transfusion requirement of patients with dengue infection, the authors observed no correlation between clinical bleed and platelet count. About 37% of patients with dengue hemorrhagic fever or dengue shock syndrome had coagulopathy. About 21.5% of platelet transfusions were considered inappropriate. Inappropriate platelet transfusions in absence of bleeding have been reported from 13% to as high as 56.2% by various authors. A study conducted in four tertiary level hospitals of Delhi observed that 73.5% of patients with dengue hemorrhagic fever and 48.7% of dengue fever classified as per WHO guidelines were given platelet transfusions. Sugianto et al. observed no significant difference in the frequency of bleeding in patients who received single unit platelet transfusion and those who did not receive any transfusion.
TRANSFUSION OF OTHER COMPONENTS
Patients with severe bleeding that compromises cardiovascular function can be given blood transfusion as a life saving measure. However, there is risk of fluid overload due to decompensated cardiac status. In such patients with massive bleeding, packed red cells may be transfused. Guidelines issued by Government of India recommend red cell transfusions for patients with overt blood loss 10% or more of blood volume and in refractory shock with declining hematocrit.
Thrombocytopenia is not the only predictor of severe bleeding as has been reported in literature. Due to multifactorial etiology of bleeding in patients with dengue, it is wise to conduct a coagulation profile in addition to platelet count before giving platelet transfusions. In a study from Taiwan, 53.8% of patients showed coagulopathy. Coagulopathy can be managed by FFP transfusions but preventive FFP transfusion is not indicated in dengue hemorrhagic fever. Use of FFP or cryoprecipitate is indicated in coagulopathy with bleeding as per the advice of the physician and after taking into account the clinical condition of the patient. Recombinant factor VIIa may be given in severe uncontrolled bleeding. It enhances thrombin generation. It also increases the activity and function of patients' and transfused platelets by direct activation of factor X on platelet surface.
Blood transfusion services constantly face challenges year after year during dengue outbreaks due to lack of evidence based guidelines for clinical use of blood and blood components. The demand for platelets and FFP is increasing due to more number of cases with dengue hemorrhagic fever and dengue shock syndrome. Transfusion of blood components is associated with many adverse effects. The major risks associated with transfusion of platelets include febrile non hemolytic transfusion reactions, allergic reactions, bacterial sepsis, transfusion related acute lung injury, alloimmunization, and platelet refractoriness, pulmonary edema and transfusion transmitted infections. Hence, it is prudent to consider transfusion only if the benefits outweigh the accompanying risks of transfusion.
Inappropriate use of blood and blood components during dengue fever outbreaks essentially depletes the inventory of blood centers. Further, lack of knowledge, absence of evidence based guidelines and panic like situation leads to flooding of transfusion services with blood and component requests. A centralized system of management with donor registries, guidelines and regular awareness programs can go a long way in better management of dengue outbreaks.
1. Heddle NM, Cook RJ, Tinmouth A, Kouroukis CT, Hervig T, Klapper E, et al A randomized controlled trial comparing standard-and low-dose strategies for transfusion
of platelets (SToP) to patients with thrombocytopenia Blood. 2009;113:1564–73
2. Kurukularatne C, Dimatatac F, Teo DL, Lye DC, Leo YS. When less is more: Can we abandon prophylactic platelet transfusion
in dengue fever? Ann Acad Med Singapore. 2011;40:539–45
3. Galel SA, Malone JM, Viele MKGreer JP, Foerster J, Lukens JN, Rodgers GM, Paraskevas F, Galder B. Transfusion
medicine Wintrobe's Clinical Hematology. 200411th ed Philadelphia Lippincott Williams and Wilkins:831–82
4. World Health Organization (WHO). Global Strategy for Dengue Prevention and Control 2012-2020. 2012 Geneva WHO Press
5. . WHO Regional Office for South East Asia Comprehensive Guidelines for Prevention and Control of Dengue and Dengue Hemorrhagic Fever. 2011Revised and Expanded New Delhi World Health Organization South East Asia Regional Office
6. WHO. Dengue Guidelines for Diagnosis, Treatment, Prevention and Control. 2009 Geneva World Health Organization
7. Gubler DJ. Dengue, urbanization and globalization: The unholy trinity of the 21(st) century Trop Med Health. 2011;39:3–11
8. Murray NE, Quam MB, Wilder-Smith A. Epidemiology of dengue: Past, present and future prospects Clin Epidemiol. 2013;5:299–309
9. Rico-Hesse R. Microevolution and virulence of dengue viruses Adv Virus Res. 2003;59:315–41
10. Gubler DJ. The global emergence/resurgence of arboviral diseases as public health problems Arch Med Res. 2002;33:330–42
11. Shepard DS, Coudeville L, Halasa YA, Zambrano B, Dayan GH. Economic impact of dengue illness in the Americas Am J Trop Med Hyg. 2011;84:200–7
12. Gubler DJ. The economic burden of dengue Am J Trop Med Hyg. 2012;86:743–4
13. Beatty ME, Beutels P, Meltzer MI, Shepard DS, Hombach J, Hutubessy R, et al Health economics of dengue: A systematic literature review and expert panel's assessment Am J Trop Med Hyg. 2011;84:473–88
14. Gubler DJMahy BW, Van Regenmortel MH. Dengue viruses Desk Encyclopedia of Human and Medical Virology. 2010 Boston Academic Press:372–82
15. Rodenhuis-Zybert IA, Wilschut J, Smit JM. Dengue virus life cycle: Viral and host factors modulating infectivity Cell Mol Life Sci. 2010;67:2773–86
16. Yacoub S, Mongkolsapaya J, Screaton G. The pathogenesis of dengue Curr Opin Infect Dis. 2013;26:284–9
17. de Alwis R, Smith SA, Olivarez NP, Messer WB, Huynh JP, Wahala WM, et al Identification of human neutralizing antibodies that bind to complex epitopes on dengue virions Proc Natl Acad Sci U S A. 2012;109:7439–44
18. Chuansumrit A, Tangnararatchakit K. Pathophysiology and management of dengue hemorrhagic fever Transfus Altern Transfus Med. 2006;8(Suppl):3–11
19. Halstead SB. Pathogenesis of dengue: Challenges to molecular biology Science. 1988;239:476–81
20. Halstead SB, Rojanasuphot S, Sangkawibha N. Original antigenic sin in dengue Am J Trop Med Hyg. 1983;32:154–6
21. Mitrakul C, Poshyachinda M, Futrakul P, Sangkawibha N, Ahandrik S. Hemostatic and platelet kinetic studies in dengue hemorrhagic fever Am J Trop Med Hyg. 1977;26:975–84
22. Boonpucknavig S, Vuttiviroj O, Bunnag C, Bhamarapravati N, Nimmanitya S. Demonstration of dengue antibody complexes on the surface of platelets from patients with dengue hemorrhagic fever Am J Trop Med Hyg. 1979;28:881–4
23. Funahara Y, Sumarmo, Shirahata A, Setiabudy-Dharma R. DHF characterized by acute type DIC with increased vascular permeability Southeast Asian J Trop Med Public Health. 1987;18:346–50
24. Anders KL, Nguyet NM, Chau NV, Hung NT, Thuy TT, Lien le B, et al Epidemiological factors associated with dengue shock syndrome and mortality in hospitalized dengue patients in Ho Chi Minh City, Vietnam Am J Trop Med Hyg. 2011;84:127–34
25. Pang J, Salim A, Lee VJ, Hibberd ML, Chia KS, Leo YS, et al Diabetes with hypertension as risk factors for adult dengue hemorrhagic fever in a predominantly dengue serotype 2 epidemic: A case control study PLoS Negl Trop Dis. 2012;6:e1641
26. Figueiredo MA, Rodrigues LC, Barreto ML, Lima JW, Costa MC, Morato V, et al Allergies and diabetes as risk factors for dengue hemorrhagic fever: Results of a case control study PLoS Negl Trop Dis. 2010;4:e699
27. Stephens HA, Klaythong R, Sirikong M, Vaughn DW, Green S, Kalayanarooj S, et al HLA-A and-B allele associations with secondary dengue virus infections correlate with disease severity and the infecting viral serotype in ethnic Thais Tissue Antigens. 2002;60:309–18
28. Appanna R, Ponnampalavanar S, Lum Chai See L, Sekaran SD. Susceptible and protective HLA class 1 alleles against dengue fever and dengue hemorrhagic fever patients in a Malaysian population PLoS One. 2010:5 e13029.10.1371/journal.pone.0013029
29. 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;48:1262–5
30. Wandt H, Frank M, Ehninger G, Schneider C, Brack N, Daoud A, et al Safety and cost effectiveness of a 10x10 (9)/L trigger for prophylactic platelet transfusions compared with the traditional 20x10 (9)/L trigger: A prospective comparative trial in 105 patients with acute myeloid leukemia Blood. 1998;91:3601–6
31. . British Committee for Standards in Haematology, Blood Transfusion
Task Force. Guidelines for the use of platelet transfusions Br J Haematol. 2003;122:10–23
32. Dutta AK, Biswas A, Baruah K, Dhariwal AC. National guidelines for diagnosis and management of dengue fever/dengue haemorrhagic fever and dengue shock syndrome J Indian Med Assoc. 2011;109:30–5
33. Lum LC, Abdel-Latif Mel-A, Goh AY, Chan PW, Lam SK. Preventive transfusion
in Dengue shock syndrome-is it necessary? J Pediatr. 2003;143:682–4
34. Stanworth SJ, Dyer C, Choo L, Bakrania L, Copplestone A, Llewelyn C, et al Do all patients with hematologic malignancies and severe thrombocytopenia need prophylactic platelet transfusions. Background, rationale, and design of a clinical trial (trial of platelet prophylaxis) to assess the effectiveness of prophylactic platelet transfusions? Transfus Med Rev. 2010;24:163–71
35. Lum LC, Goh AY, Chan PW, El-Amin AL, Lam SK. Risk factors for hemorrhage in severe dengue infections J Pediatr. 2002;140:629–31
36. Chuansumrit A, Phimolthares V, Tardtong P, Tapaneya-Olarn C, Tapaneya-Olarn W, Kowsathit P, et al Transfusion
requirements in patients with dengue hemorrhagic fever Southeast Asian J Trop Med Public Health. 2000;31:10–4
37. 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;35:239–44
38. Makroo RN, Raina V, Kumar P, Kanth RK. Role of platelet transfusion
in the management of dengue patients in a tertiary care hospital Asian J Transfus Sci. 2007;1:4–7
39. Kumar ND, Tomar V, Singh B, Kela K. Platelet transfusion
practice during dengue fever epidemic Indian J Pathol Microbiol. 2000;43:55–60
40. Kulkarni N. Study on the effectiveness of transfusion
program in dengue patients receiving platelet transfusion
Int J Blood Transfus Immunohematology. 2012;2:11–5
41. Tewari KN, Tuli NR, Devgun SC. Clinical profile of dengue fever and use of platelets in four tertiary level hospitals of Delhi in the year 2009 J Indian Acad Clin Med. 2013;14:8–12
42. Sugianto D, Samsi TK, Wulur H, Diragunsa SA, Jenning GB. The changes of platelet count in dengue hemorrhagic Cermin Dunia Kedokteran. 1994;92:14–7
43. Lai PC, Lee SS, Kao CH, Chen YS, Huang CK, Lin WR, et al Characteristics of a dengue hemorrhagic fever outbreak in 2001 in Kaohsiung J Microbiol Immunol Infect. 2004;37:266–70
44. Krishnamurti C, Kalayanarooj S, Cutting MA, Peat RA, Rothwell SW, Reid TJ, et al Mechanisms of hemorrhage in dengue without circulatory collapse Am J Trop Med Hyg. 2001;65:840–7
45. . Centers for Disease Control and Prevention (CDC). Fatal bacterial infections associated with platelet transfusions - United States, 2004 MMWR Morb Mortal Wkly Rep. 2005;54:168–70
46. Dodd RY. Current viral risks of blood and blood products Ann Med. 2000;32:469–74
47. Mangano MM, Chambers LA, Kruskall MS. Limited efficacy of leukopoor platelets for prevention of febrile transfusion
reactions Am J Clin Pathol. 1991;95:733–8
48. Kruskall MS. The perils of platelet transfusions N Engl J Med. 1997;337:1914–5
Source of Support: Nil.
Conflict of Interest: None declared.