Enteric Fever (Typhoid Fever)

Typhoid (or enteric) fever is a severe, systemic bacterial infection classically caused by the facultative intracellular and Gram-negative bacilli Salmonella Salmonella Salmonellae are gram-negative bacilli of the family Enterobacteriaceae. Salmonellae are flagellated, non-lactose-fermenting, and hydrogen sulfide-producing microbes. Salmonella enterica, the most common disease-causing species in humans, is further classified based on serotype as typhoidal (S. typhi and paratyphi) and nontyphoidal (S. enteritidis and typhimurium). Salmonella enterica serotype Typhi (S. Typhimurium, formerly S. typhi). S. paratyphi serotypes A, B, or C can cause a similar syndrome. Up to 20 million new cases of typhoid fever occur each year worldwide, most commonly in undeveloped areas with poor sanitation. Transmission occurs through the fecal-oral route, and humans are the only known reservoir. Complications of typhoid fever include intestinal hemorrhage, pericarditis Pericarditis Pericarditis is an inflammation of the pericardium, often with fluid accumulation. It can be caused by infection (often viral), myocardial infarction, drugs, malignancies, metabolic disorders, autoimmune disorders, or trauma. Acute, subacute, and chronic forms exist. Pericarditis, visceral abscesses, and septicemia. Treatment is with fluoroquinolones Fluoroquinolones Fluoroquinolones are a group of broad-spectrum, bactericidal antibiotics inhibiting bacterial DNA replication. Fluoroquinolones cover gram-negative, anaerobic, and atypical organisms, as well as some gram-positive and multidrug-resistant (MDR) organisms. Fluoroquinolones. Prevention of typhoid fever is available through vaccination Vaccination Vaccination is the administration of a substance to induce the immune system to develop protection against a disease. Unlike passive immunization, which involves the administration of pre-performed antibodies, active immunization constitutes the administration of a vaccine to stimulate the body to produce its own antibodies. Vaccination, hand Hand The hand constitutes the distal part of the upper limb and provides the fine, precise movements needed in activities of daily living. It consists of 5 metacarpal bones and 14 phalanges, as well as numerous muscles innervated by the median and ulnar nerves. Hand hygiene, and safe food and water practices.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Epidemiology and Etiology

Epidemiology

  • Most prevalent in underdeveloped areas with poor sanitation
    • South-central and Southeast Asia
    • Southern Africa
  • World Health Organization (WHO) estimates (worldwide):
    • Incidence: 11–20 million cases/year
    • Deaths: 128,000–161,000 deaths/year
  • The incidence in developed countries is low and almost always associated with travel to a high-risk area (incidence in the United States: 200–300 cases/year).

Etiology

  • Causative agent: S. enterica serotype Typhi or Salmonella Salmonella Salmonellae are gram-negative bacilli of the family Enterobacteriaceae. Salmonellae are flagellated, non-lactose-fermenting, and hydrogen sulfide-producing microbes. Salmonella enterica, the most common disease-causing species in humans, is further classified based on serotype as typhoidal (S. typhi and paratyphi) and nontyphoidal (S. enteritidis and typhimurium). Salmonella Typhi
    • Motile, encapsulated, Gram-negative bacilli
    • Facultative intracellular within macrophages
    • Produces black colonies on Hektoen agar
    • Acid labile (requires a high inoculum) 
  • Exam tip: While not commonly tested,  Salmonella Salmonella Salmonellae are gram-negative bacilli of the family Enterobacteriaceae. Salmonellae are flagellated, non-lactose-fermenting, and hydrogen sulfide-producing microbes. Salmonella enterica, the most common disease-causing species in humans, is further classified based on serotype as typhoidal (S. typhi and paratyphi) and nontyphoidal (S. enteritidis and typhimurium). Salmonella Paratyphi serotypes A, B, and C can also cause enteric fever (paratyphoid fever).
Salmonella typhi

S. Typhimurium

Image: “ Salmonella Salmonella Salmonellae are gram-negative bacilli of the family Enterobacteriaceae. Salmonellae are flagellated, non-lactose-fermenting, and hydrogen sulfide-producing microbes. Salmonella enterica, the most common disease-causing species in humans, is further classified based on serotype as typhoidal (S. typhi and paratyphi) and nontyphoidal (S. enteritidis and typhimurium). Salmonella typhi“ by Roinujs. License: CC BY-SA 4.0

Pathophysiology

Transmission

  • Fecal-oral transmission
    • Humans are the only reservoir.
    • Chronic carriers have  gallbladder Gallbladder The gallbladder is a pear-shaped sac, located directly beneath the liver, that sits on top of the superior part of the duodenum. The primary functions of the gallbladder include concentrating and storing up to 50 mL of bile. Gallbladder and Biliary Tract colonization (e.g., “Typhoid Mary”).
  • Severity of disease is dependent on:
    • Infecting species (S. Typhi versus S. Paratyphi)
    • Infectious dose (high inoculum is required to survive exposure to gastric acids)

Pathogenesis

After ingestion of  Salmonella Salmonella Salmonellae are gram-negative bacilli of the family Enterobacteriaceae. Salmonellae are flagellated, non-lactose-fermenting, and hydrogen sulfide-producing microbes. Salmonella enterica, the most common disease-causing species in humans, is further classified based on serotype as typhoidal (S. typhi and paratyphi) and nontyphoidal (S. enteritidis and typhimurium). Salmonella Typhi:

  • Bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview must survive exposure to gastric acids.
  • Bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview adhere to and invade intestinal M cells of Peyer’s patches.
  • After invasion, the bacteria replicate within macrophages in Peyer’s patches, mesenteric lymph nodes, and the spleen Spleen The spleen is the largest lymphoid organ in the body, located in the LUQ of the abdomen, superior to the left kidney and posterior to the stomach at the level of the 9th-11th ribs just below the diaphragm. The spleen is highly vascular and acts as an important blood filter, cleansing the blood of pathogens and damaged erythrocytes. Spleen. This causes an inflammatory reaction with hypertrophy of Peyer’s patches and recruitment of mononuclear cells and lymphocytes Lymphocytes Lymphocytes are heterogeneous WBCs involved in immune response. Lymphocytes develop from the bone marrow, starting from hematopoietic stem cells (HSCs) and progressing to common lymphoid progenitors (CLPs). B and T lymphocytes and natural killer (NK) cells arise from the lineage. Lymphocytes.
  • Bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview spread hematogenously through the bloodstream and lymphatic system, causing:
    • Localized infection of the lymphoid tissue and small intestine Small intestine The small intestine is the longest part of the GI tract, extending from the pyloric orifice of the stomach to the ileocecal junction. The small intestine is the major organ responsible for chemical digestion and absorption of nutrients. It is divided into 3 segments: the duodenum, the jejunum, and the ileum. Small Intestine
    • Bacteremia 
Salmonella typhi photomicrograph

This photomicrograph reveals some of the histopathology exhibited in a lymph node tissue specimen in a case of typhoid fever. Macrophages are present amongst the normal lymphocytes Lymphocytes Lymphocytes are heterogeneous WBCs involved in immune response. Lymphocytes develop from the bone marrow, starting from hematopoietic stem cells (HSCs) and progressing to common lymphoid progenitors (CLPs). B and T lymphocytes and natural killer (NK) cells arise from the lineage. Lymphocytes. Note, S. Typhi bacterial invasion of macrophages. These macrophages also contain erythrocytes Erythrocytes Erythrocytes, or red blood cells (RBCs), are the most abundant cells in the blood. While erythrocytes in the fetus are initially produced in the yolk sac then the liver, the bone marrow eventually becomes the main site of production. Erythrocytes and degenerated lymphocytes Lymphocytes Lymphocytes are heterogeneous WBCs involved in immune response. Lymphocytes develop from the bone marrow, starting from hematopoietic stem cells (HSCs) and progressing to common lymphoid progenitors (CLPs). B and T lymphocytes and natural killer (NK) cells arise from the lineage. Lymphocytes.

Image: “2213” by CDC/ Armed Forces Institute of Pathology, Charles N. Farmer. License: Public Domain

Clinical Presentation

Infection with S. Typhi results in typhoid (or enteric ) fever. Typhoid fever is a severe systemic illness associated with fever and abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain

The incubation period is 5–21 days.

Three-phase or -week progression (if untreated)
Clinical course Subjective findings
Week 1 Bacteremia
  • Gradually rising fever
  • Relative bradycardia
  • Pulse-temperature dissociation
  • Constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation
Week 2
  • Progressing illness
  • Patients appear acutely ill
  • Persistent fever: for > 3 days, unresponsive to antipyretics
  • Abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
  • “Rose spots”: small, speckled, rose-colored exanthem most commonly on the lower chest/abdomen
  • Yellow-green, “pea soup” diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea or constipation
  • Prostration
  • Typhoid tongue Tongue The tongue, on the other hand, is a complex muscular structure that permits tasting and facilitates the process of mastication and communication. The blood supply of the tongue originates from the external carotid artery, and the innervation is through cranial nerves. Oral Cavity: Lips and Tongue: greyish/yellow coated tongue Tongue The tongue, on the other hand, is a complex muscular structure that permits tasting and facilitates the process of mastication and communication. The blood supply of the tongue originates from the external carotid artery, and the innervation is through cranial nerves. Oral Cavity: Lips and Tongue with erythematous edges
Week 3
  • Ileocecal lymphatic hyperplasia of Peyer’s patches
  • Secondary bacteremia
  • Peritonitis
Clinical features of week 2 plus:
  • Hepatosplenomegaly
  • Intestinal bleeding
  • Altered mental status

Diagnosis

Diagnosis is dependent on a high degree of suspicion as cultures are often negative, take many days, and may not be available in resource-poor areas.

  • Confirmed by blood and stool cultures
    • Blood cultures will be positive for Salmonella Salmonella Salmonellae are gram-negative bacilli of the family Enterobacteriaceae. Salmonellae are flagellated, non-lactose-fermenting, and hydrogen sulfide-producing microbes. Salmonella enterica, the most common disease-causing species in humans, is further classified based on serotype as typhoidal (S. typhi and paratyphi) and nontyphoidal (S. enteritidis and typhimurium). Salmonella species in 50%70% of cases.
    • Stool cultures will be positive for Salmonella Salmonella Salmonellae are gram-negative bacilli of the family Enterobacteriaceae. Salmonellae are flagellated, non-lactose-fermenting, and hydrogen sulfide-producing microbes. Salmonella enterica, the most common disease-causing species in humans, is further classified based on serotype as typhoidal (S. typhi and paratyphi) and nontyphoidal (S. enteritidis and typhimurium). Salmonella species in 30%40% of cases.
  • If other risk factors (e.g., recent travel to a high-risk) are present, clinical diagnosis is possible based on:
    • Prolonged fever (> 3 days)
    • Gastrointestinal (GI) symptoms
      • Abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
      • Diarrhea
      • Constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation

Management and Prevention

Management

  • First-line treatment: fluoroquinolones Fluoroquinolones Fluoroquinolones are a group of broad-spectrum, bactericidal antibiotics inhibiting bacterial DNA replication. Fluoroquinolones cover gram-negative, anaerobic, and atypical organisms, as well as some gram-positive and multidrug-resistant (MDR) organisms. Fluoroquinolones (primarily ciprofloxacin)
  • If fluoroquinolone resistance is suspected, azithromycin

Prevention

  • Two vaccines are available for those traveling to high-risk areas:
    • Intramuscular, inactivated vaccine Vaccine A vaccine is usually an antigenic, non-virulent form of a normally virulent microorganism. Vaccinations are a form of primary prevention and are the most effective form due to their safety, efficacy, low cost, and easy access. Vaccination
      • Contains capsular polysaccharide
      • Must be > 2 years old
    • Oral, live-attenuated vaccine Vaccine A vaccine is usually an antigenic, non-virulent form of a normally virulent microorganism. Vaccinations are a form of primary prevention and are the most effective form due to their safety, efficacy, low cost, and easy access. Vaccination: must be > 6 years old
  • Hand hygiene, food, and water safety are also key.
  • Any infected individual must avoid preparing food for others.

Complications

Complications of typhoid are typically associated with untreated infection in 3rd phase (or week) of infection. The most common complications include:

  • GI bleeding
  • Ileal perforation
  • Pericarditis
  • Visceral abscesses
  • Osteomyelitis Osteomyelitis Osteomyelitis is an infection of the bone that results from the spread of microorganisms from the blood (hematogenous), nearby infected tissue, or open wounds (non-hematogenous). Infections are most commonly caused by Staphylococcus aureus. Osteomyelitis
  • Overwhelming sepsis Sepsis Organ dysfunction resulting from a dysregulated systemic host response to infection separates sepsis from uncomplicated infection. The etiology is mainly bacterial and pneumonia is the most common known source. Patients commonly present with fever, tachycardia, tachypnea, hypotension, and/or altered mentation. Sepsis and Septic Shock

Another complication, usually associated with asymptomatic infection, is developing a chronic carrier state:

  • Positive  Salmonella Salmonella Salmonellae are gram-negative bacilli of the family Enterobacteriaceae. Salmonellae are flagellated, non-lactose-fermenting, and hydrogen sulfide-producing microbes. Salmonella enterica, the most common disease-causing species in humans, is further classified based on serotype as typhoidal (S. typhi and paratyphi) and nontyphoidal (S. enteritidis and typhimurium). Salmonella in stool or urine cultures > 1 year after acute infection
    • More frequent in adult women and patients with cholelithiasis Cholelithiasis Cholelithiasis (gallstones) is the presence of stones in the gallbladder. Most gallstones are cholesterol stones, while the rest are composed of bilirubin (pigment stones) and other mixed components. Patients are commonly asymptomatic but may present with biliary colic (intermittent pain in the right upper quadrant). Cholelithiasis or other biliary tract Biliary tract Bile is secreted by hepatocytes into thin channels called canaliculi. These canaliculi lead into slightly larger interlobular bile ductules, which are part of the portal triads at the "corners" of hepatic lobules. The bile leaves the liver via the right and left hepatic ducts, which join together to form the common hepatic duct. Gallbladder and Biliary Tract abnormalities
    • Occurs in up to 6% of patients
    • Treatment: ciprofloxacin for at least 1 month
  • Associated with an increased risk of carcinoma of the gallbladder Gallbladder The gallbladder is a pear-shaped sac, located directly beneath the liver, that sits on top of the superior part of the duodenum. The primary functions of the gallbladder include concentrating and storing up to 50 mL of bile. Gallbladder and Biliary Tract
  • Patients must avoid working in the food industry

Differential Diagnosis

  • Amebic liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver/hepatic abscess: 
    • Most common extraintestinal manifestation of amebiasis Amebiasis Amebiasis, or amoebic dysentery, is an infection caused by the parasite Entamoeba histolytica. Transmission is through the fecal-oral route or by consumption of contaminated food and water. Most patients infected with E. histolytica are asymptomatic, but about 10% may develop dysentery. Amebiasis
    • As with typhoid fever, may present with pulmonary, cardiac, and central nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. General Structure of the Nervous System (CNS) manifestations
    • Different fever pattern
    • No rose-colored papular rash
  • Appendicitis Appendicitis Appendicitis is the acute inflammation of the vermiform appendix and the most common abdominal surgical emergency globally. The condition has a lifetime risk of 8%. Characteristic features include periumbilical abdominal pain that migrates to the right lower quadrant, fever, anorexia, nausea, and vomiting. Appendicitis: 
    • As with typhoid fever, may present with abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain and fever
    • Abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain is localized to the right lower quadrant
  • Toxoplasmosis Toxoplasmosis Toxoplasmosis is an infectious disease caused by Toxoplasma gondii, an obligate intracellular protozoan parasite. Felines are the definitive host, but transmission to humans can occur through contact with cat feces or the consumption of contaminated foods. The clinical presentation and complications depend on the host's immune status. Toxoplasma/Toxoplasmosis:
    • As with typhoid fever, may present with headache, sore throat, malaise, fever, hepatosplenomegaly, and neurological symptoms
    • History of exposure to cats
    • Immunocompromised patients will have brain abscesses with multiple ring-enhancing lesions on magnetic resonance imaging (MRI).
  • Tuberculosis Tuberculosis Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis ( TB TB Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis): 
    • As with typhoid fever, may present with abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, vomiting, diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea, malaise, fever, and weight loss
    • Infection is typically localized to the lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs with chest X-ray showing cavitations and mediastinal or hilar lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy
  • Leishmaniasis Leishmaniasis Leishmania species are obligate intracellular parasites that are transmitted by an infected sandfly. The mildest form is cutaneous leishmaniasis (CL), characterized by painless skin ulcers. The mucocutaneous type involves more tissue destruction, causing deformities. Visceral leishmaniasis (VL), the most severe form, presents with hepatosplenomegaly, anemia, thrombocytopenia, and fever. Leishmania/Leishmaniasis: 
    • As with typhoid fever, may present with hepatosplenomegaly, fever, anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview, and anorexia
    • Either skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin ulcerations or a clinical history of spiking fevers, hepatosplenomegaly, and pancytopenia with exposure to sandflies
  • Brucellosis Brucellosis Brucellosis (also known as undulant fever, Mediterranean fever, or Malta fever) is a zoonotic infection that spreads predominantly through ingestion of unpasteurized dairy products or direct contact with infected animal products. Clinical manifestations include fever, arthralgias, malaise, lymphadenopathy, and hepatosplenomegaly. Brucella/Brucellosis: 
    • As with typhoid fever, may present with malaise, fatigue, fever, headache, lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy, and myocarditis Myocarditis Myocarditis is an inflammatory disease of the myocardium, which may occur alone or in association with a systemic process. There are numerous etiologies of myocarditis, but all lead to inflammation and myocyte injury, most often leading to signs and symptoms of heart failure. Myocarditis
    • History of ingesting raw or unpasteurized dairy products or direct contact with infected animals (goats, sheep, pigs, etc.)
  • Malaria Malaria Malaria is an infectious parasitic disease affecting humans and other animals. Most commonly transmitted via the bite of a female Anopheles mosquito infected with microorganisms of the Plasmodium genus. Patients present with fever, chills, myalgia, headache, and diaphoresis. Malaria
    • As with typhoid fever, may present with headache, malaise, abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, paroxysmal high fever
    • Associated with travel history to an endemic region
    • Peripheral blood smear showing schizonts, hemolytic anemia Hemolytic Anemia Hemolytic anemia (HA) is the term given to a large group of anemias that are caused by the premature destruction/hemolysis of circulating red blood cells (RBCs). Hemolysis can occur within (intravascular hemolysis) or outside the blood vessels (extravascular hemolysis). Hemolytic Anemia, and thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia

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