The clinical features of severe malaria

In this short Medmastery article, explore the clinical features and life-threatening symptoms of severe malaria.
Last update26th Nov 2020

Malaria caused by Plasmodium falciparum is the deadliest form of malaria and is often referred to as severe malaria. While it typically begins with cyclic fever and chills, if left untreated, much more severe, life-threatening symptoms can develop quickly such as hemolysis, red blood cell (RBC) clots, and coagulation disruption.

Malaria-induced hemolytic anemia

Because P. falciparum can infect red blood cells (RBCs) of any age, more than 60% of RBCs may be parasitized, and when these cells burst it can quickly lead to massive hemolysis. This massive hemolysis causes symptoms such as hemoglobinemia and jaundice.

Hemoglobinemia overwhelms the ability of the RBCs to carry hemoglobin, so much of that hemoglobin spills over into the urine. In the acidic urine, hemoglobin is converted to the black pigment hematin, which may cause patients with severe malaria to develop a dark urine. Once severe falciparum malaria gets to this point, mortality is close to 80% if not treated, and many patients are dead within one to two days.

Figure 1. P. falciparum malaria infects a large proportion of red blood cells (RBCs) causing massive hemolysis. Hemolysis leads to jaundice, and hemoglobinemia noted by the presence of black urine.

In comparison, because of the lower proportion of RBC infection seen in P. vivax or P. ovale malaria, the extent of hemolysis, and associated anemia, would be much lower.

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Coagulopathy in malaria

Once P. falciparum invades RBCs, these parasitized RBCs, or schizonts, produce what are known as sticky knobs on the cell. These knobs cause the cell to stick to the lining of blood vessels, other schizonts, and normal red blood cells.

So, these masses of schizonts and normal RBCs can get stuck in the capillaries or venules, making it difficult for other blood cells to pass through.

This effectively blocks up the microcirculation which has a number of dangerous effects including infarcts and coagulation disruption.

Figure 2. P. falciparum schizonts stick to each other and normal red blood cells, creating a clot that blocks up microcirculation.

Infarcts

Clots made up of schizonts and normal RBCs often get caught up in the microcirculation of the brain causing potentially devastating infarcts and seizures. They can disrupt other organs causing issues like retinal infarcts or kidney failure. And when caught in the venous microcirculation—the venules—clots can lead to decreased venous blood flow, pulmonary and cerebral edema. Cerebral edema can cause elevations of intracranial pressure, subsequent brain herniation and death.

Disseminated intravascular coagulation (DIC)

In addition to causing various types of infarcts, the accumulation of red blood cells in the microcirculation can consume all the patient’s coagulation factors, leading to disseminated intravascular coagulation (DIC), a common feature of severe malaria.

Figure 3. Clots of red blood cell (RBC) schizonts and normal RBC in P. falciparum malaria can cause cerebral and retinal infarcts, kidney failure, seizures, decreased venous flow, pulmonary edema, cerebral edema, increased intracranial pressure, and brain herniation.

Again, let’s compare to P. vivax or P. ovale malaria. We see that the infected RBCs do not develop these sticky knobs, so don’t get hung up in the microcirculation like P. falciparum malaria, making these strains much less deadly.

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Recommended reading

  • Ashley, EA, Phyo, AP, and Woodrow, CJ. 2018. Malaria. Lancet391: 1608­–1621. PMID: 29631781
  • Fairhurst, RM and Wellems, TE. 2014. “Malaria (Plasmodium Species)”. In: Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases, edited by Bennett, JE, Dolin, R, Blaser, MJ. 8th edition. Philadelphia: Elsevier Saunders. (Fairhurst and Wellems 2014, 3070–3090)
  • Phillips, MA, Burrows, JN, Manyando, C, et al. 2017. Malaria. Nat Rev Dis Primers3: 17050. PMID: 28770814
  • World Health Organization. 2019. World malaria report 2019. World Health Organizationhttps://www.who.int/publications/i/item/world-malaria-report-2019
  • Zang, Y, Huang, C, Kim, S, et al. 2015. Multiple stiffening effects of nanoscale knobs on human red blood cells infected with plasmodium falciparum malaria parasite. Proc Nat Acad Sci USA112: 6068–6073. PMID: 25918423

About the author

John F. Fisher, MD MACP FIDSA
Professor of Medicine (Infectious Diseases) at the Medical College of Georgia, Augusta University, USA.
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