Severe dengue typically consists of hypovolemic shock (dengue shock
syndrome) and bleeding (dengue hemorrhagic fever) [1,2]. Two recent
papers in Indian Pediatrics highlight "atypical" features of severe
dengue, mainly as organ failure – liver, heart, lungs, kidneys, brain –
in any combinations [1,2]. These are increasingly being recognized in
recent years [1-3]. We suspect that these might be – at least partly –
iatrogenic, associated with unwarranted platelet transfusions, a popular
practice in recent years [4, 5].
Thrombocytopenia is characteristic of dengue fever
and severe dengue. Hemophagocytosis and bone marrow suppression are the
frequently described causes for thrombocytopenia [4]. We propose another
pathway for platelet depletion, which has an important bearing on
possible adverse effects of platelet transfusions [4].
We believe that platelets get sequestered on small
vessel endothelial cells in dengue, similar to what happens in
microangiopathy of thrombotic thrombocytopenic purpura (TTP) [4]. The
adhesion ligand is von Willebrand factor (vWF). Increased vWF activation
or decreased cleavage of vWF by protease ADAMTS 13 will result in
increased adhesion and platelet microthrombi [4]. In severe dengue, the
balance between vWF and ADAMTS 13 is deranged [4]. Deficiency of ADAMTS
13 will result in extremely adhesive, ultra-large vWF multimers,
resulting in platelet microthrombi [4].
Microvascular plasma leakage causes hypovolemia in
which low platelet counts seem not to be involved, at least directly.
Small vessel bleeds do not get plugged by platelets as their numbers are
grossly depleted, thus leading to uncontrolled bleeding at various
sites. But, what is the pathogenesis of organ failure? We propose that
platelet microthrombi obstruct perfusion resulting in organ hypoxemia
and failure [4]. We suspect that multi-organ failure may be partly due
to platelet transfusions given in an attempt to correct thrombocytopenia
as the added platelets may increase platelet microthrombi and further
reduce organ perfusion. Standard treatment protocols for severe dengue
do not recommend platelet transfusion as it does not seem to help in any
manner [4, 5].
The authors describing atypical manifestations have
not clarified if patients were given platelet transfusions [1-3]. When
platelet transfusion is felt to be life-saving in the face of serious
bleeding, ADAMTS 13 ought to be given prior to platelet transfusion, in
order to prevent platelet adhesion aggravating the problem. Fresh frozen
plasma and cryosupernatant are rich in ADAMTS 13 [4]. Fresh whole blood
transfusion, as recommended by WHO will also supply ADAMTS 13 [4].
When severe dengue is diagnosed, especially with
suspicion of impending organ failure, infusion of fresh frozen plasma is
a relatively easy intervention for reducing platelet adhesion. More
heroic measure would be plasma exchange for diluting out excess vWF (4).
Recently, recombinant ADAMTS 13 has become available, and is another
intervention that needs to be studied [4].
We strongly recommend the avoidance of platelet
transfusions. Investigations to evaluate the benefits (particularly
mortality reduction) of fresh frozen plasma, plasma exchange and
recombinant ADAMTS 13 in patients with severe dengue are urgently
required. Those who see large numbers of cases of severe dengue are
urged to investigate the questions raised above. If proven correct, many
lives may be saved by strict adherence to recommended management of
dengue.
1. Pawaria A, Mishra D, Juneja M, Meena J. Atypical
manifestations of dengue fever. Indian Pediatr. 2014;51:495-6.
2. Pothaprigadia S. Atypical manifestations of dengue
fever. Indian Pediatr. 2014;51: 937-8.
3. Verma R, Sharma P, Garg RK, Atam V, Singh MK,
Mehrotra HS. Neurological complications of dengue fever: Experience from
a tertiary center of north India. Ann Indian Acad Neurol. 2011;14:272-8.
4. Eapen CE, Elias E, Goel A, John TJ. Hypothesis of
mechanism of thrombocytopenia in severe dengue, providing clues to
better therapy to save lives. Current Science. 2015 (in press).
5. 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.