Paroxysmal cold hemoglobinuria (PCH) or Donath–Landsteiner hemolytic anemia (DLHA) is an autoimmune
hemolytic anemia
Hemolytic anemia or haemolytic anaemia is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells (RBCs), either in the blood vessels (intravascular hemolysis) or elsewhere in the human body (extravascular). This most commonl ...
featured by
complement-mediated intravascular hemolysis after cold exposure.
It can present as an acute non-recurrent postinfectious event in children, or chronic relapsing episodes in adults with
hematological malignancies or
tertiary syphilis. Described by
Julius Donath (1870–1950) and
Karl Landsteiner
Karl Landsteiner (; 14 June 1868 – 26 June 1943) was an Austrian-American biologist, physician, and immunologist. He emigrated with his family to New York in 1923 at the age of 55 for professional opportunities, working for the Rockefeller ...
(1868–1943) in 1904, PCH is one of the first clinical entities recognized as an
autoimmune disorder
An autoimmune disease is a condition that results from an anomalous response of the adaptive immune system, wherein it mistakenly targets and attacks healthy, functioning parts of the body as if they were foreign organisms. It is estimated tha ...
.
Paroxysmal cold hemoglobinuria is a result of
cold-reacting antibody immunoglobulin (Ig) induced hemolytic response inside vessels leading to anemia
and, thus, a
cold antibody autoimmune hemolytic anemias (CAAHA).
In most patients with DLHA, the antibody selectively targets against the red blood cells on-surface antigen called the antigen P or antigen I, respectively.
Most cases were found to be owing to
polyclonal IgG. Nonetheless,
IgM-induced DLHA has already also been described in the past.
For example, there was a case study reporting that autoimmune hemolytic anemia where an
IgA Donath–Landsteiner denoted as
-Lantibody appeared to cause Donath–Landsteiner cold hemoglobinuria.
The most notable difference between DLHA and CAD (
cold agglutinin disease) is the causative agent. For cold agglutinin disease, the causative agent a cold-active IgM antibody.
Signs and symptoms
Pediatric patients usually present with acute onset of
hemolytic anemia
Hemolytic anemia or haemolytic anaemia is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells (RBCs), either in the blood vessels (intravascular hemolysis) or elsewhere in the human body (extravascular). This most commonl ...
with
fatigue
Fatigue is a state of tiredness (which is not sleepiness), exhaustion or loss of energy. It is a signs and symptoms, symptom of any of various diseases; it is not a disease in itself.
Fatigue (in the medical sense) is sometimes associated wit ...
,
exercise intolerance
Exercise intolerance is a condition of inability or decreased ability to perform physical exercise at the normally expected level or duration for people of that age, size, sex, and muscle mass. It also includes experiences of unusually severe pos ...
,
pallor
Pallor is a pale color of the skin that can be caused by illness, emotional shock or stress, stimulant use, or anemia, and is the result of a reduced amount of oxyhaemoglobin and may also be visible as pallor of the conjunctivae of the eye ...
,
jaundice
Jaundice, also known as icterus, is a yellowish or, less frequently, greenish pigmentation of the skin and sclera due to high bilirubin levels. Jaundice in adults is typically a sign indicating the presence of underlying diseases involving ...
, and
hemoglobinuria, preceded by exposure to cold temperature and preceding viral-like illness. This may be complicated by
acute renal failure
Acute kidney injury (AKI), previously called acute renal failure (ARF), is a sudden decrease in kidney function that develops within seven days, as shown by an increase in serum creatinine or a decrease in urine output, or both.
Causes of AKI a ...
due to
nephrotoxic free hemoglobin and tubular obstruction. Although the disease may be fulminant during onset, the acute form generally follows a transient, self-limiting course.
Chronic relapsing PCH manifests as episodic hemoglobinuria and anemic symptoms, usually milder than the acute form.
While the classical syphilitic PCH becomes infrequent,
paraneoplastic cause with underlying hematological malignancies especially in the elderly should be considered.
Hepatosplenomegaly and
adenomegaly are not pertinent to PCH, unless associated with underlying
lymphoproliferative disorders. This form remains refractory if the underlying condition is not treated.
Signs and symptoms of DHLA is tied to an abrupt onset of
hemoglobinuria subsequent to cold exposure.
Exact signs and symptoms of DLHA are anemia-alike
(
dyspnea
Shortness of breath (SOB), known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathe well enough. The American Thoracic Society defines it as "a subjective experience of breathing discomfort that ...
,
palpitations
Palpitations occur when a person becomes aware of their heartbeat. The heartbeat may feel hard, fast, or uneven in their chest.
Symptoms include a very fast or irregular heartbeat. Palpitations are a sensory symptom. They are often described as ...
,
fatigue
Fatigue is a state of tiredness (which is not sleepiness), exhaustion or loss of energy. It is a signs and symptoms, symptom of any of various diseases; it is not a disease in itself.
Fatigue (in the medical sense) is sometimes associated wit ...
,
pallor
Pallor is a pale color of the skin that can be caused by illness, emotional shock or stress, stimulant use, or anemia, and is the result of a reduced amount of oxyhaemoglobin and may also be visible as pallor of the conjunctivae of the eye ...
and hemolysis-alike
(
jaundice
Jaundice, also known as icterus, is a yellowish or, less frequently, greenish pigmentation of the skin and sclera due to high bilirubin levels. Jaundice in adults is typically a sign indicating the presence of underlying diseases involving ...
,
dark urine and
pain
Pain is a distressing feeling often caused by intense or damaging Stimulus (physiology), stimuli. The International Association for the Study of Pain defines pain as "an unpleasant sense, sensory and emotional experience associated with, or res ...
).
Some signs and symptoms indicate a
medical emergency
A medical emergency is an acute injury or illness that poses an immediate risk to a person's life or long-term health, sometimes referred to as a situation risking "life or limb". These emergencies may require assistance from another, qualified ...
and that the patients with DLHA require to be hospitalized:
* Rapidly progressive anemia
* Worsening
anemia
Anemia (also spelt anaemia in British English) is a blood disorder in which the blood has a reduced ability to carry oxygen. This can be due to a lower than normal number of red blood cells, a reduction in the amount of hemoglobin availabl ...
* Severe
anemia
Anemia (also spelt anaemia in British English) is a blood disorder in which the blood has a reduced ability to carry oxygen. This can be due to a lower than normal number of red blood cells, a reduction in the amount of hemoglobin availabl ...
*
Respiratory distress
Shortness of breath (SOB), known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathe well enough. The American Thoracic Society defines it as "a subjective experience of breathing discomfort that c ...
*
Circulatory shock
Shock is the state of insufficient blood flow to the tissues of the body as a result of problems with the circulatory system. Initial symptoms of shock may include weakness, tachycardia, hyperventilation, sweating, anxiety, and increased thirst. ...
*
Renal failure
Kidney failure, also known as renal failure or end-stage renal disease (ESRD), is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney fa ...
* Severe
infection
An infection is the invasion of tissue (biology), tissues by pathogens, their multiplication, and the reaction of host (biology), host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmis ...
* Patient's condition is unstable that produces the need to closely monitor.
Cause
Infectious agents are implicated in the acute form of PCH. Viral agents include
measles
Measles (probably from Middle Dutch or Middle High German ''masel(e)'', meaning "blemish, blood blister") is a highly contagious, Vaccine-preventable diseases, vaccine-preventable infectious disease caused by Measles morbillivirus, measles v ...
,
mumps
MUMPS ("Massachusetts General Hospital Utility Multi-Programming System"), or M, is an imperative, high-level programming language with an integrated transaction processing key–value database. It was originally developed at Massachusetts Gen ...
,
Epstein-Barr virus,
cytomegalovirus
''Cytomegalovirus'' (CMV) (from ''cyto-'' 'cell' via Greek - 'container' + 'big, megalo-' + -''virus'' via Latin 'poison') is a genus of viruses in the order '' Herpesvirales'', in the family '' Herpesviridae'', in the subfamily '' Betaherp ...
,
varicella-zoster virus,
influenza virus
''Orthomyxoviridae'' () is a family of negative-sense RNA viruses. It includes nine genera: '' Alphainfluenzavirus'', '' Betainfluenzavirus'', '' Gammainfluenzavirus'', '' Deltainfluenzavirus'', '' Isavirus'', '' Mykissvirus'', '' Quaranjavir ...
, and
adenovirus
Adenoviruses (members of the family ''Adenoviridae'') are medium-sized (90–100 nm), nonenveloped (without an outer lipid bilayer) viruses with an icosahedral nucleocapsid containing a double-stranded DNA genome. Their name derives from t ...
. Non-viral agents include ''
Mycoplasma pneumoniae'' and ''
Haemophilus influenzae
''Haemophilus influenzae'' (formerly called Pfeiffer's bacillus or ''Bacillus influenzae'') is a Gram-negative, Motility, non-motile, Coccobacillus, coccobacillary, facultative anaerobic organism, facultatively anaerobic, Capnophile, capnophili ...
''. Chronic relapsing PCH is classically associated with syphilis, as well as hematological malignancies including
non-Hodgkin lymphoma
Non-Hodgkin lymphoma (NHL), also known as non-Hodgkin's lymphoma, is a group of blood cancers that includes all types of lymphomas except Hodgkin lymphomas. Symptoms include enlarged lymph nodes, fever, night sweats, weight loss, and tiredn ...
and
myeloproliferative neoplasm
Myeloproliferative neoplasms (MPNs) are a group of rare blood cancers in which excess red blood cells, white blood cells or platelets are produced in the bone marrow. ''Myelo'' refers to the bone marrow, ''proliferative'' describes the rapid grow ...
s.
DLHA can be either primary or secondary. Patients with emergent manifestation are likely deemed primary. The absolute causative agent is seldom identified.
Acute Donath–Landsteiner hemolytic anemia is linked to viral infections such as:
*
Adenovirus
Adenoviruses (members of the family ''Adenoviridae'') are medium-sized (90–100 nm), nonenveloped (without an outer lipid bilayer) viruses with an icosahedral nucleocapsid containing a double-stranded DNA genome. Their name derives from t ...
*
Congenital syphilis
Congenital syphilis is syphilis that occurs when a mother with untreated syphilis passes the infection to her baby during pregnancy or at childbirth, birth. It may present in the fetus, infant, or later. Clinical features vary and differ between ...
*
Coxsackievirus
Coxsackieviruses are a few related enteroviruses that belong to the ''Picornaviridae'' family of viral envelope, nonenveloped, linear, positive-sense single-stranded RNA viruses, as well as its genus ''Enterovirus'', which also includes poliovi ...
A9
*
Cytomegalovirus
''Cytomegalovirus'' (CMV) (from ''cyto-'' 'cell' via Greek - 'container' + 'big, megalo-' + -''virus'' via Latin 'poison') is a genus of viruses in the order '' Herpesvirales'', in the family '' Herpesviridae'', in the subfamily '' Betaherp ...
*
Epstein–Barr virus
The Epstein–Barr virus (EBV), also known as human herpesvirus 4 (HHV-4), is one of the nine known Herpesviridae#Human herpesvirus types, human herpesvirus types in the Herpesviridae, herpes family, and is one of the most common viruses in ...
*
Influenza A
''Influenza A virus'' (''Alphainfluenzavirus influenzae'') or IAV is the only species of the genus ''Alphainfluenzavirus'' of the virus family '' Orthomyxoviridae''. It is a pathogen with strains that infect birds and some mammals, as well as c ...
*
Measles
Measles (probably from Middle Dutch or Middle High German ''masel(e)'', meaning "blemish, blood blister") is a highly contagious, Vaccine-preventable diseases, vaccine-preventable infectious disease caused by Measles morbillivirus, measles v ...
*
Mumps
MUMPS ("Massachusetts General Hospital Utility Multi-Programming System"), or M, is an imperative, high-level programming language with an integrated transaction processing key–value database. It was originally developed at Massachusetts Gen ...
*
Parvovirus
Parvoviruses are a family of animal viruses that constitute the family ''Parvoviridae''. They have linear, single-stranded DNA (ssDNA) genomes that typically contain two genes encoding for a replication initiator protein, called NS1, and the p ...
*
Varicella zoster virus
Varicella zoster virus (VZV), also known as human herpesvirus 3 (HHV-3, HHV3), is one of nine known herpes viruses that can infect humans. It causes chickenpox (varicella) commonly affecting children and young adults, and shingles (herpes zos ...
Pathogens of bacterial infections that are linked to acute DLHA
* ''
Mycoplasma pneumoniae''
* ''
Haemophilus influenzae
''Haemophilus influenzae'' (formerly called Pfeiffer's bacillus or ''Bacillus influenzae'') is a Gram-negative, Motility, non-motile, Coccobacillus, coccobacillary, facultative anaerobic organism, facultatively anaerobic, Capnophile, capnophili ...
''
* ''
Klebsiella pneumoniae
''Klebsiella pneumoniae'' is a Gram-negative, non-motile, encapsulated, lactose- fermenting, facultative anaerobic, rod-shaped bacterium. It appears as a mucoid lactose fermenter on MacConkey agar.
Although found in the normal flora of the mo ...
''
* ''
Escherichia coli
''Escherichia coli'' ( )Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. is a gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus '' Escherichia'' that is commonly fo ...
''
In addition to the commonly-seen causes mentioned above, oncologic reasons may also establish. DLHA has been rarely weighted in by
non-Hodgkin lymphoma
Non-Hodgkin lymphoma (NHL), also known as non-Hodgkin's lymphoma, is a group of blood cancers that includes all types of lymphomas except Hodgkin lymphomas. Symptoms include enlarged lymph nodes, fever, night sweats, weight loss, and tiredn ...
,
as well as
oat cell carcinoma.
Pathophysiology
The exact pathogenesis is not fully elucidated. The hallmark feature is the formation of polyclonal
IgG autoantibody
An autoantibody is an antibody (a type of protein) produced by the immune system that is directed against one or more of the individual's own proteins. Many autoimmune diseases (notably lupus erythematosus) are associated with such antibodies.
Pr ...
against the
P antigen, which is a polysaccharide surface antigen on red blood cells in most humans. As a weak, biphasic antibody, it adsorbs on to the P antigen in the cold temperature as in the peripheral circulation in the body in the primary phase, and fixes initial components (up to C2) of the
classical complement pathway
The classical complement pathway is one of three pathways which activate the complement system, which is part of the immune system. The classical complement pathway is initiated by antigen-antibody complexes with the antibody isotypes IgG and I ...
. Upon recirculation to the core temperature of 37°C in the secondary phase, Anti-P autoantibody dissociates itself from the red blood cell, however, complement components remain bound and rest of the classic complement cascade proceeds till the formation of
membrane attack complex (MAC) that disrupts red cell membrane resulting in
intravascular hemolysis.
The causative agent of DLHA is a cold-active immunoglobulin commonly denoted as the
D–L autoantibody
An autoantibody is an antibody (a type of protein) produced by the immune system that is directed against one or more of the individual's own proteins. Many autoimmune diseases (notably lupus erythematosus) are associated with such antibodies.
Pr ...
which demonstrates bi-phasic
hemolysin capability of causing serious hemolysis even when the titer detection is low, which is because of its capacity to detach itself from the lysed RBCs and consequently bind intact
erythrocytes
Red blood cells (RBCs), referred to as erythrocytes (, with -''cyte'' translated as 'cell' in modern usage) in academia and medical publishing, also known as red cells, erythroid cells, and rarely haematids, are the most common type of blood cel ...
according to the temperature changes.
D-L antibodies are most commonly targeted against P antigens than I antigens and others expressed on the RBC membrane.
The D-L hold on tightly to RBC surfaces during the peripheral circulation systems such as human extremities, where temperatures are likely cooler than in comparison to core body temperature.
After successful attachment to RBC surfaces, the D–L then activates the complement cascade, leading to RBC membrane perforation (i.e., intra-vascular hemolysis phenomenon).
Complement activation and consequent hemolysis would become reality if and only if binding-RBCs has travelled to the core part of the body at a warmer temperature around .
Because of the reasons given above, the results of the direct antiglobulin test (DAT) with anti-C3 are highly likely to be positive while to be negative for anti-IgG or anti-IgM, only when the DAT is being performed at approximately and then incubated at around .
Diagnosis
Hemoglobinuria is not necessary for diagnosis because hemoglobinuria is sometimes absent in the case. Additionally, a history of exposure to cold temperatures is not always attained.
Given the fact that hemoglobinuria as well as a personal history of exposure to cold temperatures are not always present, the diagnosis heavily relies on laboratory testing.
Laboratory investigations
The purposes of laboratory investigations are to:
# Confirm the presence of
intravascular hemolysis in terms of metabolic products of red cells and hematopoietic response.
# Establish the diagnosis of
autoimmune hemolytic anemia
Autoimmune hemolytic anemia (AIHA) occurs when a person's immune system produces antibodies directed against their own red blood cells (RBCs). These antibodies attach to red cells, causing them to break down ( lyse), and reducing the number of ox ...
and differentiate from other AIHA.
# Identify other supporting features as in
hematopathological findings.
For intravascular hemolysis, the laboratory parameters include increased serum free
hemoglobin
Hemoglobin (haemoglobin, Hb or Hgb) is a protein containing iron that facilitates the transportation of oxygen in red blood cells. Almost all vertebrates contain hemoglobin, with the sole exception of the fish family Channichthyidae. Hemoglobin ...
,
lactate dehydrogenase
Lactate dehydrogenase (LDH or LD) is an enzyme found in nearly all living cells. LDH catalyzes the conversion of pyruvic acid, pyruvate to lactic acid, lactate and back, as it converts NAD+ to NADH and back. A dehydrogenase is an enzyme that t ...
,
unconjugated bilirubin, and reduced
haptoglobin. Urine tests may show elevated
hemoglobinuria and
hemosiderinuria in chronic cases.
Reticulocytosis may not be apparent in the acute phase or when there is viral-induced
myelosuppression
Bone marrow suppression also known as myelotoxicity or myelosuppression, is the decrease in production of cells responsible for providing immunity (leukocytes), carrying oxygen (erythrocytes), and/or those responsible for normal blood clotting ( ...
.
Once the clinical suspicion of autoimmune hemolytic anemia is made,
direct antiglobulin test (DAT) or direct Coombs' test is the first line of investigation to confirm the presence of warm autoantibodies. Testing with polyspecific and IgG-specific antiglobulin agents is usually negative, and that with C3-specific agent may be positive. On excluding
warm autoimmune hemolytic anemia
Warm antibody autoimmune hemolytic anemia (WAIHA) is the most common form of autoimmune haemolytic anemia. About half of the cases are of unknown cause, with the other half attributable to a predisposing condition or medications being taken. Contr ...
(WAIHA), the cold agglutinin titer should be examined for
cold agglutinin disease (CAD). The diagnosis of PCH is suspected when both WAIHA and CAD are excluded. The
complement level is usually low.
Donath-Landsteiner test is the confirmatory test for PCH.
It involves the cooling of the patient's serum to 4°C to allow the absorption of anti-P autoantibodies to the red cells, followed by warming to 37°C to activate complement fixation and hemolysis. Indirect DL test with addition of ABO-compatible P antigen-positive blood can be performed in case the direct DL test is negative, since the complement in the original serum may be consumed and result in false negative.
The laboratory tests comprise
complete blood count
A complete blood count (CBC), also known as a full blood count (FBC) or full haemogram (FHG), is a set of medical laboratory tests that provide cytometry, information about the cells in a person's blood. The CBC indicates the counts of white blo ...
and
peripheral blood smear
A blood smear, peripheral blood smear or blood film is a thin layer of blood smeared on a glass microscope slide and then stained in such a way as to allow the various blood cells to be examined microscopically. Blood smears are examined in the i ...
.
The hematopathological findings can reflect both the presence of intravascular hemolysis and the underlying immunological process.
The complete blood count usually shows
normocytic anemia
Normocytic anemia is a type of anemia and is a common issue that occurs for people typically over 85 years old. Its prevalence increases with age, reaching 44 percent in men older than 85 years. The most common type of normocytic anemia is anemia o ...
.
Reticulocytosis may be subtle in the acute phase. Peripheral blood smear may show corresponding
polychromasia. Neutrophil erythrophagocytosis is suggestive of PCH, while the absence of
red cell agglutination as in CAD or microspherocytosis in WAIHA should also be noted. The laboratory test results will reveal evaluations like
anisocytosis,
nucleated red blood cell
A nucleated red blood cell (NRBC), also known by several other names, is a red blood cell that contains a cell nucleus. Almost all vertebrate organisms have hemoglobin-containing cells in their blood, and with the exception of mammals, all of th ...
s,
poikilocytosis
Poikilocytosis is variation in the shapes of red blood cells. Poikilocytes may be oval, teardrop-shaped, sickle-shaped or irregularly contracted.
Normal red blood cells are round, flattened disks that are thinner in the middle than at the edges. A ...
,
polychromasia,
spherocytosis, and
erythrophagocytosis by
neutrophils
Neutrophils are a type of phagocytic white blood cell and part of innate immunity. More specifically, they form the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. Their functions vary in different ...
.
Blood typing
Blood compatibility testing is conducted in a medical laboratory to identify potential incompatibilities between Human blood group systems, blood group systems in blood transfusion. It is also used to diagnose and prevent some complications of pr ...
is supposed to be performed with every patient even if their anemia is mild since the
hemoglobin
Hemoglobin (haemoglobin, Hb or Hgb) is a protein containing iron that facilitates the transportation of oxygen in red blood cells. Almost all vertebrates contain hemoglobin, with the sole exception of the fish family Channichthyidae. Hemoglobin ...
can fall all of a sudden and require prompt
blood transfusion
Blood transfusion is the process of transferring blood products into a person's Circulatory system, circulation intravenously. Transfusions are used for various medical conditions to replace lost components of the blood. Early transfusions used ...
.
Anti-immunoglobulin G (anti-Ig) often disassociates itself from the surface of red blood cells under warm degrees of temperatures.
Thus, the
direct antiglobulin test for
anti-immunoglobulin G often manifests a negative results.
That's why it's important to note that the indirect antiglobulin test must be carried out in an environment at cold temperatures.
According to
Medscape
Medscape is a website providing access to medical information for clinicians and medical scientists; the organization also provides continuing education for physicians and other health professionals. It references medical journal articles, Con ...
, the so-called Donath–Landsteiner bithermic hemolytic test is an assay of hemolysis where the serum of the patient goes incubated with normal complement and red blood cells under to to permit the components in the initial stage of complement to be settled.
Afterwards, the specimen goes incubated under so that the later components of complement can then be enabled.
The membrane attack complex leads the red blood cells to undergo
lysis
Lysis ( ; from Greek 'loosening') is the breaking down of the membrane of a cell, often by viral, enzymic, or osmotic (that is, "lytic" ) mechanisms that compromise its integrity. A fluid containing the contents of lysed cells is called a ...
.
Blood chemistry,
serology
Serology is the scientific study of Serum (blood), serum and other body fluids. In practice, the term usually refers to the medical diagnosis, diagnostic identification of Antibody, antibodies in the serum. Such antibodies are typically formed in r ...
,
urinalysis
Urinalysis, a portmanteau of the words ''urine'' and ''analysis'', is a Test panel, panel of medical tests that includes physical (macroscopic) examination of the urine, chemical evaluation using urine test strips, and #Microscopic examination, m ...
and suchlike may also be performed. For patients of DLHA who perform the
serologic testing, summaries for
syphilis
Syphilis () is a sexually transmitted infection caused by the bacterium ''Treponema pallidum'' subspecies ''pallidum''. The signs and symptoms depend on the stage it presents: primary, secondary, latent syphilis, latent or tertiary. The prim ...
,
mycoplasmal infection, or
viruses
A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea. Viruses are found in almo ...
such as,
adenovirus
Adenoviruses (members of the family ''Adenoviridae'') are medium-sized (90–100 nm), nonenveloped (without an outer lipid bilayer) viruses with an icosahedral nucleocapsid containing a double-stranded DNA genome. Their name derives from t ...
,
cytomegalovirus
''Cytomegalovirus'' (CMV) (from ''cyto-'' 'cell' via Greek - 'container' + 'big, megalo-' + -''virus'' via Latin 'poison') is a genus of viruses in the order '' Herpesvirales'', in the family '' Herpesviridae'', in the subfamily '' Betaherp ...
,
Epstein–Barr virus
The Epstein–Barr virus (EBV), also known as human herpesvirus 4 (HHV-4), is one of the nine known Herpesviridae#Human herpesvirus types, human herpesvirus types in the Herpesviridae, herpes family, and is one of the most common viruses in ...
,
influenza A
''Influenza A virus'' (''Alphainfluenzavirus influenzae'') or IAV is the only species of the genus ''Alphainfluenzavirus'' of the virus family '' Orthomyxoviridae''. It is a pathogen with strains that infect birds and some mammals, as well as c ...
,
measles
Measles (probably from Middle Dutch or Middle High German ''masel(e)'', meaning "blemish, blood blister") is a highly contagious, Vaccine-preventable diseases, vaccine-preventable infectious disease caused by Measles morbillivirus, measles v ...
,
mumps
MUMPS ("Massachusetts General Hospital Utility Multi-Programming System"), or M, is an imperative, high-level programming language with an integrated transaction processing key–value database. It was originally developed at Massachusetts Gen ...
, and
varicella might be shown positive.
It's up to the underlying pathological conditions.
Classification
AIHA can be classified as
warm autoimmune hemolytic anemia
Warm antibody autoimmune hemolytic anemia (WAIHA) is the most common form of autoimmune haemolytic anemia. About half of the cases are of unknown cause, with the other half attributable to a predisposing condition or medications being taken. Contr ...
or
cold autoimmune hemolytic anemia, which includes
cold agglutinin disease and paroxysmal cold hemoglobinuria. These classifications are based on the characteristics of the autoantibodies involved in the pathogenesis of the disease. Each has a different underlying cause, management, and prognosis, making classification important when treating a patient with AIHA.
Autoimmune hemolytic anemia
Autoimmune hemolytic anemia (AIHA) occurs when a person's immune system produces antibodies directed against their own red blood cells (RBCs). These antibodies attach to red cells, causing them to break down ( lyse), and reducing the number of ox ...
:
:*
Warm-antibody type
::*
Primary
Primary or primaries may refer to:
Arts, entertainment, and media Music Groups and labels
* Primary (band), from Australia
* Primary (musician), hip hop musician and record producer from South Korea
* Primary Music, Israeli record label
Work ...
::*
Secondary (
lymphoproliferative disorders,
autoimmune disorder
An autoimmune disease is a condition that results from an anomalous response of the adaptive immune system, wherein it mistakenly targets and attacks healthy, functioning parts of the body as if they were foreign organisms. It is estimated tha ...
s)
:*
Cold-antibody type (
anemia
Anemia (also spelt anaemia in British English) is a blood disorder in which the blood has a reduced ability to carry oxygen. This can be due to a lower than normal number of red blood cells, a reduction in the amount of hemoglobin availabl ...
)
::*Primary cold agglutinin disease
::*Secondary cold agglutinin syndrome
:::*Associated with
malignant disease
:::*Acute, transient, infection-associated (acute
cold antibody mediated AIHA complicating ''
Mycoplasma pneumoniae'' or
viral infection
A viral disease (or viral infection) occurs when an organism's body is invaded by pathogenic viruses, and infectious virus particles (virions) attach to and enter susceptible cells.
Examples include the common cold, gastroenteritis, COVID-19, t ...
s
)
:::*Chronic (
lymphoproliferative disorders)
:*Paroxysmal cold hemoglobinuria
::*Idiopathic
::*Secondary
:::*Acute, transient (Infections other than
syphilis
Syphilis () is a sexually transmitted infection caused by the bacterium ''Treponema pallidum'' subspecies ''pallidum''. The signs and symptoms depend on the stage it presents: primary, secondary, latent syphilis, latent or tertiary. The prim ...
)
:::*Chronic (syphilis)
:*
Mixed cold- and warm-antibody type
::*Idiopathic
::*Secondary (
lymphoproliferative disorders,
autoimmune disorder
An autoimmune disease is a condition that results from an anomalous response of the adaptive immune system, wherein it mistakenly targets and attacks healthy, functioning parts of the body as if they were foreign organisms. It is estimated tha ...
s)
:*Drug-induced immune hemolytic anemia
::*Autoimmune type
::*Drug absorption type
::*Neoantigen type
Management
Acute PCH is usually transient and self-limiting.
Supportive treatment includes rest, normothermia and
transfusion when indicated.
Intensive care for the development of acute kidney injury should be offered.
Plasmapheresis
Plasmapheresis (from the Greek language, Greek πλάσμα, ''plasma'', something molded, and ἀφαίρεσις ''aphairesis'', taking away) is the removal, treatment, and return or exchange of blood plasma or components thereof from and to the ...
is proposed to be an adjunctive measure to facilitate recovery.
Steroid
A steroid is an organic compound with four fused compound, fused rings (designated A, B, C, and D) arranged in a specific molecular configuration.
Steroids have two principal biological functions: as important components of cell membranes t ...
s and other
immunosuppressants
Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications, are drugs that inhibit or prevent the activity of the immune system.
Classification
Immunosuppressive drugs can be classified ...
are sometimes administered and the beneficial effect is uncertain.
Immunotherapy
Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as ''activation immunotherapies,'' while immunotherap ...
is considered in refractory to corticosteroids and immunosuppression.
Monoclonal antibodies
A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a Lineage (evolution), cell lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell.
Mon ...
e.g.
rituximab
Rituximab, sold under the brand name Rituxan among others, is a monoclonal antibody medication used to treat certain autoimmune diseases and types of cancer. It is used for non-Hodgkin lymphoma, chronic lymphocytic leukemia (in children and ad ...
(anti-CD20) and
eculizumab (anti-C5) have been used but the therapeutic benefits are controversial. Antibiotic therapy should be given if syphilitic cause is confirmed, while investigations and management for hematological malignancies should be pursued in adult patients with unexplained PCH.
Patients with DLHA should be instructed to avoid exposure to cold weather, particularly if the environment is extreme cold. The risk of hemolysis associated with strenuous exercise should be told to the patients.
Patients with DLHA whose anemia is neither mild nor stable and the
renal function
Assessment of kidney function occurs in different ways, using the presence of symptoms and signs, as well as measurements using urine tests, blood tests, and medical imaging.
Functions of a healthy kidney include maintaining a person's flu ...
is not practically normal generally need medical attention and treatment for DLHA.
If the patient with DLHA is in medical emergency, health care providers including
hematologist
Hematology ( spelled haematology in British English) is the branch of medicine concerned with the study of the cause, prognosis, treatment, and prevention of diseases related to blood. It involves treating diseases that affect the production ...
should take actions to preclude the patient from developing severe anemia and/or acute renal failure. At the meanwhile, renal function and hemoglobin of the patient should be closely watched until normalized and stable.
Prognosis
Most patients do not require medical intervention. Nevertheless, the rare chances of life-threatening acute drop in hemoglobin are always there and in which are deemed to develop
hypovolemic shock
Hypovolemic shock is a form of Shock (circulatory), shock caused by severe hypovolemia (insufficient blood volume or extracellular fluid in the body). It can be caused by severe dehydration or blood loss. Hypovolemic shock is a medical emergency ...
and
cardiac failure
Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome caused by an impairment in the heart's ability to fill with and pump blood.
Although symptoms vary based on which side of the heart is affected, HF typically pre ...
due to severe
anemia
Anemia (also spelt anaemia in British English) is a blood disorder in which the blood has a reduced ability to carry oxygen. This can be due to a lower than normal number of red blood cells, a reduction in the amount of hemoglobin availabl ...
, and to be complicated by acute
tubular necrosis as a result of
hemoglobinuria over the aftermath.
In addition to the rarely happened severe anemia and complications, prognosis of DLHA is deemed to be very good. Most patients recovered spontaneously not longer than 30 days since the disease onset.
Long-term mild hemolytic anemia has been reported for several children who were in the likelihood of recurrence on exposure to any kind of cold or with illness.
Case studies of those with recurrent DLHA suggest that repeated episodes of the hemolysis should not be regarded as
false positive
A false positive is an error in binary classification in which a test result incorrectly indicates the presence of a condition (such as a disease when the disease is not present), while a false negative is the opposite error, where the test resu ...
because the chances do truly exist when the patient has a D-L antibody to an antigen other than
anti-P.
Chronic syphilis-associated DLHA resolves when the underlying disease receives appropriate treatment.
Epidemiology
Estimated
incidence of PCH is 0.4 per 100000 population,
and the
prevalence
In epidemiology, prevalence is the proportion of a particular population found to be affected by a medical condition (typically a disease or a risk factor such as smoking or seatbelt use) at a specific time. It is derived by comparing the number o ...
ranges from 1.6% to 40% in patients with autoimmune hemolytic anemia.
The prevalence depends on the
sensitivity of the immunologic methods applied.
The age of onset is often <5 years in the pediatric population,
with male predominance ranging from 2.5:1 to 5:1 in male-to-female ratio.
The majority of PCH were accounted by congenital or tertiary
syphilis
Syphilis () is a sexually transmitted infection caused by the bacterium ''Treponema pallidum'' subspecies ''pallidum''. The signs and symptoms depend on the stage it presents: primary, secondary, latent syphilis, latent or tertiary. The prim ...
in the early 1900s. Since the application of antibiotic therapy and prenatal screening, syphilitic PCH has become a rare entity.
It is now increasingly recognized in pediatric patients with preceding viral-like illness.
Acute AIHA is uncommon.
Acute DLHA occurs more in childhood than in adulthood.
The D-L autoantibody is an ordinary cause of AIHA in children.
It is predicted that 30–40% among all pediatric AIHA cases may have DLHA.
Male-to-female ratio of the prevalence was shown as 2.1:1, meaning that DHLA is more often seen in males.
No racial or ethnic difference on prevalence has been noted as of early 2019.
History
In 1865, it was widely accepted as a common sense that cold exposure may result in hemoglobinuria paroxysms.
After decades of devoted researches, now the elucidation of the etiology and diagnostic methods of DLHA have been learned and developed.
Discovering the D–L antibody has empowered DLHA to be differentiated from other hemoglobinuria that something other than D-L is responsible for.
As of 2019, it is concluded that the existence of the Donath–Landsteiner antibody is clearly pathognomonic for the DLHA.
See also
*
Anemia of prematurity
*
Cold agglutinin disease
*
Cold sensitive antibody
*
Fanconi anemia
*
Hemolytic anemia
Hemolytic anemia or haemolytic anaemia is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells (RBCs), either in the blood vessels (intravascular hemolysis) or elsewhere in the human body (extravascular). This most commonl ...
*
List of hematologic conditions
References
External links
{{Diseases of RBCs
Acquired hemolytic anemia
Autoimmune hemolytic anemia